INFLAMMATION - Plants for Human Health Institute · 2017-09-18 · inflammation remains a mystery. When our body’s powers of correction go wrong, they can work against us. Unlike

INFLAMMATION

Editor, NaturePhilip Campbell

PublishingSamia MantouraClaudia Banks

Insights EditorRitu Dhand

Production EditorDavina Dadley-Moore

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Inflammation is the body’s immediate response to damage to its tissues and cells by pathogens, noxious stimuli such as chemicals, or physical injury. Acute inflammation is a short-term

response that usually results in healing: leukocytes infiltrate the damaged region, removing the stimulus and repairing the tissue. Chronic inflammation, by contrast, is a prolonged, dysregulated and maladaptive response that involves active inflammation, tissue destruction and attempts at tissue repair. Such persistent inflammation is associated with many chronic human conditions and diseases, including allergy, atherosclerosis, cancer, arthritis and autoimmune diseases.

The processes by which acute inflammation is initiated and develops are well defined, but much less is known about the causes of chronic inflammation and the associated molecular and cellular pathways. This Insight highlights recent advances in our knowledge of the exogenous and endogenous inducers of chronic inflammation, as well as the inflammatory mediators and cells that are involved. We hope that these articles will contribute to a better understanding of inflammatory responses, and ultimately result in the design of more effective therapies for the numerous debilitating diseases with a chronic inflammatory component.

Ursula Weiss, Senior Editor

Cover illustrationA polarized light micrograph of crystals of uric acid, which causes the inflammatory condition gout. (Courtesy of R. J. Green/SPL)

REVIEWS428 Origin and physiological roles

of inflammation

R. Medzhitov

436 Cancer-related inflammation

A. Mantovani, P. Allavena, A. Sica & F. Balkwill

445 The development of allergic inflammation

S. J. Galli, M. Tsai & A. M. Piliponsky

455 From endoplasmic-reticulum stress to the inflammatory response

K. Zhang & R. J. Kaufman

HYPOTHESIS463 The role of exercise and PGC1α

in inflammation and chronic disease

C. Handschin & B. M. Spiegelman

REVIEW470 Integration of metabolism and

inflammation by lipid-activated nuclear receptors

S. J. Bensinger & P. Tontonoz

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Vol 454 | Issue no. 7203 | 24 July 2008www.nature.com/nature

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MICHAEL ANFTI l lustration ANNA & ELENA BALBUSSO

Inflammation has been found to be an underlying cause in many diseases, making it a hot topic in the health media. But what do we really know about chronic inflammation and its effects on the body?

Understanding Inflammation

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aAs scientists have searched for the mysteries behind the diseases most likely to afflict us, they have alighted on one factor common to virtually all of them: inflammation. Chronic inflamma-tion, headlines now regularly state, has a role in a host of common and often deadly diseases, including Alzheimer’s, arthritis, cancer, diabetes, heart disease, and possibly even depression.

Unsurprisingly, this news brings with it a raft of self-proclaimed reme-dies purporting to fight inflammation. Diets, herbs, supplements, and exercise regimens have flooded the market with promises to keep inflammation in check and improve overall health.

But is there evidence that over-the-counter products or sweeping lifestyle changes will reduce inflammation’s damaging effects? Scientists caution that despite its current high profile, inflam-mation remains a mystery. “Basic science

hasn’t yet answered the major questions about inflammation,” says Michelle Petri, a rheumatologist and a director of the Johns Hopkins Lupus Center. Researchers like Petri have been studying low-level inflam-mation as a culprit in a number of diseases for decades. What they have discovered has led to an emerging understanding of how lifestyle choices—like diet, dental health, and exercise—may influence inflammation and its potentially damaging downsides.

Despite its current high profile, Petri says, inflammation remains a mystery.

When our body’s powers of correction go wrong, they can work against us. Unlike the inflammation that follows a sudden infection or injury, the chronic kind produces a steady, low level of inflammation within the body that can contribute to the development of disease.


i Inflammation is a vital part of the human immune system. When harmful bacteria or viruses enter your body, when you scrape or twist your knee, the body’s defense system kicks into high gear. Chemicals ramp up the body to fight, bathing the damaged area with blood, fluid, and proteins; creating swelling and heat to protect and repair damaged tissue; and setting the stage for healing.

Sentinel cells first alert the immune system to the presence of invaders. An-other set of cells releases chemicals that signal the capillaries to leak blood plas-ma, which surrounds and slows down trespassers. Another group of sentinels, called macrophages, releases cytokines, which are specialized germ fighters. Im-munizing B- and T-cells join in, destroy-ing both the pathogens and the tissues they have damaged. Finally, a last wave of cytokines is released to end the job and signal the immune system that its work is done. Its mission completed, the immune system calls off its dogs.

When our body’s powers of correc-tion go wrong, however, they can work against us. Think of the acute heat and swelling that protect us during a normal immune response—a fever, or the redness and pain that surround a new in-jury, for example—and you can get a hint of what chronic inflammation is. Unlike the inflammation that follows a sudden infection or injury, the chronic kind produces a steady, low level of inflamma-tion within the body that can contribute to the development of disease. It’s the result, in part, of an overfiring immune system. Low levels of inflammation can get triggered in the body even when there’s no disease to fight or injury to heal, and sometimes the system can’t shut itself off. Arteries and organs break down under the pressure, leading to other diseases, including cancer and diabetes.

Scientists don’t fully understand how the immune system becomes short-circuited, but they have long known that some diseases, such as lupus and rheumatoid arthritis, emerge after the immune system has gone awry and attacked healthy tissue. Increasingly, as Americans and other Westerners live longer and get larger (35 percent of Americans are obese), researchers have also found that low-level immune responses triggered by extra weight and a lack of exercise can contribute to the development of other illnesses.

“For a long time, we had the idea that inflammation was involved in certain autoimmune diseases, but now we’re seeing this lower level of inflammation in people who are obese and people who are sedentary,” says Kimberly Gudzune, a


physician at Johns Hopkins and a clinical researcher who focuses on obesity. “We see a link between obesity and some diagnostic markers for inflammation, but we don’t know what causes them. We worry that there’s something brewing for these people, that they are at higher risk for heart disease, cancer, and diabetes.”

Researchers have discovered that fat cells can trigger the release of a steady, low hum of cytokines that, in lieu of an invader to attack, go after healthy nerves, organs, or tissues. As we gain weight, the release becomes prolific, affecting our body’s ability to use insulin, sometimes leading to type 2 diabetes.

They have also learned that inflam-matory cells can have an effect elsewhere in the body—for example, chronically in-fected and inflamed gums in the mouth can cause damage that leads to heart attack and stroke. And they know that inflammation contributes to congestive heart failure and uncontrolled hyperten-sion, and that it somehow has a role in the tangled cells that are the hallmarks of Alzheimer’s disease.

Researchers continue to find answers about how inflammation contributes to cancer. Inflammatory cells produce free

radicals that destroy genetic material, including DNA, leading to mutations that cause cells to endlessly grow and divide. More immune cells are then called in, creating inflammation that feeds the growth of tumors.

The link between inflammation and cancer can sometimes be direct. When too much stomach acid—a feature of the immune system that evolved to fight foodborne bacteria—creeps up the esophagus, it causes inflammation and chronic heartburn. Extended exposure to this acid changes the nature of the cells lining the esophagus, increasing the risk of cancer.

In colon cancer patients, certain com-munities of bacteria associated with di-arrhea can create cancer with help from inflammatory cytokines. Cells protected by mucus can become inflamed when that mucus wall is breached by bacteria, says Cynthia Sears, a doctor who spe-cializes in infectious disease research at Johns Hopkins. “The lining in the colon makes peptides”—short chains of amino acids that act to protect the lining of the organ—“to thwart bacteria. If there aren’t enough peptides, bacteria can get a foot-hold, which means even more bacteria,” Sears says. As inflammation ramps up to fight it, so does the risk of cancer.

“We see a link between obesity and some diagnostic markers for inflammation, but we don’t know what causes them. We worry that there’s something brewing for these people, that they are at higher risk for heart disease, cancer, and diabetes.”


iIf inflammation is the behind-the-cur-tain factor in so many diseases, what can we do to keep it at bay? Researchers admit that they’re still figuring this out.

Petri has studied lupus for more than three decades and has been investigat-ing the effects of chronic inflammation. “Lupus is basically friendly fire,” Petri ex-plains. “We can’t get the immune system to calm itself down.”

Treating chronic inflammation, whether for lupus or other chronic ailments, is a challenge. Researchers have an idea that inflammation exists as part of a self-reinforcing loop system. If they could figure out how to interrupt or reverse one stage in that loop, then they might be able to develop drugs to stop it. But how do you tone down the immune response enough to control the inflam-mation but not so much that a body can’t fight disease? “We’ve done 20 to 25

years of clinical trials on lupus drugs,” Petri says, by way of example. “We’ve had maybe one success and 30 failures.”

Currently, there are no prescription drugs that specifically target chronic inflammation. (There are, of course, over-the-counter medications that treat the minor and temporary inflamma-tion and accompanying pain caused by injuries or procedures, such as surgery. These are not meant to treat chronic inflammation.) Some drugs, such as hydroxychloroquine, once used to battle malaria, are useful in treating some lupus patients, but they don’t cure the disease. Aspirin and statins have shown promise in reducing inflammation in some people, but researchers aren’t sure how broadly useful such drugs are in that role. With the exception of far-from-perfect anti-inflammatory drugs, such as prednisone, a corticosteroid that brings with it a slew of side effects, scientists are still researching how best to contain inflammation. “We need something that can work broadly and quickly, and with-out a lot of side effects,” says Petri.

Finding a drug that both interrupts the immune cycle and maintains a healthy immune response is important not just for people battling illness but for all of us, because as we age, inflamma-tion increases in the body. Scientists ar-en’t sure how and why, but interestingly, the study of HIV is offering some insight.

HIV triggers chronic inflammation in the body, even after medications have


rendered levels of the virus undetect-able in blood tests. Certain cytokines involved in that inflammation process can profoundly decrease testosterone levels, leading to muscle loss. “It’s pos-sible that the chronic inflammation in people with HIV is similar to the chronic inflammation we see in aging,” says Todd Brown, an endocrinologist who research-es the link between bodily markers for inflammation and chronic diseases found in people with HIV. If researchers can understand that process and create treatments to disrupt it in people with HIV, they could potentially translate their findings into treatments for similar muscle loss in aging.

Jeremy Walston is a Johns Hopkins geriatrician who investigates immune system response and muscle function in the elderly. He has been searching for markers that highlight the early signs of inflammation. Some blood tests for inflammation markers exist, but the researchers have uncovered two new markers that they believe may predict mortality and mark signs of late-in-life decline. “These are powerful inflamma-tory molecules that, when chronically expressed, lead to declines in stem cells and a remodulation of the immune sys-tem,” says Walston. “They also contribute to cell death,” particularly in the elderly, he says.

As the quest for diagnostic measures and therapies continues, researchers point to simple lifestyle measures we can all take to help prevent chronic inflammation. Scientists are skeptical of cure-all claims found in the new crop of anti-inflamma-tion diet books, but they do recommend dropping pounds (and the harmful fat cells that come with obesity) and avoid-ing the now common American diet high in fats and sugars.

“Losing weight can have profound effects on lowering inflammation,” says Brown, who adds that eating a diet rich

aFinding a drug that both interrupts the immune cycle and maintains a healthy immune response is important not just for people battling illness but for all of us as we age.


in fruits and vegetables and low in fats, processed foods, and sugars is generally a good idea, though more study needs to be done to determine how it might affect inflammation. Exercising, which causes an acute inflammatory response in the short term, but an anti-inflammatory one when we regularly get moving, is anoth-er strong step to take, he adds.

Other researchers advise getting plenty of sleep, lowering stress levels, and seeking out treatment for inflam-mation-inducing culprits, such as gum disease and high cholesterol levels. Avoid contact with heavy metals such as mercury, which is found in danger-ous amounts in some large fish, and limit exposure to substances, such as diesel exhaust and cigarette smoke, that can set off the immune system. Additional studies by Brown and his colleagues have also shown some advantage in increasing our intake of omega-3 fatty acids and vitamin D, though more research is needed.

Walston and others caution against popping dietary supplements touted as anti-inflammatory cures. Some so-called remedies, such as turmeric, taken in large amounts, may actually be toxic to the liver and other organs.

For most of us, keeping inflamma-tion in check comes down to common sense basics: eat well, don’t smoke, get

moving, get more rest, and see your doctor for regular physicals, which could help stop chronic inflammation before it becomes rampant. “All of the things our grandmothers told us were good for us are actually good for us,” says Brown. “Until we have a more nu-anced understanding of what inflam-mation does, that’s what we have to fall back on.” /

For most of us, keeping inflammation in check comes down to common sense basics: eat well, don’t smoke, get moving, get more rest, and see your doctor for regular physicals, which could help stop chronic inflammation before it becomes rampant.

9/18/2017 What is an inflammation? - PubMed Health

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Informed Health Online [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-.

What is an inflammation?Last Update: January 7, 2015; Next update: 2018.

When a wound swells up, turns red and hurts, it may be a sign of inflammation. Inflammation is – very generally speaking – thebody’s immune system’s response to stimulus. This can be bacteria colonizing a wound or a splinter piercing your finger, forexample. Inflammation happens when the immune system fights against something that may turn out to be harmful.

Causes of an inflammationInflammation may have many different causes. These are the most common:

Pathogens (germs) like bacteria, viruses or fungi

External injuries like scrapes or foreign objects (for example a thorn in your finger)

Effects of chemicals or radiation

Diseases or conditions that cause inflammation often have a name ending in “-itis.” For example:

Cystitis, an inflammation of the bladder

Bronchitis, an inflammation of the bronchi

Otitis media, a middle ear infection

Dermatitis, a disease where the skin is inflamed

Signs of an inflammationThere are five signs that may indicate an acute inflammation:

Redness

Heat

Swelling

Pain

Loss of function

There is a loss of function, for example, when the inflamed limb can no longer be moved properly or when the sense of smell isworse during a cold, or when it is more difficult to breathe when you have bronchitis.

This means that an inflammation does not start when a wound has been infected by bacteria, festers, or heals poorly, but alreadyas the body is trying to fight against the harmful stimulus or a viral infection.

Not all five signs occur in every inflammation. Some inflammations occur “silently” and do not cause any symptoms.

The body’s general responseIf the inflammation is severe, it may cause general reactions in the body. This may include the following signs and symptoms:

General symptoms of feeling sick, exhaustion and fever: These symptoms are a sign that the immune defense is very activeand needs a lot of energy, which may be lacking for other activities. If the rate of metabolism is higher due to a fever, moredefense substances and cells can be produced.

Changes in the blood such as an increased number of defense cells.

A very rare but dangerous complication of an inflammation is called sepsis. Sepsis may occur if bacteria multiply quickly in acertain part of the body and then suddenly enter the bloodstream in large quantities. This can happen if the body does notsucceed in fighting the inflammation locally, the pathogens are very aggressive, or the immune system is severely weakened.

Chills, feeling very ill, and very high fever can also be signs of blood poisoning. If blood poisoning is suspected, medical assistanceis urgently needed.

What happens when you have an inflammationMany different immune cells can take part in an inflammation. They release different substances, the inflammatory mediators.These include the tissue hormones bradykinin and histamine. They cause the narrow blood vessels in the tissue to expand,

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allowing more blood to reach the injured tissue. For this reason the inflamed area turns red and becomes hot.

More defense cells are also brought along with the blood to the injured tissue, to help with the healing process. Both hormonescan also irritate nerves and cause pain signals to be sent to the brain. If the inflammation hurts, you usually favor the affected partof the body.

The inflammatory mediators have yet another function: they increase the permeability of the narrow vessels, so that more defensecells can enter the affected tissue. The defense cells also carry more fluid into the inflamed tissue, which is why it often swells up.After this fluid is transported out of the tissue once again a while later and the swelling disappears again.

The mucous membranes also release more fluid during inflammation. This happens for example when you have a stuffy nose andthe nasal mucous membranes are inflamed. Then the nasal secretions can help to quickly flush the viruses out of the body.

Inflammations can also cause chronic diseasesAn inflammation is not always a helpful response of the body. In certain diseases the immune system fights against its own cellsby mistake, causing harmful inflammatory responses. These include, for example:

Rheumatoid arthritis, where many joints throughout the entire body are permanently inflamed

Psoriasis, a chronic skin disease

Inflammations of the bowel like Crohn’s disease or ulcerative colitis

These diseases are called chronic inflammatory diseases, and can last for years or even a lifetime in varying degrees of severityand activity.

Sources

Andreae S. Lexikon der Krankheiten und Untersuchungen. Stuttgart: Thieme; 2008.

Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of internal medicine. New York:McGraw-Hill Companies. 18th ed; 2011.

Pschyrembel W. Klinisches Wörterbuch. Berlin: De Gruyter; 2014.

IQWiG health information is written with the aim of helping people understand the advantages and disadvantages of themain treatment options and health care services.

Because IQWiG is a German institute, some of the information provided here is specific to the German health care system.The suitability of any of the described options in an individual case can be determined by talking to a doctor. We do notoffer individual consultations.

Our information is based on the results of good-quality studies. It is written by a team of health care professionals,scientists and editors, and reviewed by external experts. You can find a detailed description of how our health informationis produced and updated in our methods.

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Chronic Diseases Caused by Chronic Inflammation Require Chronic Treatment:Anti-inflammatory Role of Dietary SpicesSahdeo Prasad and Bharat B. Aggarwal*

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA*Corresponding author: Bharat B. Aggarwal, Ph.D., Professor of Cancer Medicine (Biochemistry), The University of Texas MD Anderson Cancer Center, 1901 EastRoad, Unit1950; Houston TX 77054, USA, Tel: 713-794-1817; E-mail: [email protected] date: May 23, 2014, Accepted date: July 18, 2014, Published date: July 25, 2014

Copyright: © 2014 Prasad S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Noncommunicable chronic diseases such as inflammatory bowel diseases, cancer, diabetes, obesity, andpulmonary, cardiovascular, and neurodegenerative diseases are becoming the leading cause of death throughoutthe world. Unhealthy diet, smoking, lack of exercise, stress, radiation exposure, and environmental pollution areamong the common causes of chronic diseases. Most of these risk factors are closely linked to chronicinflammation, which leads to the development of various chronic diseases. Diets high in fruits, vegetables, legumes,fiber, and certain spices have been shown to suppress chronic inflammation and prevent the development of chronicdiseases. In this review we discuss the evidence for the molecular basis of inflammation and how inflammationmediates most chronic diseases. We also present clinical and experimental models showing the molecular effects ofselected spices and spice-derived nutraceuticals such as cardamonin, curcumin, capsaicin, gingerol, thymoquinone,and piperine on these inflammatory pathways and the potential role of nutraceuticals in preventing chronic diseases.

Keywords: Inflammation; Chronic diseases, Spices; Inflammatorypathways; Nutraceuticals

IntroductionChronic diseases, defined as diseases of long duration and slow

progression, include inflammatory bowel disease (IBD), heart disease,stroke, cancer, chronic respiratory diseases, neurological diseases,obesity, and diabetes. According to the U.S. Centers for DiseaseControl and Prevention, together these diseases account for 63% of alldeaths worldwide and about 70% of all deaths (1.7 million each year)in the United States. The chief causes of these diseases are the changesin diet and lifestyle brought about by industrialization, economicdevelopment, urbanization, and market globalization, all of whichhave accelerated over the past 10 years. Most chronic diseases arepreventable because they are linked to lifestyle. A modified diet, dailyexercise, and avoiding tobacco can prolong life by preventing theoccurrence of chronic diseases or improving the management ofillnesses that do occur. Among these modifiable determinants ofchronic diseases, nutrition may be the most influential, and scientificevidence increasingly supports the view that alterations in diet havestrong effects on health throughout life [1].

Over the past few decades, studies have investigated the possibleprotective role of plant foods against chronic diseases. Severalepidemiological studies have revealed that greater consumption offruits and vegetables is associated with a lower risk of chronic diseasessuch as cancer [2]. The World Health Organization stated that dietshigh in fruits and vegetables may have a protective effect against manycancers. More specifically, intake of fruits and vegetables probablyreduce the risk for colorectal, pancreatic, lung, oral, esophageal, andstomach cancers. Conversely, obesity, excess consumption of red andpreserved meat, alcohol may be associated with an increased risk ofcancer. (http://www.who.int/dietphysicalactivity).

Among the foods containing beneficial active compounds, spiceshave their own particular importance. Some common spices and theirbioactive components are shown in Figure 1. In general, spices areconsumed in the form of dried seed, fruit, root, bark, or vegetativesubstance. Spices usually are used in nutritionally insignificantquantities as a food additive for flavor or color or as a preservative.Spices also are sometimes eaten as vegetables or used for otherpurposes, such as medicine, religious rituals, cosmetics, or perfumery.In this review, we will discuss the link between inflammation andchronic diseases, the anti-inflammatory activities of some spices andspice-derived nutraceuticals, and the use of spices and spice-derivednutraceuticals in the prevention and treatment of chronic diseases.

Role of Inflammation in Chronic DiseaseInflammation is a response of the immune system to injury,

irritation, or infection caused by invading pathogens, radiationexposure, very high or low temperatures, or autoimmune processes.Therefore, inflammation is a mechanism for removing damaged cells,irritants, or pathogens. Inflammation is considered to be beneficialwhen it is short term and under control within the immune system(acute inflammation). Inflammation that persists longer is known aschronic inflammation. This inflammation is characterized by thesimultaneous destruction and healing of tissue [3].

The various factors known to induce chronic inflammatoryresponses also cause numerous chronic diseases. These factors includebacterial, viral, and parasitic infections (eg, Helicobacter pylori,Epstein-Barr virus, human immunodeficiency virus, flukes,schistosomes); chemical irritants (eg, tumor promoters such asphorbol ester 12-O-tetradecanoylphorbol-13-acetate, also known asphorbolmyristate acetate); andnondigestible particles (eg, asbestos,silica) [4,5]. Inflammation produces reactive oxygen species andreactive nitrogen species, which cause oxidative damage and furtherlead to chronic diseases [6]. Inflammation also recruits leukocytes that

Prasad and Aggarwal, J Clin Cell Immunol 2014,5:4

http://dx.doi.org/10.4172/2155-9899.1000238

Review Article Open Access

J Clin Cell Immunol Inflammatory Bowel Disease ISSN:2155-9899 JCCI, an open access journal

Journal of Clinical & CellularImmunology

mailto:[email protected]

http://dx.doi.org/10.4172/2155-9899.1000238

secrete inflammatory cytokines and angiogenic factors to the site oftissue insult. These cytokines are required for proper wound healingand to stimulate epithelial cell proliferation; however, if uncontrolledthese cytokines can lead to inflammatory disorders. All these

inflammatory products have shown to be regulated by the nucleartranscription factor NF-κB, which is considered the master moleculeof inflammation.

Figure 1: Anti-inflammatory spices and their bioactive molecules.

Citation: Prasad S, Aggarwal BB (2014) Chronic Diseases Caused by Chronic Inflammation Require Chronic Treatment: Anti-inflammatory Roleof Dietary Spices. J Clin Cell Immunol 5: 238. doi:10.4172/2155-9899.1000238

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The transcription factor NF-κB is activated in response to a widevariety of stimuli such as stress (physical, psychological, mechanical,or chemical), tobacco, radiation, asbestos, dietary agents,environmental pollutants, obesity, and various infectious agents. NF-κB is activated by at least two separate pathways “canonical orclassical” and “non-canonical or alternate”. Canonical pathway istriggered by microbial products and proinflammatory cytokines suchas TNF-α and IL-1, usually leading to activation of RelA (p65)- or cRel(p50/p105)- containing complexes while non-canonical or alternativepathway is activated by lymphotoxin β, CD40 ligand, B cell activatingfactor, and receptor activator of NF-κB ligand, resulting in activationof RelB/p52 complexes [7]. The NF-κB activation pathway typicallyinvolves activation of NF-κB inhibitor α (IκBα) kinase (known asIKK), leading to phosphorylation, ubiquitination, and degradation ofIκBα, nuclear translocation of the p50 and p65 subunits of NF-κB,DNA binding and transcription of NF-κB target gene. Althoughcanonical NF-κB activation is mediated through the activation ofIKKβ, noncanonical activation involves IKKα [8]. Binding of NF-kBon target genes results in transcription of over 500 genes involved ininflammation, immunoregulation, growth regulation, carcinogenesis,and apoptosis [7]. The activation of NF-κB in various immune cells,including T cells, B cells, macrophages, dendritic cells, andneutrophils, leads to expression of proinflammatory cytokines. Theactivation of NF-κB has also been shown to production ofproinflammatory cytokine and chemokine in disease tissue frompatients [9]. Another study also showed that proinflammatorycytokine production in human atherosclerotic plaques is NF-κB-dependent [10]. Thus, NF-κB plays a crucial role in inflammation.

Besides NF-κB, STAT3 pathway is also known to contribute to theinflammatory microenvironment. STAT3 is activated by manycytokines and growth factors, including epidermal growth factor,platelet-derived growth factor, and IL-6, oncogenic proteins, such asSrc and Ras as well as by numerous carcinogens, such as cigarettesmoke and tumor promoters [11]. The activation of STAT3 isregulated by phosphorylation at its tyrosine residue at 705 by receptorand nonreceptor protein tyrosine kinases. The phosphorylation ofSTAT3 in the cytoplasm leads to its dimerization, translocation intothe nucleus, and DNA binding which result in transcription of genesthat regulate inflammation, cell proliferation, differentiation, andapoptosis [11]. In addition, phosphorylation at serine 727 has beenimplicated in the activation of STAT3 [12]. STAT3 promoteinflammatory environment by regulating the expression of cytokines,chemokines and other mediators [13,14]. STAT3 is highlyinterconnected with NF-κB signaling and interacts with NF-κB. Forexample the pro-inflammatory cytokine IL-6, encoded by NF-κBtarget genes, is important for STAT3 activation. STAT3 and NF-κBalso co-regulate numerous oncogenic and inflammatory genes [15].These indicate that NF-κB and STAT3 alone or in combinationproduce inflammation and inflammatory microenvironment.

There is a strong association between chronic inflammatoryconditions and chronic diseases. Chronic inflammation damages thecells of the brain, heart, arterial walls, and other anatomic structures;this damage leads to various inflammatory chronic diseases. Studies onthe causes of inflammation at the molecular level showed thatnumerous biomarkers are involved in the process of inflammation.Many of these biomarkers—transcription factors such as NF-κB andSTAT3; inflammatory cytokines and chemokines such as tumornecrosis factor-alpha (TNF)-α, interleukin (IL)-1, IL-6, IL-8, andMCP-1; inflammatory enzymes such as cyclooxygenase (COX)-2, 5-lipoxygenase (LOX), 12-LOX, and matrix metalloproteinases (MMPs);

and other factors such as prostate-specific antigen (PSA), C-reactiveprotein (CRP), adhesion molecules, vascular endothelial growth factor(VEGF), and TWIST are found common in most chronic diseases[16].

IBD is a group of inflammatory conditions of the colon and smallintestine comprising in Crohn disease (CD) and ulcerative colitis(UC). IBD causes inflammation anywhere along the lining of digestivetract and often spreads deep into affected tissues. A number ofcytokines/chemokines and their receptors have shown to beupregulated in patients with IBD. For example, the overproduction ofvarious cytokines such as IL-2, IL-12, IL-18, IFN-γ, and TNF-α hasbeen well documented in patients with CD [17,18]. A pilot study of 33IBD patients (19 with CD and 14 with UC) and 33 matched healthycontrols showed that cytokine and chemokine levels increased withdisease severity [19]. Kader et al. [20] identified IBD serum biomarkerssuch as cytokines, growth factors, and soluble receptors in 65 patientswith CD and 23 with UC; the researchers found that the levels of 4cytokines [placental growth factor (PLGF), IL-7, IL-12p40, and TGF-β1] were significantly higher in patients with clinical remission than inthose with active disease. Besides these, increased levels of NF-κB,myeloperoxidase, and fecal calprotectin were reported in healthy twinswith IBD [21]. The association of STAT3 in IBD was also described inCD and UC populations [22]. These studies indicate thatinflammatory transcription factors and cytokines are integral to IBD.

Epidemiological evidence points to a connection betweeninflammation and a predisposition for the development of cancer, ie,long-term inflammation leads to the development of dysplasia.Various pro-inflammatory biomarkers have been found to be elevatedin several cancers. The pro-inflammatory biomarker STAT3 wasfound to be activated in 82% of patients with late-stage prostate cancer[23-25]. Another inflammatory transcription factor, NF-κB, was foundin 60% of colorectal cancer patients [26]. Also, the overproduction ofcytokines has shown to be associated with cancer-related fatigue [27].

Inflammation has also been shown to mediate cardiovasculardiseases [28,29]. CRP, an acute-phase protein produced by the liverduring bacterial infections and inflammation, was found to be acommon marker for detecting cardiovascular and atheroscleroticdiseases [30]. Inflammation is also a cause of autoimmune diseasessuch as rheumatoid arthritis, in which excess levels of cytokines suchas TNF-α, IL-6, IL-1β, and IL-8 are often found [31]. Multiplesclerosis, another autoimmune disease, is caused by chronicinflammation in the central nervous system. Activated NF-κB is foundin patients with multiple sclerosis [32]. Elevated levels of othercytokines such as IL-1α, IL-2, IL-4, IL-6, IL-10, IFN-γ, TGF-β1,TGF-β2, and TNF-α have also been found in frozen sections of centralnervous system tissue from multiple sclerosis patients [33]. Similarly,cerebrospinal fluid samples from patients with Alzheimer disease,Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis,and schizophrenia have been shown to exhibit the overexpression ofcytokines and NF-κB [34]. Likewise, in patients with diabetes, highlevels of CRP, IL-6, IL-1, and TNF-α—along with abnormal expressionof NF-κB—have been observed [35-37]. The studies listed aboveindicate mounting evidence of a stronger association betweeninflammation and chronic diseases than was once believed.

Role of Spices in Regulation of InflammationFor centuries, spices available in nature have been used as

medicines against inflammation. Numerous studies have shown that


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some spices have great potential to inhibit chronic inflammation.Turmeric, one of the common spices used in daily life in Asiancountries, has been used as a medicine against inflammation. Theactive component of turmeric, curcumin, is a potent inhibitor ofinflammation. Studies on animal models have shown that curcumin iseffective in preventing UC and inflammation. Over the past fewdecades, curcumin has been shown to inhibit myeloperoxidase,COX-1, COX-2, LOX, TNF-α, IFN-γ, iNOS, and NF-κB in patientswith IBD [38].

Curcumin at concentrations of 0.5 and 20 μM inhibited pro-inflammatory cytokine (TNF-α, IL-1β, and IL-8) production inducedby lipopolysaccharide (LPS) in lung inflammatory cells ex vivo [39].Treatment with curcumin also inhibited the upregulation of COX-2 inultraviolet B-irradiated HaCaT cells [40]. In one study, curcumin wasfound to inhibit the NF-κB activation induced by TNF in humanmyeloid ML-1a cells. Specifically, curcumin blocked phorbol ester-and hydrogen peroxide-mediated activation of NF-κB [41], indicatingthat curcumin inhibits free radical–induced inflammation. Anotherstudy found that the constitutive phosphorylation of STAT3transcription factors was inhibited by curcumin treatment. In multiplemyeloma cells, curcumin suppressed both constitutive and IL-6-induced STAT3 activation [42]. Treatment with curcumin also wasshown to block the activation of AP-1 and NF-κB induced by IL-1αand TNF-α cytokines [43]. This study indicated that curcumin inhibitscytokine-induced inflammation by suppressing inflammatorypathways.

Capsaicin, a major ingredient of pepper, has been shown to inhibitNF-κB activation. Phorbol ester-induced activation of AP-1 was alsoabolished by capsaicin pretreatment [44]. Capsaicin inhibitedconstitutive and IL-6-induced STAT3 activation. The activation ofJAK1 and c-Src, which are implicated in STAT3 activation, were alsoinhibited by capsaicin [45]. Capsaicin treatment in HepG2 cellsresulted in a transient increase in the nuclear translocation of Nrf2,enhancing the binding of Nrf2 to the antioxidant response element(ARE) [46]. Thus, capsaicin inhibits inflammation by inhibitingdifferent inflammatory pathways.

Nigella sativa (also known as black cumin), a plant commonly usedin Ayurvedic medicine for more than 2,000 years, exhibits anticanceractivity through its inhibition of the inflammatory pathway. Thepredominant bioactive component of N. sativa, thymoquinone,suppressed NF-κB activation, which was correlated with the inhibitionof IκBα kinase activation and the direct binding of nuclear p65 to theDNA [47]. Thymoquinone also inhibited both constitutive and IL-6-induced STAT3 phosphorylation, which correlated with the inhibitionof c-Src and JAK2 activation, in multiple myeloma cells [48]. Thisinhibition of inflammatory transcription factors indicates thatthymoquinone has anti-inflammatory activities.

Cardamonin, a chalcone, has shown potent anti-inflammatoryeffects in vitro and in vivo. In a cellular model of inflammation,cardamonin inhibited the production of nitric oxide (NO) andprostaglandin E(2) (PGE(2)) and attenuated the expression of TNF-α,IL-6, IL-1β, inducible NO synthase (iNOS), and COX-2. Cardamoninalso prevented the nuclear translocation of NF-κB. In a mouse modelof endotoxin shock, cardamonin suppressed TNF-α, IL-6, andIL-1βsecretion in LPS-induced mouse blood serum [49].

Piperine, an alkaloid found in black pepper, inhibited cerebralischemia-induced inflammation in Wistar rats. In same study,piperine also reduced the levels of pro-inflammatory cytokines IL-1β,

IL-6, and TNF-α in the ischemic rats and lowered the expression ofCOX-2, NOS-2, and NF-κB. Both cytosolic and nuclear NF-κB weredownregulated in the ischemic rats [50]. Thus, piperine exhibits anti-inflammatory activities by suppressing cytokines and inflammatorytranscription factors.

Ginger is known for its ethnobotanical applications as an anti-inflammatory agent. It has been found that [6] gingerol, an activecomponent of ginger, inhibited the production of TNF-α, IL-1β, andIL-12 from LPS-stimulated macrophages [51]. In an in vitro study [6],gingerol and 6-shogaol, another active compound of ginger, inhibitedMAPK and PI3K/Aktphosphorylation and NF-κB and STAT3translocation [52].

Dietary zerumbone, a sesquiterpene phytochemical present inAsian ginger, can prevent inflammation, as observed in a mouse modelof ultraviolet B–induced corneal damage. In the mice given dietaryzerumbone, corneal damage was ameliorated by the inhibition of NF-κB activation and nuclear translocation; concomitant decreases iniNOS and TNF-α expression were also seen in these mice [53].However, another report suggested that zerumbone induces theexpression of IL-1α, IL-1β, IL-6, and tumor TNF-α in colorectalcarcinoma cell lines, which implies that zerumbone increases theproduction of pro-inflammatory cytokines in cancerous tissues in thecolon and that this biochemical property may cause side-effects [54].

Taken together, these reports from animal and in vitro studies haverevealed that spices have a strong potential to inhibit inflammation.Spices and spice-derived nutraceuticals suppressed most, if not all,inflammatory biomarkers. The major biomarker of inflammation isNF-κB, which is inhibited by spice-derived nutraceuticals. Theinhibition of inflammatory transcription factors is not restricted toNF-κB. Spice-derived nutraceuticals also inhibited cytokines andinflammatory enzymes. Some active components of spices alsosuppressed constitutive and inducible STAT3. Thus, the studiescollectively suggest that spices could be used for targetinginflammatory molecules in the prevention and treatment of chronicdiseases.

Clinical Aspects of Dietary Spices Against ChronicDiseases

Extensive preclinical studies over the past 3 decades have indicatedcurcumin’s therapeutic potential against a wide range of humandiseases [12]. These preclinical studies have formed a solid basis forevaluating curcumin’s efficacy in clinical trials. Clinical studies haveshown that co-administration of curcumin with conventional drugs iseffective against IBD and well tolerated [38]. In one study of patientswith ulcerative proctitis and CD, curcumin decreased the symptomsand inflammatory markers in all patients [55]. In another study of IBDpatients, curcumin (360 mg 3 or 4 times/day for 3 months)significantly reduced clinical relapse. Curcumin inhibited majorinflammatory mechanisms such as COX-2, LOX, TNF-α, IFN-γ, andNF-κB [56]; and thus it opens bright prospects for the treatment ofIBD. In addition, curcumin has shown to be effective in maintenancetherapy in patients with quiescent UC. In a randomized, double-blindstudy with 89 patients, those treated with curcumin (1 g twice daily)plus sulphasalazine or mesalazine for 6 months had a lower relapserate than those treated with placebo plus sulphasalazine or mesalazine[57]. In a study of cultured ex vivo colonic mucosal biopsies andcolonic myofibroblasts from children and adults with active IBD,curcumin reduced p38 MAPK activation, enhanced IL-10, and


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reduced IL-1βlevel [58]. Thus curcumin holds promise as a noveltherapy for patients with IBD.

Spice-derived nutraceuticals also have been studied in cancertreatment. Our group has shown that 8 g of curcumin is safe and welltolerated and that it downregulated the expression of NF-κB, COX-2,and phosphorylated STAT3 in peripheral blood mononuclear cellsfrom pancreatic cancer patients [59]. Another single-blind,randomized, placebo-controlled study evaluated the effects of oralcurcumin with piperine on pain and oxidative stress biomarkers in 25patients with tropical pancreatitis [60]. Curcumin-piperine therapyproduced significantly reduced the erythrocyte malondialdehyde levelscompared with curcumin plus placebo and a significant increase inGSH levels but without improvement in pain. The authors of thisstudy concluded that curcumin with piperine may reverse lipidperoxidation in patients who have tropical pancreatitis [60]. In a phaseII clinical trial of patients with advanced pancreatic cancer, 8 g ofcurcumin per day orally inhibited the expression of NF–κB, COX-2,and pSTAT3 in peripheral blood mononuclear cells. Clinical biologicalactivity was seen in 2 patients, and 1 patient had stable disease formore than 18 months. Interestingly, 1 additional patient had a brief,but marked, tumor regression accompanied by significant increases inserum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptorantagonists). The study concluded that oral curcumin, despite limitedabsorption, was well tolerated and demonstrated biological activity insome patients [59].

Curcumin has demonstrated potential against colorectal cancer innumerous clinical trials. In 1 study, in 15 patients with advanced,treatment-refractory colorectal cancer received 440 mg of Curcumaextract containing 36 mg of curcumin for 29 days, resulting in a 59%decrease in lymphocytic glutathione S-transferase activity. LeukocyticDNA damage was constant within each patient and unaffected bytreatment. The researchers observed no dose-limiting toxicities andreported that the Curcuma extract was well tolerated [61]. In a study of15 patients with advanced, treatment-refractory colorectal cancer, adaily dose of 3.6 g of curcumin caused 62% and 57% decreases ininducible prostaglandin E2 production in blood samples taken 1 hourafter the dose administered on days 1 and 29, respectively [62].Curcumin in combination with quercetin suppresses adenomas inpatients with familial adenomatous polyposis [63]. Five patients withfamilial adenomatous polyposis received curcumin (480 mg) andquercetin (20 mg) orally 3 times a day. After 6 months of treatment,the number and size of the patients’ polyps were reduced with nosignificant toxicity [63].

In patients with breast or prostate cancer, curcuminwas found to bewell tolerated. The maximum tolerated dose of curcumin was found tobe 8 g per day, whereas the recommended dose was 6 g per day for 7consecutive days every 3 weeks when combined with a standard doseof docetaxel [64]. In a randomized, double-blind, controlled study, 85men who underwent prostate biopsies were given soy isoflavones andcurcumin. In the patient group with baseline PSA values greaterthan10ng/mL, PSA levels decreased among those who receivedisoflavones and curcumin [65]. Another study investigated the safety,tolerability, and clinical efficacy of curcumin in 29 patients withasymptomatic, relapsed, or plateau-phase multiple myeloma. Oralcurcumin (2, 4, 6, 8, or 12 g/day in 2 divided doses) was well toleratedand significantly downregulated the constitutive activation of NF–κBand STAT3; curcumin also inhibited the expression of COX-2 in mostpatients [66].

Curcumin has shown effectiveness in patients with other chronicinflammatory diseases. The signs and symptoms of osteoarthritis weredecreased in patients who received 200 mg of curcumin (present inMeriva). Curcumin inhibited serum inflammatory biomarkers such asIL-1β, IL-6, soluble CD40 ligand, soluble vascular cell adhesionmolecule-1, and erythrocyte sedimentation [67]. In a randomized,double-blind, placebo-controlled clinical trial, curcumin delayed thedevelopment of type 2 diabetes in a prediabetes population [68]. Atotal of 240 participants received curcumin (1.5 g/day) or placebo.After 9 months of treatment, 16.4% of participants in the placebogroup were diagnosed with diabetes, but no participants treated withcurcumin developed diabetes. The authors of this study concluded thatthe curcumin might be beneficial in a prediabetes population [68].

Fenugreek seeds (Trigonella foenum-graecum) have been shown toimprove blood glucose and the serum lipid profile in insulin-dependent (type 1) diabetic patients. In patients who ate a fenugreekdiet, fasting blood sugar was significantly reduced, glucose toleranceimproved, and 24-hour urinary glucose excretion was reduced by 54%.Also, levels of total cholesterol, LDL and VLDL cholesterol, andtriglycerides in the serum were significantly reduced [69]. An inverserelationship between the risk of gallbladder cancer and the amount ofvegetables (including fenugreek) consumed was observed in 153patients with gallbladder cancer and 153 controls with gallstonedisease [70]. In a double-blind, placebo-controlled study conducted in50 patients with Parkinson disease, fenugreek capsules (300 mg, twicedaily) had an excellent safety and tolerability profile. Thus, it has beenconcluded that fenugreek can be useful in the management ofParkinson disease [71].

Oral capsaicin has been reported to substantially reduce oralmucositis pain from cancer therapy [72]. A 12-week double-blind,placebo-controlled randomized study of capsaicin cream (0.075%) inthe treatment of chronic distal painful polyneuropathy found noevidence of superior efficacy of capsaicin cream [73]. In contrast,another study showed that after 8 weeks of treatment, patients treatedwith capsaicin cream had an average pain reduction of 53% versus17% for those treated with placebo [74]. In a double-blind,randomized, controlled trial of 100 patients with mild to moderateknee osteoarthritis, 0.0125% capsaicin gel was reported be effective[75]. Thus, capsaicin reduces pain in patients with chronic diseases.

Piperine has been reported to enhance the oral bioavailability ofother supplements and drugs. In one study, piperine (20 mg) wasadministered along with phenytoin in human volunteers, and samplescollected 12 hours later showed that piperine significantly increasedthe mean plasma concentration of phenytoin [76]. In a placebo-controlled pilot study, 8 healthy adult males were randomly assignedto receive nevirapine (200 mg) alone or with piperine (20 mg). Thelevels of nevirapine were higher in blood of individuals treated withnevirapine and piperine than in those treated with nevirapine alone,providing evidence that piperine enhanced the bioavailability ofnevirapine [77].

Ginger has also great potential against inflammatory diseases. In apilot trial, 20 people at increased risk for colorectal cancer were givenof ginger (2 g) or placebo daily for 28 days. Differences between the 2groups in levels of biomarkers for cell proliferation, apoptosis, anddifferentiation in colorectal epithelial cells with normal appearanceindicated that ginger may reduce proliferation, increase apoptosis, andincrease differentiation [78]. Another study in patients with acuterespiratory distress syndrome, diet enriched with ginger showed lowerserum levels of inflammatory cytokines IL-1, IL-6, and TNF-α [79].


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Cinnamon's effects on blood glucose were identified in a meta-analysisof clinical trials, which found that consuming whole cinnamon or ascinnamon extract significantly reduced fasting blood glucose levels inpeople with type 2 diabetes or prediabetes [80]. The studies describedabove show than various spices act against inflammation in vitro, inanimal models, and in patients.

Role of Dietary Spices in Preventing Chronic DiseasesBecause spices have chemical properties that reduce inflammation,

the occurrence of some chronic diseases can be prevented byincreasing the consumption of spices (Figure 2). For example,differences in spice consumption could be the reason the occurrenceof cancer in India, where spices are used routinely, is much lower thanin the United States [81].

Figure 2: An intimate relationship of inflammation and chronicdiseases and the role of spices and spice-derived nutraceuticals intheir treatment.Life style risk factors such as high fat diet, tobacco,environmental pollution, stress, radiation and infection induceinflammation through activation of inflammatory transcriptionfactors including NF-κB. NF-κB further activates variousproinflammatory cytokines including interleukins, TNF-α, COX-2,5-LOX, CRP and PSA. Interleukins, specifically IL-6, activatesanother transcription factor STAT3. Persistent activation of NF-κBand STAT3 leads to development of various chronic diseases.However, dietary spices could prevent development of chronicdiseases by blocking activation of proinflammatory transcriptionfactors and cytokines.

Curcumin has displayed a protective role in mouse models of IBDand in human UC by reducing neutrophil infiltration and levels ofinflammatory molecules. In rat model of IBD, treatment withcurcumin decreased levels of inflammatory molecules indicating,curcumin could be effective in the prevention and treatment of IBD[82]. Another preclinical study showed that curcumin interfered withinflammation in colonic epithelial cells by inhibiting chemokineexpression neutrophil chemotaxis and chemokinesis, which results inthe prevention of IBD [83]. Besides these, curcumin as well ascyclodextin-conjugated curcumin decreased the degree of colitiscaused by the administration of dextran sodium sulfate (DSS) [84,85].In primary cultures of human intestinal microvascular endothelialcells, curcumin inhibited the expression of VCAM-1, Akt, p38 MAPK,and NF-κB and thus may have a therapeutic role against endothelialactivation in IBD [86].

Curcumin may have therapeutic potential, as it was found to beassociated with the suppression of inflammatory cytokines andenzymes, transcription factors, and gene products linked with cellsurvival, proliferation, invasion, and angiogenesis. Curcuminexhibited anticancer activities in in vitro and in animal models ofcancer. Several phase I and phase II clinical trials have indicated thatcurcumin is safe [87].

Numerous lines of evidence suggest that curcumin mediatescardioprotective effects through diverse mechanisms. Several studieshave suggested that curcumin protects the heart from ischemia/reperfusion injury [88,89]. Venkatesan [90] showed that curcumin alsodecreased acute adriamycin-induced myocardial toxicity in rats. Inpreclinical studies of diabetes, curcumin can lower levels of bloodglucose, raise pancreatic β-cells’ antioxidant status, and facilitatePPAR-γ activation [91]. Curcumin can also induce hypoglycemia inrats with streptozotocin-induced diabetes [92]. The most likelymechanism for this action is that curcumin inhibits cholesterol,induces antioxidant and scavange free radicals.

Capsaicin also has shown chemopreventive and chemoprotectiveeffects [93]. In a mouse model, topical capsaicin was shown to inhibitskin tumors induced by phorbol 12-myristate 13-acetate [44]. In astudy of 29 normotensive and 13 hypertensive people with alopecia,capsaicin and isoflavone reduced arterial blood pressure; this likelyresulted from elevated levels of serum IGF-I [94]. Capsaicin has alsobeen found to be protective against stress-induced neurologicalimpairment. In an animal model, capsaicin administered at 10 mg/kg1 hour before the introduction of stress mitigated stress-inducedcognitive and Alzheimer disease-like pathological alterations [95]. Inother animal studies, capsaicin had preventive effects against neonatalhypoxic-ischemic brain injury [95], epileptogenesis [96], and diabeticneuropathy [97]; it also reduced toxin-induced neuroparalytic effectsin neuromuscular junctions [98].

Cardamonin has shown potential against several cancer types, suchas colorectal and gastric cancers, sarcoma, and multiple myeloma.Cardamonin inhibited the proliferation, invasion, and angiogenesis ofcancer cells [99,100]. Cardamonin also suppressed bone loss, whichoften occurs in multiple myeloma, breast cancer, and prostate cancerpatients [101]. Cardamonin also enhances cell death of colorectalcancer cells induced by TRAIL through induction of ROS-CHOP-mediated death receptor as well as suppression of decoy receptor andcell survival proteins [102]. Beside this, cardamonin exhibitscardioprotective effects. It induced relaxation of phenylephrine-preconstricted mesenteric arteries in a rat model [103]. In a study offructose-induced diabetes in rats, cardamonin reduced insulin


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resistance and smooth muscle hyperplasia of the major vessels [104].Cardamonin has been shown to act against systemic hypertension byinhibiting I(Ca(L)) and stimulating K(Ca)1.1 current [105]. Recently,thymoquinone was shown to prevent and ameliorate colonicinflammation in a mouse model of IBD. Treatment of mice withthymoquinone ameliorated of DSS-induced colitis by lowering colonicmyeloperoxidase activity and malondialdehyde levels and raisingglutathione levels [106]. A rat model showed that pretreatment for 3days with 10 mg/kg of thymoquinone completely prevented aceticacid-induced colitis, while 500 mg/kg of sulfasalazine provided lessprotection [107].

Thymoquinone has been shown to inhibit proliferation in severalcancer cell lines and to inhibit angiogenesis and tumor growth in vitroand in vivo [47,108]. Thymoquinone also reduced diabetes-relatedinflammation and protected β cells [109]. In a study of rats withstreptozotocin-induced diabetes, thymoquinone protected the kidneysagainst oxidative stress [110]. Thymoquinone may protect neuronsagainst toxicity and apoptosis. In a rat study, thymoquinoneameliorated ethanol-induced neurotoxicity in the primary corticalneurons, indicating its potential as a treatment against neonatalalcohol exposure [111]. Cinnamaldehyde, a compound in cinnamon,has shown activity against several chronic diseases. For example,cinnamaldehyde inhibits proliferation and induces apoptosis in cancercells [112]. The compound also exhibits antidiabetic, antioxidant, andhypolipidemic activity [113] and acts as a vasorelaxant on isolated rataorta [114].

Piperine has been found to be effective against IBD alone or incombination with other natural products. In one study, piperineincombination with tea polyphenol inhibited DSS-induced colitis. Micetreated with the combination had reduced levels of histologicaldamage to the colon and lipid peroxidation; the colon tissue had adecreased level of myeloperoxidase (a marker for neutrophilaccumulation) and higher levels of superoxide dismutase andglutathione peroxidase (antioxidant enzymes) [115]. Piperinecombined with a hydroalcoholic extract of Amaranthusroxburghianusand piperine had effects against UC that were comparable to those ofprednisolone [116]. Recently, a combination of the polyphenols,quercetin and piperine, which was encapsulated into reconstituted oilbodies, was shown to protect against DSS-induced colitis and weightloss [117].

Piperine inhibited the growth of 4T1 mammary carcinoma cells invitro and lung metastases in mice [118]. Co-administration of piperinealso improved the antitumor efficacy of the chemotherapeutic agentdocetaxel in a mouse xenograft model of castration-resistant prostatecancer [119] and of 5-fluorouracil in in vitro and in vivo models [120].In mice with alloxan-induced diabetes, piperine lowered blood glucoselevels at subacute doses but raised blood glucose levels at high doses[121]. Piperine was also shown protection against corticosterone-induced neurotoxicity in cultured rat pheochromocytoma cells [122].In another study, piperine was shown to protect against epilepsy-associated depression; this antidepressant activity was likely due topiperine’s activity as a monoamine oxidase inhibitor and itsneuroprotective properties [123].

Ginger has been shown to ameliorate UC. In a rat model, gingerextract reduced the effects of acetic acid-induced UC [124]. In support,Hsiang et al. [125] showed that ginger extract and gingerone reducedthe effects of 2,4,6-trinitrobenzene sulphonic acid-induced colitis byinhibiting NF-κB activity and IL-1β signaling. Furthermore, gingervolatile oil found to reduce colitis symptoms in a rat model by

decreasing the colon weight/length ratio, ulcer severity, ulcer area, andulcer index with a concomitant decrease in the inflammation inducedby acetic acid [126]. [6]-Gingerol has demonstrated antioxidant, anti-inflammatory, and anticancer properties. In a preclinical study ofhepatocellular carcinoma, [6]-Gingerol and [6]-shogaol inhibitedinvasion and metastasis through multiple molecular mechanisms [52].The antitumor potential of [6]-gingerol was demonstrated when itprevented skin tumor growth and induced apoptosis in a mouse model[127]. It has also been shown that crude ginger extract and gingeroleach reduced joint swelling in an animal model of rheumatoid arthritis[128]. The neuroprotective effect of [6]-gingerol was demonstrated inSH-SY5Y cells when pretreatment with the compound protectedagainst cytotoxicity and apoptosis [129]. In a study of arsenic-intoxicated mice, [6]-gingerol had an anti-hyperglycemic effect andimproved insulin signaling [130].

Zerumbone has been found to be effective against colitis. In a studymouse model, oral zerumbone lowered the DSS-induced levels ofIL-1β, TNF-α and PGE(2) and suppressed colitis [131].Zerumbonewas also shown to suppress tumor growth and induceapoptosis in various cancer cell lines. In a mouse model of skin cancer,zerumbone inhibited both tumor initiation and promotion through itsantioxidant inducing nature and activation of phase II drugmetabolizing enzymes along with attenuation of proinflammatorymolecules [132]. A mouse model of colon cancer demonstrated thatzerumbone prevented tumorigenesis and that this effect was mediatedthrough its modulation of antiproliferative mechanisms, apoptosis,and inflammatory molecules [133]. These studies indicatezerumbone’s potential against chronic diseases such as cancer.

ConclusionSpices have been used as traditional medicine against chronic

diseases for thousands of years. Numerous preclinical study resultssuggest that spices and spice-derived nutraceuticals are associated witha decreased risk of inflammation-regulated chronic diseases. Moreclinical trials are needed to strengthen this preclinical evidence.Because chronic diseases require a long time to manifest, structuringsuch clinical trials will be difficult. However, to validate theimportance of spices in daily life, long-term prospective epidemiologystudies and well-controlled clinical trials of spices are needed. TheDietary Approaches to Stop Hypertension (DASH) diet, whichfeatures high intakes of spices, fruits, vegetables, legumes, and nuts;moderate amounts of low-fat dairy products; low amounts of animalprotein and sweets; and sodium reduction, is recommended becausethe DASH diet diet has a potential to prevent cancer. Until furtherevidence is available, we recommend increasing the amount ofinexpensive, nontoxic nutraceuticals such as spices in the daily diet tohelp prevent the occurrence of chronic diseases.

AcknowledgementsWe thank Department of Scientific Publications for carefully

editing the manuscript. Dr. Aggarwal is the Ransom Horne, Jr.,Professor of Cancer Research.

Funding SourceThis work was supported by a grant from the Center for Targeted

Therapy of MD Anderson Cancer Center.


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References1. Weisburger JH (1998) Worldwide prevention of cancer and other

chronic diseases based on knowledge of mechanisms. Mutat Res 402:331-337.

2. Ames BN, Wakimoto P (2002) Are vitamin and mineral deficiencies amajor cancer risk? Nat Rev Cancer 2: 694-704.

3. Aggarwal BB, Vijayalekshmi RV, Sung B (2009) Targeting inflammatorypathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15: 425-430.

4. Balkwill F, Mantovani A (2001) Inflammation and cancer: back toVirchow? Lancet 357: 539-545.

5. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860-867.

6. Hussain SP1, Hofseth LJ, Harris CC (2003) Radical causes of cancer. NatRev Cancer 3: 276-285.

7. Gupta SC, Sundaram C, Reuter S, Aggarwal BB (2010) Inhibiting NF-ÎºBactivation by small molecules as a therapeutic strategy. Biochim BiophysActa 1799: 775-787.

8. Aggarwal BB, Sung B (2011) NF-ÎºB in cancer: a matter of life and death.Cancer Discov 1: 469-471.

9. Aupperle K, Bennett B, Han Z, Boyle D, Manning A, et al. (2001) NF-kappa B regulation by I kappa B kinase-2 in rheumatoid arthritissynoviocytes. J Immunol 166: 2705-2711.

10. Monaco C, Andreakos E, Kiriakidis S, Mauri C, Bicknell C, et al. (2004)Canonical pathway of nuclear factor kappa B activation selectivelyregulates proinflammatory and prothrombotic responses in humanatherosclerosis. Proc Natl Acad Sci U S A 101: 5634-5639.

11. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, TharakanST, et al. (2009) Signal transducer and activator of transcription-3,inflammation, and cancer: how intimate is the relationship?. Ann N YAcad Sci 1171: 59-76.

12. Aggarwal BB, Harikumar KB (2009) Potential therapeutic effects ofcurcumin, the anti-inflammatory agent, against neurodegenerative,cardiovascular, pulmonary, metabolic, autoimmune and neoplasticdiseases. Int J Biochem Cell Biol 41: 40-59.

13. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation andimmunity: a leading role for STAT3. Nat Rev Cancer 9: 798-809.

14. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-relatedinflammation. Nature 454: 436-444.

15. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, et al. (2009) IL-6 andStat3 are required for survival of intestinal epithelial cells anddevelopment of colitis-associated cancer. Cancer Cell 15: 103-113.

16. Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. CancerCell 6: 203-208.

17. Rutgeerts P, Geboes K (2001) Understanding inflammatory boweldisease--the clinician's perspective. Eur J Surg Suppl : 66-72.

18. Desreumaux P, Brandt E, Gambiez L, Emilie D, Geboes K, et al. (1997)Distinct cytokine patterns in early and chronic ileal lesions of Crohn'sdisease. Gastroenterology 113: 118-126.

19. Alex P, Zachos NC, Conklin LS, Kwon JH, Harris ML, et al. (2008)Distinct cytokine patterns as effective indicators of disease activity andseverity in IBD. Gastroenterology 134: A204–A204.

20. Kader HA, Tchernev VT, Satyaraj E, Lejnine S, Kotler G, et al. (2005)Protein microarray analysis of disease activity in pediatric inflammatorybowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, andIL-12p40 levels in Crohn's disease and ulcerative colitis patients inremission versus active disease. Am J Gastroenterol 100: 414-423.

21. Zhulina Y, Hahn-Stromberg V, Shamikh A, Peterson CG, Gustavsson A,et al. (2013) Subclinical inflammation with increased neutrophil activityin healthy twin siblings reflect environmental influence in thepathogenesis of inflammatory bowel disease. Inflamm Bowel Dis 19:1725-1731.

22. Sugimoto K (2008) Role of STAT3 in inflammatory bowel disease. WorldJ Gastroenterol 14: 5110-5114.

23. Horinaga M, Okita H, Nakashima J, Kanao K, Sakamoto M, et al. (2005)Clinical and pathologic significance of activation of signal transducer andactivator of transcription 3 in prostate cancer. Urology 66: 671-675.

24. Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, et al. (2002)Constitutive activation of Stat3 in human prostate tumors and cell lines:direct inhibition of Stat3 signaling induces apoptosis of prostate cancercells. Cancer Res 62: 6659-6666.

25. Tam L, McGlynn LM, Traynor P, Mukherjee R, Bartlett JM, et al. (2007)Expression levels of the JAK/STAT pathway in the transition fromhormone-sensitive to hormone-refractory prostate cancer. Br J Cancer97: 378-383.

26. Scartozzi M, Bearzi I, Pierantoni C, Mandolesi A, Loupakis F, et al.(2007) Nuclear factor-kB tumor expression predicts response andsurvival in irinotecan-refractory metastatic colorectal cancer treated withcetuximab-irinotecan therapy. J Clin Oncol 25: 3930-3935.

27. Klein B, Zhang XG, Jourdan M, Portier M, Bataille R (1990)Interleukin-6 is a major myeloma cell growth factor in vitro and in vivoespecially in patients with terminal disease. Curr Top MicrobiolImmunol 166: 23-31.

28. Berg AH, Scherer PE (2005) Adipose tissue, inflammation, andcardiovascular disease. Circ Res 96: 939-949.

29. Thomas TH, Advani A (2006) Inflammation in cardiovascular diseaseand regulation of the actin cytoskeleton in inflammatory cells: the actincytoskeleton as a target. Cardiovasc Hematol Agents Med Chem 4:165-182.

30. Tomiyama H, Okazaki R, Koji Y, Usui Y, Hayashi T, et al. (2005)Elevated C-reactive protein: a common marker for atheroscleroticcardiovascular risk and subclinical stages of pulmonary dysfunction andosteopenia in a healthy population. Atherosclerosis 178: 187-192.

31. Deon D, Ahmed S, Tai K, Scaletta N, Herrero C, et al. (2001) Cross-talkbetween IL-1 and IL-6 signaling pathways in rheumatoid arthritissynovial fibroblasts. J Immunol 167: 5395-5403.

32. Gveric D, Kaltschmidt C, Cuzner ML, Newcombe J (1998) Transcriptionfactor NF-kappaB and inhibitor I kappaBalpha are localized inmacrophages in active multiple sclerosis lesions. J Neuropathol ExpNeurol 57: 168-178.

33. Woodroofe MN, Cuzner ML (1993) Cytokine mRNA expression ininflammatory multiple sclerosis lesions: detection by non-radioactive insitu hybridization. Cytokine 5: 583-588.

34. Young AM, Campbell EC, Lynch S, Dunn MH, Powis SJ, et al. (2012)Regional susceptibility to TNF-α induction of murine braininflammation via classical IKK/NF-κB signalling. PLoS One 7: e39049.

35. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetesmellitus. JAMA 286: 327-334.

36. Mendoza-Núñez VM, Rosado-Pérez J, Santiago-Osorio E, Ortiz R,Sánchez-Rodríguez MA, et al. (2011) Aging linked to type 2 diabetesincreases oxidative stress and chronic inflammation. Rejuvenation Res14: 25-31.

37. Jeffcoate WJ (2005) Abnormalities of vasomotor regulation in thepathogenesis of the acute charcot foot of diabetes mellitus. Int J LowExtrem Wounds 4: 133-137.

38. Baliga MS, Joseph N, Venkataranganna MV, Saxena A, Ponemone V, etal. (2012) Curcumin, an active component of turmeric in the preventionand treatment of ulcerative colitis: preclinical and clinical observations.Food Funct 3: 1109-1117.

39. Literat A, Su F, Norwicki M, Durand M, Ramanathan R, et al. (2001)Regulation of pro-inflammatory cytokine expression by curcumin inhyaline membrane disease (HMD). Life Sci 70: 253-267.

40. Cho YC, You SK, Kim HJ, Cho CW, Lee IS, et al. (2010) Xanthohumolinhibits IL-12 production and reduces chronic allergic contact dermatitis.Int Immunopharmacol 10: 556-561.

41. Singh S, Aggarwal BB (1995) Activation of transcription factor NF-kappaB is suppressed by curcumin (diferuloylmethane) [corrected]. J BiolChem 270: 24995-25000.


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42. Bharti AC, Donato N, Aggarwal BB (2003) Curcumin(diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3phosphorylation in human multiple myeloma cells. J Immunol 171:3863-3871.

43. Xu YX, Pindolia KR, Janakiraman N, Chapman RA, Gautam SC (1997)Curcumin inhibits IL1 alpha and TNF-alpha induction of AP-1 and NF-kB DNA-binding activity in bone marrow stromal cells. HematopatholMol Hematol 11: 49-62.

44. Han SS, Keum YS, Seo HJ, Chun KS, Lee SS, et al. (2001) Capsaicinsuppresses phorbol ester-induced activation of NF-kappaB/Rel and AP-1transcription factors in mouse epidermis. Cancer Lett 164: 119-126.

45. Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, et al.(2007) Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13: 3024-3032.

46. Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, et al. (2007) Capsaicininduces heme oxygenase-1 expression in HepG2 cells via activation ofPI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potentialtarget. Antioxid Redox Signal 9: 2087-2098.

47. Sethi G, Ahn KS, Aggarwal BB (2008) Targeting nuclear factor-kappa Bactivation pathway by thymoquinone: role in suppression ofantiapoptotic gene products and enhancement of apoptosis. Mol CancerRes 6: 1059-1070.

48. Li F, Rajendran P, Sethi G (2010) Thymoquinone inhibits proliferation,induces apoptosis and chemosensitizes human multiple myeloma cellsthrough suppression of signal transducer and activator of transcription 3activation pathway. Br J Pharmacol 161: 541-554.

49. Kim YJ, Ko H, Park JS, Han IH, Amor EC, et al. (2010) Dimethylcardamonin inhibits lipopolysaccharide-induced inflammatory factorsthrough blocking NF-kappaB p65 activation. Int Immunopharmacol 10:1127-1134.

50. Vaibhav K, Shrivastava P, Javed H, Khan A, Ahmed ME, et al. (2012)Piperine suppresses cerebral ischemia-reperfusion-induced inflammationthrough the repression of COX-2, NOS-2, and NF-κB in middle cerebralartery occlusion rat model. Mol Cell Biochem 367: 73-84.

51. Tripathi S, Maier KG, Bruch D, Kittur DS (2007) Effect of 6-gingerol onpro-inflammatory cytokine production and costimulatory moleculeexpression in murine peritoneal macrophages. J Surg Res 138: 209-213.

52. Weng CJ, Chou CP, Ho CT, Yen GC (2012) Molecular mechanisminhibiting human hepatocarcinoma cell invasion by 6-shogaol and 6-gingerol. Mol Nutr Food Res 56: 1304-1314.

53. Chen BY, Lin DP, Wu CY, Teng MC, Sun CY, et al. (2011) Dietaryzerumbone prevents mouse cornea from UVB-induced photokeratitisthrough inhibition of NF-κB, iNOS, and TNF-α expression andreduction of MDA accumulation. Mol Vis 17: 854-863.

54. Murakami A, Miyamoto M, Ohigashi H (2004) Zerumbone, an anti-inflammatory phytochemical, induces expression of proinflammatorycytokine genes in human colon adenocarcinoma cell lines. Biofactors 21:95-101.

55. Holt PR, Katz S, Kirshoff R (2005) Curcumin therapy in inflammatorybowel disease: a pilot study. Dig Dis Sci 50: 2191-2193.

56. Hanai H, Sugimoto K (2009) Curcumin has bright prospects for thetreatment of inflammatory bowel disease. Curr Pharm Des 15:2087-2094.

57. Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, et al. (2006)Curcumin maintenance therapy for ulcerative colitis: randomized,multicenter, double-blind, placebo-controlled trial. Clin GastroenterolHepatol 4: 1502-1506.

58. Epstein J, Docena G, MacDonald TT, Sanderson IR (2010) Curcuminsuppresses p38 mitogen-activated protein kinase activation, reducesIL-1beta and matrix metalloproteinase-3 and enhances IL-10 in themucosa of children and adults with inflammatory bowel disease. Br JNutr 103: 824-832.

59. Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, etal. (2008) Phase II trial of curcumin in patients with advanced pancreaticcancer. Clin Cancer Res 14: 4491-4499.

60. Durgaprasad S, Pai CG, Vasanthkumar, Alvres JF, Namitha S (2005) Apilot study of the antioxidant effect of curcumin in tropical pancreatitis.Indian J Med Res 122: 315-318.

61. Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, et al. (2001)Pharmacodynamic and pharmacokinetic study of oral Curcuma extractin patients with colorectal cancer. Clin Cancer Res 7: 1894-1900.

62. Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, et al. (2004)Phase I clinical trial of oral curcumin: biomarkers of systemic activity andcompliance. Clin Cancer Res 10: 6847-6854.

63. Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, et al.(2006) Combination treatment with curcumin and quercetin ofadenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol4: 1035-1038.

64. Bayet-Robert M, Kwiatkowski F, Leheurteur M, Gachon F, Planchat E, etal. (2010) Phase I dose escalation trial of docetaxel plus curcumin inpatients with advanced and metastatic breast cancer. Cancer Biol Ther 9:8-14.

65. Ide H, Tokiwa S, Sakamaki K, Nishio K, Isotani S, et al. (2010) Combinedinhibitory effects of soy isoflavones and curcumin on the production ofprostate-specific antigen. Prostate 70: 1127-1133.

66. Bharti AC, Shishodia S, Reuben JM, Weber D, Alexanian R, et al. (2004)Nuclear factor-kappaB and STAT3 are constitutively active in CD138+cells derived from multiple myeloma patients, and suppression of thesetranscription factors leads to apoptosis. Blood 103: 3175-3184.

67. Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, et al. (2010)Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex,during extended administration in osteoarthritis patients. Altern MedRev 15: 337-344.

68. Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R,Phisalaphong C, Jirawatnotai S (2012) Curcumin extract for preventionof type 2 diabetes. Diabetes Care 35: 2121-2127.

69. Sharma RD, Raghuram TC, Rao NS (1990) Effect of fenugreek seeds onblood glucose and serum lipids in type I diabetes. Eur J Clin Nutr 44:301-306.

70. Rai A, Mohapatra SC, Shukla HS (2006) Correlates between vegetableconsumption and gallbladder cancer. Eur J Cancer Prev 15: 134-137.

71. Nathan J, Panjwani S, Mohan V, Joshi V, Thakurdesai PA (2014) Efficacyand safety of standardized extract of Trigonella foenum-graecum L seedsas an adjuvant to L-Dopa in the management of patients with Parkinson'sdisease. Phytother Res 28: 172-178.

72. Berger A, Henderson M, Nadoolman W, Duffy V, Cooper D, et al. (1995)Oral capsaicin provides temporary relief for oral mucositis painsecondary to chemotherapy/radiation therapy. J Pain Symptom Manage10: 243-248.

73. Low PA, Opfer-Gehrking TL, Dyck PJ, Litchy WJ, O'Brien PC (1995)Double-blind, placebo-controlled study of the application of capsaicincream in chronic distal painful polyneuropathy. Pain 62: 163-168.

74. Ellison N, Loprinzi CL, Kugler J, Hatfield AK, Miser A, et al. (1997)Phase III placebo-controlled trial of capsaicin cream in the managementof surgical neuropathic pain in cancer patients. J Clin Oncol 15:2974-2980.

75. Kosuwon W, Sirichatiwapee W, Wisanuyotin T, Jeeravipoolvarn P,Laupattarakasem W (2010) Efficacy of symptomatic control of kneeosteoarthritis with 0.0125% of capsaicin versus placebo. J Med AssocThai 93: 1188-1195.

76. Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P (2006) Effectof piperine on the steady-state pharmacokinetics of phenytoin in patientswith epilepsy. Phytother Res 20: 683-686.

77. Kasibhatta R, Naidu MU (2007) Influence of piperine on thepharmacokinetics of nevirapine under fasting conditions: a randomised,crossover, placebo-controlled study. Drugs R D 8: 383-391.

78. Citronberg J, Bostick R, Ahearn T, Turgeon DK, Ruffin MT, et al. (2013)Effects of ginger supplementation on cell-cycle biomarkers in thenormal-appearing colonic mucosa of patients at increased risk forcolorectal cancer: results from a pilot, randomized, and controlled trial.Cancer Prev Res (Phila) 6: 271-281.


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79. Vahdat Shariatpanahi Z, Mokhtari M, Taleban FA, Alavi F, SalehiSurmaghi MH, et al. (2013) Effect of enteral feeding with ginger extractin acute respiratory distress syndrome. J Crit Care 28: 217.

80. Davis PA, Yokoyama W (2011) Cinnamon intake lowers fasting bloodglucose: meta-analysis. J Med Food 14: 884-889.

81. Aggarwal B, Prasad S, Sung B, Krishnan S, Guha S (2013) Prevention andTreatment of Colorectal Cancer by Natural Agents From Mother Nature.Curr Colorectal Cancer Rep 9: 37-56.

82. Motawi TK, Rizk SM, Shehata AH (2012) Effects of curcumin andGinkgo biloba on matrix metalloproteinases gene expression and otherbiomarkers of inflammatory bowel disease. J Physiol Biochem 68:529-539.

83. Larmonier CB, Midura-Kiela MT, Ramalingam R, Laubitz D, JanikashviliN, et al. (2011) Modulation of neutrophil motility by curcumin:implications for inflammatory bowel disease. Inflamm Bowel Dis 17:503-515.

84. Deguchi Y, Andoh A, Inatomi O, Yagi Y, Bamba S, et al. (2007)Curcumin prevents the development of dextran sulfate Sodium (DSS)-induced experimental colitis. Dig Dis Sci 52: 2993-2998.

85. Yadav VR, Suresh S, Devi K, Yadav S (2009) Effect of cyclodextrincomplexation of curcumin on its solubility and antiangiogenic and anti-inflammatory activity in rat colitis model. AAPS PharmSciTech 10:752-762.

86. Binion DG, Heidemann J, Li MS, Nelson VM, Otterson MF, et al. (2009)Vascular cell adhesion molecule-1 expression in human intestinalmicrovascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-kappaB: inhibitory role of curcumin. Am J PhysiolGastrointest Liver Physiol 297: G259-268.

87. Kunnumakkara AB, Anand P, Aggarwal BB (2008) Curcumin inhibitsproliferation, invasion, angiogenesis and metastasis of different cancersthrough interaction with multiple cell signaling proteins. Cancer Lett269: 199-225.

88. Srivastava G, Mehta JL (2009) Currying the heart: curcumin andcardioprotection. J Cardiovasc Pharmacol Ther 14: 22-27.

89. Yeh CH, Chen TP, Wu YC, Lin YM, Jing Lin P (2005) Inhibition ofNFkappaB activation with curcumin attenuates plasma inflammatorycytokines surge and cardiomyocytic apoptosis following cardiacischemia/reperfusion. J Surg Res 125: 109-116.

90. Venkatesan N (1998) Curcumin attenuation of acute adriamycinmyocardial toxicity in rats. Br J Pharmacol 124: 425-427.

91. Nishiyama T, Mae T, Kishida H, Tsukagawa M, Mimaki Y, et al. (2005)Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.)suppress an increase in blood glucose level in type 2 diabetic KK-Aymice. J Agric Food Chem 53: 959-963.

92. Mahesh T, Sri Balasubashini MM, Menon VP (2004) Photo-irradiatedcurcumin supplementation in streptozotocin-induced diabetic rats: effecton lipid peroxidation. Therapie 59: 639-644.

93. Aggarwal BB, Shishodia S (2004) Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoningfor seasoning. Ann N Y Acad Sci 1030: 434-441.

94. Harada N, Okajima K (2009) Effects of capsaicin and isoflavone on bloodpressure and serum levels of insulin-like growth factor-I in normotensiveand hypertensive volunteers with alopecia. Biosci Biotechnol Biochem 73:1456-1459.

95. Jiang X, Jia LW, Li XH, Cheng XS, Xie JZ, et al. (2013) Capsaicinameliorates stress-induced Alzheimer's disease-like pathological andcognitive impairments in rats. J Alzheimers Dis 35: 91-105.

96. Lee TH, Lee JG, Yon JM, Oh KW, Baek IJ, et al. (2011) Capsaicinprevents kainic acid-induced epileptogenesis in mice. Neurochem Int 58:634-640.

97. Zhang F, Challapalli SC, Smith PJ (2009) Cannabinoid CB(1) receptoractivation stimulates neurite outgrowth and inhibits capsaicin-inducedCa(2+) influx in an in vitro model of diabetic neuropathy.Neuropharmacology 57: 88-96.

98. Thyagarajan B, Krivitskaya N, Potian JG, Hognason K, Garcia CC, et al.(2009) Capsaicin protects mouse neuromuscular junctions from theneuroparalytic effects of botulinum neurotoxin a. J Pharmacol Exp Ther331: 361-371.

99. Park MK, Jo SH, Lee HJ, Kang JH, Kim YR, et al. (2013) Novelsuppressive effects of cardamonin on the activity and expression oftransglutaminase-2 lead to blocking the migration and invasion of cancercells. Life Sci 92: 154-160.

100. Park S, Gwak J, Han SJ, Oh S (2013) Cardamonin suppresses theproliferation of colon cancer cells by promoting Î²-catenin degradation.Biol Pharm Bull 36: 1040-1044.

101. Sung B, Prasad S, Yadav VR, Gupta SC, Reuter S, et al. (2013) RANKLsignaling and osteoclastogenesis is negatively regulated by cardamonin.PLoS One 8: e64118.

102. Yadav VR, Prasad S, Aggarwal BB (2012) Cardamonin sensitizes tumourcells to TRAIL through ROS- and CHOP-mediated up-regulation ofdeath receptors and down-regulation of survival proteins. Br J Pharmacol165: 741-753.

103. Wang ZT, Lau CW, Chan FL, Yao X, Chen ZY, et al. (2001) Vasorelaxanteffects of cardamonin and alpinetin from Alpinia henryi K. Schum. JCardiovasc Pharmacol 37: 596-606.

104. Liao Q, Shi DH, Zheng W, Xu XJ, Yu YH (2010) Antiproliferation ofcardamonin is involved in mTOR on aortic smooth muscle cells in highfructose-induced insulin resistance rats. Eur J Pharmacol 641: 179-186.

105. Fusi F, Cavalli M, Mulholland D, Crouch N, Coombes P, et al. (2010)Cardamonin is a bifunctional vasodilator that inhibits Ca(v)1.2 currentand stimulates K(Ca)1.1 current in rat tail artery myocytes. J PharmacolExp Ther 332: 531-540.

106. Lei X, Liu M, Yang Z, Ji M, Guo X, et al. (2012) Thymoquinone preventsand ameliorates dextran sulfate sodium-induced colitis in mice. Dig DisSci 57: 2296-2303.

107. Mahgoub AA (2003) Thymoquinone protects against experimental colitisin rats. Toxicol Lett 143: 133-143.

108. Peng L, Liu A, Shen Y, Xu HZ, Yang SZ, et al. (2013) Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-ÎºB pathway. Oncol Rep 29: 571-578.

109. Al Wafai RJ (2013) Nigella sativa and thymoquinone suppresscyclooxygenase-2 and oxidative stress in pancreatic tissue ofstreptozotocin-induced diabetic rats. Pancreas 42: 841-849.

110. Sayed AA (2012) Thymoquinone and proanthocyanidin attenuation ofdiabetic nephropathy in rats. Eur Rev Med Pharmacol Sci 16: 808-815.

111. Ullah I, Ullah N, Naseer MI, Lee HY, Kim MO (2012) Neuroprotectionwith metformin and thymoquinone against ethanol-induced apoptoticneurodegeneration in prenatal rat cortical neurons. BMC Neurosci 13:11.

112. Nangle MR, Gibson TM, Cotter MA, Cameron NE (2006) Effects ofeugenol on nerve and vascular dysfunction in streptozotocin-diabeticrats. Planta Med 72: 494-500.

113. Kumar S, Vasudeva N, Sharma S (2012) GC-MS analysis and screening ofantidiabetic, antioxidant and hypolipidemic potential of Cinnamomumtamala oil in streptozotocin induced diabetes mellitus in rats. CardiovascDiabetol 11: 95.

114. Yanaga A, Goto H, Nakagawa T, Hikiami H, Shibahara N, et al. (2006)Cinnamaldehyde induces endothelium-dependent and -independentvasorelaxant action on isolated rat aorta. Biol Pharm Bull 29: 2415-2418.

115. Brückner M, Westphal S, Domschke W, Kucharzik T, Lügering A (2012)Green tea polyphenol epigallocatechin-3-gallate shows therapeuticantioxidative effects in a murine model of colitis. J Crohns Colitis 6:226-235.

116. Nirmal SA, Ingale JM, Pattan SR, Bhawar SB (2013) Amaranthusroxburghianus root extract in combination with piperine as a potentialtreatment of ulcerative colitis in mice. J Integr Med 11: 206-212.

117. Cavalcanti E, Vadrucci E, Delvecchio FR, Addabbo F, Bettini S, et al.(2014) Administration of reconstituted polyphenol oil bodies efficiently


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suppresses dendritic cell inflammatory pathways and acute intestinalinflammation. PLoS One 9: e88898.

118. Lai LH, Fu QH, Liu Y, Jiang K, Guo QM, et al. (2012) Piperine suppressestumor growth and metastasis in vitro and in vivo in a 4T1 murine breastcancer model. Acta Pharmacol Sin 33: 523-530.

119. Makhov P, Golovine K, Canter D, Kutikov A, Simhan J, et al. (2012) Co-administration of piperine and docetaxel results in improved anti-tumorefficacy via inhibition of CYP3A4 activity. Prostate 72: 661-667.

120. Bezerra DP, de Castro FO, Alves AP, Pessoa C, de Moraes MO, et al.(2008) In vitro and in vivo antitumor effect of 5-FU combined withpiplartine and piperine. J Appl Toxicol 28: 156-163.

121. Atal S, Agrawal RP, Vyas S, Phadnis P, Rai N (2012) Evaluation of theeffect of piperine per se on blood glucose level in alloxan-induceddiabetic mice. Acta Pol Pharm 69: 965-969.

122. Mao QQ, Huang Z, Ip SP, Xian YF, Che CT (2012) Protective effects ofpiperine against corticosterone-induced neurotoxicity in PC12 cells. CellMol Neurobiol 32: 531-537.

123. Pal A, Nayak S, Sahu PK, Swain T (2011) Piperine protects epilepsyassociated depression: a study on role of monoamines. Eur Rev MedPharmacol Sci 15: 1288-1295.

124. El-Abhar HS, Hammad LN, Gawad HS (2008) Modulating effect ofginger extract on rats with ulcerative colitis. J Ethnopharmacol 118:367-372.

125. Hsiang CY, Lo HY, Huang HC, Li CC, Wu SL, et al. (2013) Gingerextract and zingerone ameliorated trinitrobenzene sulphonic acid-induced colitis in mice via modulation of nuclear factor-κB activity andinterleukin-1β signalling pathway. Food Chem 136: 170-177.

126. Rashidian A, Mehrzadi S, Ghannadi AR, Mahzooni P, Sadr S, et al. (2014)Protective effect of ginger volatile oil against acetic acid-induced colitis inrats: a light microscopic evaluation. J Integr Med 12: 115-120.

127. Nigam N, George J, Srivastava S, Roy P, Bhui K, et al. (2010) Induction ofapoptosis by [6]-gingerol associated with the modulation of p53 andinvolvement of mitochondrial signaling pathway in B[a]P-inducedmouse skin tumorigenesis. Cancer Chemother Pharmacol 65: 687-696.

128. Funk JL, Frye JB, Oyarzo JN, Timmermann BN (2009) Comparativeeffects of two gingerol-containing Zingiber officinale extracts onexperimental rheumatoid arthritis. J Nat Prod 72: 403-407.

129. Lee C, Park GH, Kim CY, Jang JH (2011) [6]-Gingerol attenuates Î²-amyloid-induced oxidative cell death via fortifying cellular antioxidantdefense system. Food Chem Toxicol 49: 1261-1269.

130. Chakraborty D, Mukherjee A, Sikdar S, Paul A, Ghosh S, et al. (2012) [6]-Gingerol isolated from ginger attenuates sodium arsenite inducedoxidative stress and plays a corrective role in improving insulin signalingin mice. Toxicol Lett 210: 34-43.

131. Murakami A, Hayashi R, Tanaka T, Kwon KH, Ohigashi H, et al. (2003)Suppression of dextran sodium sulfate-induced colitis in mice byzerumbone, a subtropical ginger sesquiterpene, and nimesulide:separately and in combination. Biochem Pharmacol 66: 1253-1261.

132. Murakami A, Tanaka T, Lee JY, Surh YJ, Kim HW, et al. (2004)Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumorinitiation and promotion stages in ICR mice. Int J Cancer 110: 481-490.

133. Kim M, Miyamoto S, Yasui Y, Oyama T, Murakami A, et al. (2009)Zerumbone, a tropical ginger sesquiterpene, inhibits colon and lungcarcinogenesis in mice. Int J Cancer 124: 264-271.

This article was originally published in a special issue, entitled: "InflammatoryBowel Disease", Edited by Dr. Nancy Louis, Emory University, USA and Dr.Ostanin Dmitry Vladimirovich, Louisiana State University Health SciencesCenter, USA


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8/30/2017 Chemical and in vitro assessment of Alaskan coastal vegetation antioxidant capacity. - PubMed - NCBI

https://www.ncbi.nlm.nih.gov/pubmed/24147955 1/2

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J Agric Food Chem. 2013 Nov 20;61(46):1102532. doi: 10.1021/jf403697z. Epub 2013 Nov 5.

Chemical and in vitro assessment of Alaskan coastal vegetationantioxidant capacity.Kellogg J , Lila MA.

AbstractAlaska Native (AN) communities have utilized tidal plants and marine seaweeds as food andmedicine for generations, yet the bioactive potential of these resources has not been widelyexamined. This study screened six species of Alaskan seaweed ( Fucus distichus , Saccharinalatissima , Saccharina groenlandica , Alaria marginata , Pyropia fallax , and Ulva lactuca ) and onetidal plant ( Plantago maritima ) for antioxidant activity. Total polyphenolic content (TPC) wasdetermined, and chemical antioxidant capacity was assessed by 2,2diphenyl1picrylhydrazyl(DPPH) radical scavenging, ferrous ion chelating, and nitric oxide (NO) inhibition assays. In vitroinhibition of radical oxygen species (ROS) generation and NO synthesis was evaluated in a RAW264.7 macrophage culture. Greatest TPC (557.2 μg phloroglucinol equivalents (PGE)/mg extract)was discovered in the ethyl acetate fraction of F. distichus, and highest DDPH scavenging activitywas exhibited by F. distichus and S. groenlandica fractions (IC50 = 4.295.12 μg/mL). These resultssupport the potential of Alaskan coastal vegetation, especially the brown algae, as natural sources ofantioxidants for preventing oxidative degeneration and maintaining human health.

PMID: 24147955 DOI: 10.1021/jf403697z

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8/30/2017 Chemopreventive Activity of Polyphenolics from Black Jamapa Bean (Phaseolus vulgaris L.) on HeLa and HaCaT Cells - Journal of Agricultural and Food Ch…

http://pubs.acs.org/doi/abs/10.1021/jf052974m 1/2

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Chemopreventive Activity of Polyphenolics from Black Jamapa Bean(Phaseolus vulgaris L.) on HeLa and HaCaT CellsXochitl Aparicio-Fernández,†Teresa García-Gasca,‡Gad G. Yousef,§Mary Ann Lila,§Elvira González de Mejia,‖andGuadalupe Loarca-Pina*†Programa de Posgrado en Alimentos del Centro de la Republica (PROPAC), Research and Graduate Studies in FoodScience, School of Chemistry, Universidad Autónoma de Querétaro, Querétaro, Qro., 76010 México, Nutrition School,Natural Sciences Faculty, Universidad Autónoma de Querétaro, Querétaro, Qro., 76010 México, Department of NaturalResources and Environmental Sciences, University of Illinois at Urbana-Champaign, 1201 South Dorner Drive, Urbana,Illinois 61801, and Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 228ERML, 1201 W Gregory, Urbana, Illinois 61801

J. Agric. Food Chem., 2006, 54 (6), pp 2116–2122DOI: 10.1021/jf052974mPublication Date (Web): February 24, 2006Copyright © 2006 American Chemical Society

Abstract

The antiproliferative effects of 100% methanol crude extract and of Toyopearl and silica gelfractions from the seed coats of black Jamapa beans (Phaseolus vulgaris L.) were evaluatedusing HeLa, human adenocarcinoma cells, and HaCaT, human premalignant keratinocytes. The100% methanol crude extract [172.2 μM equiv of (+)-catechin] increased adhesion of HeLa cells;however, 3- and 5-fold higher concentrations decreased the number of cells attached as a functionof the treatment time. The highest concentration tested diminished the cell adhesion until 40%(after 24 h) to almost 80% (after 72 h). The IC50 values showed that the 100% methanol crudeextract was the most effective inhibitor of HeLa cell proliferation, even when it was dissolved indimethylsulfoxide (DMSO) [34.5 μM equiv of (+)-catechin] or in medium [97.7 μM equiv of (+)-catechin]. The Toyopearl 5 (TP5) fraction and silica gel 2 (SG2) fraction inhibited 60% of the HeLacell proliferation. The IC50 was 154 μM equiv of (+)-catechin of the 100% methanol crude extracton HaCaT cells. Toyopearl fractions TP4 and TP6 significantly inhibited HaCaT cell proliferation,but the silica gel fractions did not have a significant effect. The 100% methanol crude extract (35μg of dry material/mL) decreased the number of HeLa cells in the G0/G1 phase from 68.9% (forcontrol cells) to 51.4% (for treated cells) and increased apoptosis (2.9 and 21.2% for control andtreated cells, respectively). The results indicated that black Jamapa beans could be a source ofpolyphenolic compounds, which have an inhibitory effect toward HeLa cancer cells but are lessaggressive on HaCaT premalignant cells.

Keywords: Phaseolus vulgaris; polyphenolic compounds; cytotoxicity; HeLa cells; HaCaT cells

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8/30/2017 Chemopreventive Activity of Polyphenolics from Black Jamapa Bean (Phaseolus vulgaris L.) on HeLa and HaCaT Cells - Journal of Agricultural and Food Ch…

http://pubs.acs.org/doi/abs/10.1021/jf052974m 2/2

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8/30/2017 Impact of Cranberries on Gut Microbiota and Cardiometabolic Health: Proceedings of the Cranberry Health Research Conference 2015

http://advances.nutrition.org/content/7/4/759S.full#aff-10 1/16

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Advances in Nutrition: An International Review Journaladvances.nutrition.org

doi: 10.3945/ an.116.012583Adv Nutr July 2016 Adv Nutr vol. 7: 759S770S, 2016

Impact of Cranberries on Gut Microbiotaand Cardiometabolic Health: Proceedingsof the Cranberry Health ResearchConference 20151,2,3

Jeffrey B Blumberg4,*, Arpita Basu5, Christian G Krueger6,7, Mary Ann Lila8,

Catherine C Neto9, Janet A Novotny10, Jess D Reed6,7, Ana RodriguezMateos11, and

Cheryl D Toner12,13

Author Affiliations

↵*To whom correspondence should be addressed. Email: [email protected].

Abstract

Recent advances in cranberry research have expanded the evidence for the role of thisVaccinium berry fruit in modulating gut microbiota function and cardiometabolic risk factors.The Atype structure of cranberry proanthocyanidins seems to be responsible for much ofthis fruit’s efficacy as a natural antimicrobial. Cranberry proanthocyanidins interfere withcolonization of the gut by extraintestinal pathogenic Escherichia coli in vitro and attenuategut barrier dysfunction caused by dietary insults in vivo. Furthermore, new studies indicatesynergy between these proanthocyanidins, other cranberry components such asisoprenoids and xyloglucans, and gut microbiota. Together, cranberry constituents and theirbioactive catabolites have been found to contribute to mechanisms affecting bacterialadhesion, coaggregation, and biofilm formation that may underlie potential clinical benefitson gastrointestinal and urinary tract infections, as well as on systemic antiinflammatoryactions mediated via the gut microbiome. A limited but growing body of evidence fromrandomized clinical trials reveals favorable effects of cranberry consumption on measuresof cardiometabolic health, including serum lipid profiles, blood pressure, endothelialfunction, glucoregulation, and a variety of biomarkers of inflammation and oxidative stress.These results warrant further research, particularly studies dedicated to the elucidation ofdoseresponse relations, pharmacokinetic/metabolomics profiles, and relevant biomarkersof action with the use of fully characterized cranberry products. Freezedried wholecranberry powder and a matched placebo were recently made available to investigators tofacilitate such work, including interlaboratory comparability.

Keywords:

cranberry proanthocyanidins microbiome cardiometabolic antimicrobial

Introduction

Dietary guidance is consistent in recommending greater consumption of fruit andvegetables to promote health. Indeed, the 2015 Dietary Guidelines Advisory Committeereport noted that greater fruit and vegetable intake was the only characteristic of dietarypatterns that was consistently identified in their report in every conclusion statement acrosshealth outcomes (1). Although the report does not recommend specific types of fruit, therehas been a growing body of evidence that the phytochemical composition of berry fruit maydifferentiate them from other fruits and underlie some of their putative benefits. Recentadvances in analytical methods have improved the characterization of polyphenols in berryfruit and subsequently the data in foodcomposition and metabolomics databases that areessential for observational studies. Furthermore, the development of a standard referencematerial (SRM)14 and matched placebos for use in clinical trials has provided an importantand innovative component for the design and conduct of new randomized clinical trials.This review, prepared from the proceedings of the Cranberry Health Research Conferenceheld in conjunction with the Berry Health Benefits Symposium in Madison, Wisconsin, 12–15 October 2015, focuses particularly on advances in the field during the last 5 y withregard to the gut microbiota and cardiometabolic health.

Cranberries and the Gut Microbiota

Molecular mechanisms.



Much of the attention regarding the impact of cranberries on the gut microbiota has beendirected to studies of the effect of cranberry extracts or juice on uropathogens and urinarytract infections (UTIs) (2, 3). However, this focus has expanded to encompass a broaderrange of the cranberry’s antimicrobial, antifungal, and antiviral actions against Helicobacterpylori (4–6), Streptococcus mutans (7), Porphyromonas gingivalis (8), Staphylococcusaureus (9), Pseudomonas aeruginosa (10), Cryptococcus neoformans (6), Haemophilusinfluenzae (11), Candida albicans (12, 13), and extraintestinal pathogenic Escherichia coli(ExPEC) (14). Cranberry constituents, particularly the proanthocyanidins, flavonols, andhydroxycinnamic acids, may act against these pathogens by preventing bacterial adhesionand coaggregation, decreasing biofilm formation and/or reducing inflammation rather thanvia bactericidal activity. This expanding body of research includes in vitro, ex vivo, andanimal studies that have suggested potential clinical effects and have helped to elucidatemechanisms of action as well as human studies that have shown physiologic effects (3–5,14).

The antimicrobial properties of cranberry proanthocyanidins have been generallyassociated with their degree of polymerization (DP) and ratio of A to Btype linkages. Forexample, by using an in vitro broth microdilution assay for growth inhibition of several yeastspecies, treatment of cultures with cranberry fractions of varying composition showed thatcranberry proanthocyanidin fractions with a larger DP were found to be more effective thanthose with a smaller DP at inhibiting the growth of Candida spp. (12). In comparingprimarily Atype proanthocyanidins from cranberries with primarily Btypeproanthocyanidins from apples, Feliciano et al. (15) found that, although both increasedagglutination and reduced epithelial cell invasion by ExPEC, the strongest effects wereassociated with a higher percentage of Atype linkages. This observation is consistent withother research that showed that Atype proanthocyanidins interact most strongly withbacterial virulence factors and more effectively decrease bacterial motility (16, 17).

Microbiota biofilm.

The prevention of biofilm formation, an early step in the development of infection, throughinterference in the coaggregation of bacteria is a welldocumented antimicrobialmechanism of cranberry proanthocyanidins. The extensively hydroxylated structure ofproanthocyanidins encourages intermolecular hydrogen bonding, allowing smallermolecules to aggregate and interact with receptors on cell surfaces. Thus, many studies ofhighmolecularweight nondialyzable material from cranberry juice concentrate revealpotent antiadhesion activity with microbial species, including those found in the oral cavity,stomach, small intestine, and colon (6, 11, 14, 18, 19). However, although purifiedcranberry proanthocyanidins are more effective in some antimicrobial assays than arecrude or mixed extracts, several studies suggest that other compounds in cranberrypossess antibacterial properties that alone or in combination with proanthocyanidins mayenhance overall protection against infection. For example, PinzónArango et al. (20)exposed E. coli to cranberry juice cocktail (CJC) or cranberry proanthocyanidins over 48 hand found that the proanthocyanidins reduced whereas the CJC completely eliminatedbiofilm formation. Candidate CJC constituents may include nonphenolic compounds suchas isoprenoids like ursolic acid and xyloglucans, hemicellulose oligosaccharides found inhighmolecularweight nondialyzable fractions (21). Hotchkiss et al. (22) found thatarabinoxyloglucans isolated from pectinasetreated cranberry hulls prevented the adhesionof E. coli strains to bladder and colonic epithelial cells in vitro.

Bacterial adhesion to cells and other surfaces involves basic physical forces such aselectrostatic and steric interactions, van der Waals forces, and surface charge, as well asboth specific and nonspecific interactions of surface proteins and carbohydrates such asglucans, adhesins, and sugarspecific lectins (23–25). Using atomic force microscopy, Liuet al. (26) found that exposure to cranberry juice decreased the adhesion forces of Pfimbriated E. coli (HB101pDC1) and altered the conformation and length of the Pfimbriae.PinzónArango et al. (24) found that these fimbrial changes were reversible, even forcultures grown in the presence of cranberry juice. de Llano et al. (27) showed the efficacyof colonic metabolites of cranberry polyphenols, including hydroxylated benzoic andphenylacetic acids, in inhibiting the adhesion and biofilm formation of uropathogenic E. colito bladder epithelial cells, a relation that underscores the critical need to elucidate the roleof the gut microbiota in transforming cranberry polyphenols to bioactive and bioavailablecompounds.

Gut microbiota metabolism and function.

The gut microbiota is now appreciated as a critical factor in nutrition and health, influencingthe bioavailability and metabolism of food components and affecting body systems,including brain and immune functions. The integrity of the gut mucosal barrier is essential



for maintaining a chemical and physical barrier against food, environmental antigens, andmicrobes (28, 29). Goblet cells migrate up the villi after differentiating from crypt stem cellsand turn over with the epithelial layer every 3–5 d. Goblet cells secrete mucins, particularlymucin 2 (Muc2), that contribute substantially to the maintenance of mucosal integrity (30).Mucin secretion is regulated by a complex network of cholinergic stimulation and Thelper 2(Th2) cytokines IL4 and IL13 (31–35).

Dysfunction of the gut barrier and dysbiosis have been associated with typical Westerndiets high in saturated fat and low in fiber and phytochemicals, patterns that may lead toincreased permeability of bacterial LPS and a pathogenassociated molecular pattern thatstimulates innate immune responses in macrophages, neutrophils, endothelial cells, andadipocytes. LPS plays a role in acute infectionrelated inflammatory responses and is foundin blood and tissues with both postprandial and chronic inflammation (36–39). With the useof mice (CEABAC10) that express human carcinoembryonic antigenrelated cell adhesionmolecules (CEACAMs), MartinezMedina et al. (37) found that a highfat, highsugar dietincreased intestinal permeability and TNFα secretion, which resulted in a greater ability ofadherentinvasive E. coli (AIEC) to colonize gut mucosa and induce inflammation. This dietalso induced gut barrier dysfunction reflected by reduced levels of Muc2 mRNA, increasedpermeability of 4kDa fluorescein isothiocyanatedextran, and decreased numbers of gobletcells. It is worth noting that AIEC may contribute substantially to the etiology of Crohndisease, an inflammatory bowel disease in which CEACAM6 is overexpressed on theapical surface of ileum epithelium (40). Furthermore, variant AIEC type 1 pili adhere toCEACAM6, a key step in the colonization of the ileum and chronic inflammation present inCrohn disease. In addition, after feeding mice a highfat, highsugar diet, Anhê et al. (41)reported that the addition of a cranberry extract attenuated the consequent chronicinflammation associated with gut barrier dysfunction, including reductions in plasma LPS,cyclooxygenase2, and TNFα. Furthermore, the ratio of NFκB to inhibitor κB wassignificantly lower in the jejunal tissue of the mice fed cranberry extract relative to the micefed the highfat, highsugar diet. Also suggesting the capacity of cranberry polyphenols toreduce intestinal oxidative stress and inflammation, in vitro experiments with Caco2/15intestinal cells by Denis et al. (42) revealed positive but differential effects of low, medium,and highmolecularmass polyphenols from cranberries on oxidative stress,proinflammatory cytokines, NFκB activation, and nuclear factor E2related factor 2 (Nrf2)downregulation, as well as PPARγ coactivator 1α.

Interestingly, the effects of highfat, highsugar diets on gut barrier function in mice aresimilar to those observed in animal models of parenteral nutrition and elemental enteralnutrition (EEN) (43, 44). EEN induces dysfunction of gutassociated lymphoid tissue,including decreased lymphocytes in Peyer’s patch and reduced tissue Th2 cytokines, andsuppresses mucosal barrier function when compared with normal nutrition (43, 45–48). Theaddition of cranberry proanthocyanidins to EEN was found to increase ileal tissue IL4 andIL13 concentrations, goblet cell number and size, and the secretion of intestinal Muc2,attenuating the impairment of the mucosal barrier integrity after EEN alone (44). Pierre etal. (43) reported that the addition of cranberry proanthocyanidins significantly supportedother indexes of gutassociated lymphoid tissue function impaired by EEN in mice,indicated in part by decreased Peyer’s patch lymphocytes and lower concentrations oftissue Th2 cytokines. Cranberry proanthocyanidins also helped to restore the EENinduceddecreases in polymeric Ig receptor, a transport protein involved in enterocyte transcytosisof secretory IgA (sIgA) from B cells in the lamina propria into the intestinal lumen. EENdecreases in luminal concentrations of sIgA were attenuated by cranberryproanthocyanidins; intestinal sIgA opsonizes bacterial antigens such as the virulencefactors of pathogenic E. coli, rendering them less viable and more susceptible to killing bylymphocytes. The addition of cranberry proanthocyanidins also significantly preventedEENinduced decreases in tissue IL4 and phosphorylated signal transducers andactivators of transcription 6 (STAT6).

Clinical studies are necessary to determine whether the results from these mouse modelscan be translated to the capacity of cranberry phytochemicals to reduce dietinducedintestinal inflammation in humans. Interestingly, there is limited evidence suggesting aneffect of cranberry on systemic immune function in humans, which may be partly mediatedvia gut metabolism of cranberry polyphenols. For example, a randomized, doubleblindplacebocontrolled study documented increased ex vivo proliferation of γδT cells, immunecells located within the epithelium of the gastrointestinal and reproductive tracts, after theconsumption of a cranberry beverage for 10 wk (49).

ExPEC in the gut.



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Although ExPEC generally do not cause acute enteric disease, their colonization in the gutincreases the risk of subsequent extraintestinal infection, including UTIs, septicemia,surgical wound infections, and neonatal meningitis (50, 51). ExPEC attach to and invadeepithelial cells through adhesins expressed on type I pili (protein FimH) and P fimbriae(fimbrial adhesin PapG) and persist inside the host cell in vacuoles where they may evadeimmune detection. ExPEC, uropathogenic E. coli, and the AIEC associated with Crohndisease have similar virulence factors and are within the same E. coli phylogroups (B2 andD) (40). These phylogroups differ from enteropathogenic E. coli and Shiga toxin–producingE. coli, such as O157:H7, because enteropathogenic E. coli and Shiga toxin–producing E.coli cause acute intestinal disease and produce attaching and effacing lesions of theintestinal epithelium. Gut colonization by ExPEC is a likely cause of a chronic inflammatorystate because ExPEC may evade immune detection and colonize enterocytes. Thecontinuous presence of E. coli LPS in the gut mucosa may cause chronic intestinalinflammation. Although ExPEC have a meaningful impact on public health via theirconsequences on morbidity and mortality, they have not received concordant attentionbecause they have been highly susceptible to antibiotics. However, 20–45% of ExPEChave become resistant to firstline antibiotics such as cephalosporins, fluoroquinolones,and trimethoprimsulfamethoxazole (52, 53). Thus, it is becoming critical to appreciate andfurther investigate the potential role for dietary bioactive components in reducing suchinfections.

Recently, Feliciano et al. (15) showed that Atype proanthocyanidins have greaterbioactivity than Btype proanthocyanidins for increasing ExPEC agglutination anddecreasing their invasion (and subsequent colonization) of gut epithelial cells, an importantobservation for the elucidation of the effect of cranberry proanthocyanidins on UTIs. Assuggested by Feliciano et al. (15) and other studies described above, decreasing intestinalcolonization and associated inflammation may be achieved by usual serving sizes ofcranberry juice without the requirement for absorption of its constituent proanthocyanidinsinto the circulation or their appearance in the urine. It is important to note that recentrandomized clinical trials have confirmed and extended the body of evidence showingcranberry’s bacterial antiadhesion activity in urine ex vivo (3, 54), its capacity to reduce therecurrence of UTIs (55), and its therapeutic efficacy in preventing UTIs in gynecologicsurgery patients after catheter removal (56). Nonetheless, additional research that usessimilarly relevant ex vivo and in vivo models can be used to substantiate the structurefunction relation of Atype proanthocyanidins to intestinal and extraintestinal infections andto develop preventive and therapeutic strategies against increasingly antibioticresistantclasses of pathogens (57, 58). Such an effort could be advanced by the availability of acranberry SRM as discussed below.

Cranberries and Cardiometabolic Health

A limited but growing number of clinical research studies (59–72) have focused oncardiometabolic health (Tables 1 and 2). The most commonly examined risk factors forcardiometabolic conditions in these studies have included serum lipid profiles, bloodpressure (BP), endothelial function, glucoregulation, and a variety of biomarkers ofinflammation and oxidative stress. Although the results of this research have generallybeen promising, a clear and consistent picture of this emerging area is confounded bysometimes marked differences in the cranberry products (cranberry juices, driedcranberries, and cranberry extracts) and doses used, as well as the characteristics of thestudy populations (2, 73). Although few animal model studies have examined this topic,Kim et al. (74–76) reported that 5% cranberry powder added to atherogenic diets with orwithout intraperitoneal LPS administration produced positive effects on serum lipids,proinflammatory cytokines, oxidative stress, and antioxidant capacity in rodents.

TABLE 1

Summary of randomized placebocontrolled trials on the

cardiometabolic effects of cranberry1

TABLE 2

Summary of openlabel trials onthe effects of cranberry on

cardiometabolic markers1



Lipid profile.

Early reports by Ruel et al. (66–68) found that interventions with lowcalorie cranberry juicewere associated with increases in plasma HDL cholesterol as well as with reductions inplasma oxidized LDL cholesterol, adhesion molecules, and matrix metalloproteinase 9. Leeet al. (59) showed a reduction in both LDL cholesterol and total cholesterol in a trial in 30patients with type 2 diabetes (T2D) who consumed cranberry extract supplements daily for12 wk. In a doubleblind, placebocontrolled trial, Shidfar et al. (60) reported that 58 menwith T2D who consumed 1 cup cranberry juice/d for 12 wk experienced decreases in apoBand increases in apo A1 and paraoxonase1, although data on LDL, HDL, and totalcholesterol were not reported. In an 8wk randomized clinical trial of lowcalorie cranberryjuice consumption by 56 healthy adults, Novotny et al. (61) found that TGs weresignificantly decreased in the cranberry group whereas other elements of the lipid profilewere unchanged.

BP.

Previous studies of the effect of cranberry juice on BP suggested a potential benefit on BP(67, 69). More recent studies also examined changes in BP after cranberry intake (59, 61–65). The durations of these studies ranged from 1 to 4 mo and tested intakes of totalpolyphenols ranging from 346 to 835 mg/d; and study populations were heterogeneous,including subjects with obesity, metabolic syndrome, T2D, coronary artery disease (CAD),and risk factors for cardiovascular disease (CVD), as well as healthy volunteers. With dailydoses of CJC increasing every 4 wk from 0–125 to 250–500 mL, systolic BP decreased by3 mm Hg with the 500mL intervention compared with baseline in obese men (67). Of themore recent studies, only the study performed in healthy individuals and with the lowestdose of polyphenols showed an improvement in BP, with a reduction of 4.7 mm Hg indiastolic BP achieved after 8 wk of daily supplementation (61).

Endothelial function.

Endothelial dysfunction, often characterized by a decrease in nitric oxide production andimpaired flowmediated vasodilation (FMD), is a critical factor underlying the developmentand progression of atherosclerosis (77). In a randomized controlled trial with a crossoverdesign, Dohadwala et al. (63) found that daily supplementation with cranberry juice for 4 wkdid not improve FMD or peripheral artery tonometry in 44 patients with CAD, although anuncontrolled pilot study in a subset of the same population showed a modest improvementin FMD 4 h after an acute dose of cranberry juice. In a 4wk trial with a cranberry juicedrink, Flammer et al. (64) found no significant changes in peripheral artery tonometry inindividuals with endothelial dysfunction and other CVD risk factors. Further research on theeffect of cranberries on measures of vascular reactivity is required in healthy individualsexamining both the doseresponse and time course of the intervention.

Recently, in a clinical study of 10 healthy adults, Feliciano et al. (78) identified andquantified by ultraperformance liquid chromatography/quadrupoletimeofflight massspectrometry analysis a total of 60 cranberryderived phenolic metabolites in plasma andurine after the acute ingestion of cranberry juice containing 787 mg polyphenols. Thesemetabolites included sulfates of pyrogallol, valerolactone, benzoic acids, phenylaceticacids, and glucuronides of flavonols, as well as sulfates and glucuronides of cinnamicacids. Their concentrations ranged from in the low nanomolars to the high micromolarsdepending on the compound. Among these 60 phenolic metabolites, 12 were found to beindependent predictors of time (0–6 h) dependent increases in FMD after an acute dose(range: 409–1909 mg total polyphenols) (79). These results indicate that cranberrypolyphenols can acutely increase endothelial function in healthy individuals. Arterialstiffness, commonly assessed by pulsewave velocity or the augmentation index (ameasure of the enhancement of central aortic pressure by a reflected pulse wave), is anestablished risk factor for CVD (80–82). In their randomized clinical trial of patients withCAD, Dohadwala et al. (63) found that a 4wk intervention with cranberry juice significantlyreduced the carotidfemoral pulsewave velocity. However, no changes in the augmentationindex were observed by Ruel et al. (65) after 4 wk of supplementation with cranberry juicein 35 volunteers presenting with obesity and other cardiovascular risk factors.

Glucoregulation.

Berry fruit polyphenols have been shown by in vitro experiments and animal models toinhibit carbohydrate digestion and glucose absorption in the intestine, stimulate insulinsecretion from β cells in the pancreas, regulate glucose release from the liver, and activateinsulin receptors and glucose uptake in insulinsensitive tissues (83–85). Emerging clinicalevidence suggests that dietary modification to increase polyphenol intakes from wholefood



sources can lead to improved glycemic control in T2D (86, 87). While exploring theantidiabetic effects of a cranberry extract in highfat, highsugar–fed mice, Anhê et al. (41)found a decrease in glucoseinduced hyperinsulinemia and improved insulin sensitivityalong with a reduction in weight gain and visceral obesity. As noted above, along with theseimprovements, the cranberry extract also altered the gut microbiome by increasing mucindegrading bacteria. In light of the evolving link between the gut microbiota and diabetes,these findings provide an important connection between the studies documenting theeffects of cranberry on gut barrier function and the potential to reverse the dysbiosis andmetabolic inflammation underlying diabetes (88).

Human studies testing lowcalorie cranberry juice and unsweetened dried cranberries wereshown to produce favorable acute postprandial glycemic responses in adults with T2D (70,71). However, the limited number of longerterm studies in patients with T2D generateddiscordant outcomes. Shidfar et al. (60) reported that daily cranberry juice consumed for 12wk by 58 male patients with T2D induced significant decreases in fasting blood glucosewhen compared with the placebo group. In contrast, in a trial of 30 patients with T2D, Leeet al. (59) found no impact of daily supplementation with cranberry extracts for 12 wk onfasting blood glucose or glycated hemoglobin. In a diet therapy intervention in 27 adultswith T2D, Chambers and Camire (89) found no significant effect of treatment with cranberryextract on measures of glycemia. However, in 12 healthy volunteers in a randomizedcrossover trial, Törrönen et al. (90) found that a berry puree containing cranberries wasable to delay the postprandial plasma response to sucrose. Clinical trials in patients withmetabolic syndrome have suggested some benefit associated with cranberry interventionbut not specifically on outcomes of glycemic control (62, 72, 91).

Biomarkers of inflammation.

In their analysis of observational data collected from NHANES, Duffey and Sutherland (92,93) found inverse associations of popular polyphenolcontaining beverages, such ascranberry juice, with obesity and inflammation. In their 8wk randomized clinical trial,Novotny et al. (61) showed a reduction in Creactive protein (CRP) after daily consumptionof cranberry juice. In a clinical trial of 56 subjects with metabolic syndrome, Simão et al.(72) reported that daily intake of lowcalorie cranberry juice for 8 wk had no significanteffect on proinflammatory cytokines IL1, IL6, and TNFα but did reduce biomarkers of lipidperoxidation and advanced oxidation protein products. Similarly, in an 8wk study of 36patients with metabolic syndrome, Basu et al. (62) observed increases in plasmabiomarkers of antioxidant capacity and decreases in lipid peroxidation after the dailyconsumption of lowcalorie cranberry juice. These results are consistent with in vitroexperiments showing that cranberry polyphenols decreased the generation of reactiveoxygen species and lipid peroxides and increased glutathione peroxidase activity andphosphocJun Nterminal kinase (94).

Cranberries and Health: Knowledge Gaps

The recent growing body of research on cranberries and health is a part of the emergingevidence from in vitro, animal model, and human studies of plant polyphenols as protectivedietary agents that act both directly and indirectly via their metabolites and/or interactionswith the gut microbiota. Improvements in these research approaches, particularly inanalytical methods as diverse as MS and genesequencing methods for microbialcommunities, are making important contributions to our understanding of polyphenolmechanisms and functions.

However, an important need in cranberry health research is the consistent use of a fullycharacterized SRM to help promote the generation of more readily comparable andreplicable research protocols. SRMs have been available for some other polyphenolrichfoods, including highbush blueberries (95) and California table grapes (96), for in vitro,animal, and human studies. Although SRMs for cranberries have been developed by theNational Institute of Standards and Technology and the Office of Dietary Supplements ofthe NIH, these materials are intended for the validation of analytical methods and qualityassurance for inhouse control materials. Furthermore, these SRMs are not accompaniedby matching placebos for use in research studies. Wide availability of cranberry SRMs insufficient quantities to conduct in vivo human health research remained lacking untilrecently. Because concerns for study accuracy and quality were raised because of thediversity of cranberry products available commercially and in research protocols (97), TheCranberry Institute undertook the development of a cranberry reference material in 2014 toensure the authenticity and consistency of cranberry products used in research on humanhealth.



The first question to be answered was whether the SRM would be developed from wholefruit or one of the many processed forms in which cranberry is consumed. The impact ofprocessing, particularly juicing, on the phytochemical content and profile of freshcranberries has been characterized (98, 99). Grace et al. (100) compared fresh and freezedried cranberries to cranberrycontaining commercial products including juices (fromconcentrate and not from concentrate), sweetened dried cranberries, and cranberry sauces(homemade and commercially canned). Cranberry skins and flesh were crosscomparedfor anthocyanin and proanthocyanidin content. Proanthocyanidins were typically higher inskins than in flesh with the exception of the proanthocyanidin A2 dimer. Anthocyanin andproanthocyanidin concentrations were lower in juice reconstituted from concentrate. Ingeneral, the retention of proanthocyanidins in processed cranberries was found to berobust, whereas anthocyanins were sensitive to degradation. Grace et al. (101) exploredways to better concentrate and stabilize cranberry bioactive compounds via complexingconcentrated juices with proteins isolated from soy, hemp, peanuts, and peas forformulating both beverage and solidfood products. By using an in vitro model to simulatedigestion, Ribnicky et al. (102) were able to show that protein complexes with blueberrypolyphenols remained more intact and bioaccessible than the free bioactive compounds.

To retain and encourage the study of the complete phytochemical profile of cranberry, theSRM is a freezedried wholecranberry powder (FWCP). It is produced from a blend ofcranberry varieties grown in Wisconsin and approximating the proportion available in themarketplace (i.e., 56% Stevens plus 11% each of Ben Lear, Grygleski, Pilgrim, and HyRedvarieties for the first batch produced in 2015). The berries are individually frozen afterharvest, freezedried, and ground into powder form. Silicon dioxide (3% total volume ofpowder) is added as an anticaking agent. The production process is fully documented fromharvest to storage. Each 50 g (0.5 cup) of whole cranberries produces ∼4.5 g FWCP.

Complete specifications for each nutrient and phytochemical ingredient were prepared byusing a series of assays, including matrixassisted laser desorption/ionization timeofflightMS for authentication of proanthocyanidins (103, 104), 4(dimethylamino)cinnamaldehydeassay for quantification of soluble proanthocyanidins (57, 103, 105), and butanolhydrochloric acid for quantification of insoluble proanthocyanidins as well ascharacterization of efficacy via an established in vitro antiadhesion assay andmicrobiological testing.

Accurate quantification of proanthocyanidins for health research is essential but alsoproblematic because proanthocyanidins are complex polydispersed heterooligomers (57).Previously, the procyanidin A2 (ProA2) dimer was recommended as the standard of choicefor proanthocyanidin analysis in the 4(dimethylamino)cinnamaldehyde assay becausecranberry proanthocyanidins contain ≥1 “Atype” interflavan bonds (106). However, currentevidence shows that the use of the ProA2 dimer as a standard for quantification of complexproanthocyanidin oligomers results in a serious underestimation of proanthocyanidins(107). To address this problem, a cranberry proanthocyanidin standard (cPAC), reflectiveof the structural heterogeneity of proanthocyanidins found in fresh cranberry (i.e., DP,hydroxylation pattern, and ratio of A to Btype interflavan bonds), was developed. The useof the cPAC to quantify proanthocyanidin content in FWCP resulted in values that were 3.6times those determined by ProA2. Thus, adoption of this cPAC standard reflects animprovement over the use of ProA2 for the accurate quantification of cranberryproanthocyanidins (105). Because these findings were only recently published, the solubleproanthocyanidin content of the FWCP is reported as both cPAC and ProA2 equivalents,allowing researchers time to adopt the new methodology. The cPAC was also used toquantify the FWCP insoluble proanthocyanidins by the butanolhydrochloric acid method.

The polyphenol content of the FWCP includes the following: 28.35 mg total polyphenols(gallic acid equivalents)/g, 31.20 mg total soluble proanthocyanidins (cPACs)/g, 8.77 mgsoluble proanthocyanidins (ProA2)/g, 10.38 mg insoluble proanthocyanidins (cPACs)/g,5.98 mg anthocyanins (cyanidin3galactoside equivalents)/g, 9.01 mg flavonols (quercetin3rhamnoside equivalents)/g, and 1.81mg hydroxycinnamic acids (caffeic acidequivalents)/g (108). The FWCP processing and packaging facilities are compliant withFDA regulations. A suitable placebo was created from a blend of maltodextrin, citric acid,artificial flavoring, fructose, and foodgrade coloring agents (109). Calcium silicate is addedto the FWCP and placebo as a flow agent.

The use of the FWCP should help overcome some of the critical limitations associated withpast studies that used uncharacterized or only partly characterized cranberry foods orextracts. Recipes for the administration of FWCP and placebo in human studies have beendeveloped and are made freely available to researchers. Like other studies of whole foods,it is recommended that protocols that use the FWCP not apply this material directly to




target tissues, with some possible exceptions such as oral and gastrointestinal cells. In vitroand ex vivo research approaches should consider the use of metabolite(s) on the basis oftheir likely bioavailability to these tissues, an approach not often followed in early studies ofpolyphenolrich foods and extracts. The design of clinical trials that use the FWCP shouldalso be informed by human bioavailability data generated from studies of other cranberryfoods and extracts (Table 3) (110–114), although some consideration should be directed toresults from animal models (115). However, because the product matrices andpharmacokinetic characteristics of these other products will undoubtedly differ, new studieson the absorption, metabolism, and elimination of the bioactive compounds in the FWCPmust be undertaken. Although the availability of the FWCP as an SRM for clinical researchmay help ensure the consistency and full characterization of the cranberry intervention, theneed to perform reasonable doseresponse and timecourse studies for each healthrelatedoutcome remains an important priority, as does the need to develop biomarkers ofcompliance to the intervention.

TABLE 3

Summary of human trialsinvestigating the bioavailability and

pharmacokinetic variables of cranberry1

Summary

Cranberry juice, dried cranberries, and various cranberry extracts have been shown via invitro, animal model, and human studies to possess an array of biochemical and physiologicactivities mediated by their phytochemical constituents. Although the greatest researchfocus has been reasonably placed on their rich content of polyphenols, emerging evidenceof their actions on the gut microbiota and cardiometabolic functions suggests that attentionis also warranted on their synergy with cranberry phenolic acids, isoprenoids, andoligosaccharides. Acting in high concentrations within the gastrointestinal lumen, thesecranberry compounds may act to quench reactive oxygen species, modulate inflammatorypathways, adhere to carbohydrates and proteins on bacterial surfaces, exert prebioticeffects, and alter the dynamic crosstalk between intestinal epithelial cells and the gutmicrobiota. These actions may underlie not only the antimicrobial effects of cranberries buttheir role in the complex pathogenesis of UTIs and inflammatory bowel diseases. Theimportance of these relations beyond the gastrointestinal tract has grown substantially withthe recognition of the broad role that the gut microbiota plays in regulating energyhomeostasis, glucose and lipid metabolism, and systemic inflammation, all factorsassociated with the maintenance of cardiometabolic health.

Further substantiating the actions and mechanisms of cranberry constituents can best beaccomplished by taking advantage of recent advances in cranberry research. For example,efforts to identify biomarkers of compliance to clinical protocols, as well as their relation tophysiologic and health outcomes, may evolve from improved understanding of cranberryconstituents (e.g., the specific nature of proanthocyanidin interflavan bonds and DP, as wellas a more robust phytochemical profile) and the numerous bioactive catabolites arisingfrom the biotransformation of cranberry constituents by the gut microbiota and phase I, II,and III metabolism pathways. Furthermore, a greater degree of accuracy, consistency, andquality of new studies has become possible with the availability of a fully characterizedFWCP and matched placebo as SRMs.

Acknowledgments

JBB and CDT outlined and coedited this article in addition to their contribution to thewriting; JBB, AB, CGK, MAL, CCN, JAN, JDR, ARM, and CDT contributed to the writingand review of the manuscript. All authors read and approved the final manuscript. Weappreciate the excellent moderation of the Cranberry Health Research Conferencepresentations and panel discussions by Amy Howell (Rutgers University), Christina Khoo(Ocean Spray Cranberries, Inc), and the active participation by the panelists: CY OliverChen (Tufts University), André Marette (Université Laval), Yeonwha Park (University ofMassachusetts at Amherst), Navindra Seeram (University of Rhode Island), David Sela(University of Massachusetts at Amherst), and Christine Wu (University of Illinois atChicago).

Footnotes



↵1 Published in a supplement to Advances in Nutrition. Presented at the CranberryHealth Research Conference, held in Madison, Wisconsin, 12 October 2015 andsponsored by the Cranberry Institute (CI), the US Cranberry Marketing Committee(CMC), and the American Cranberry Growers Association. The SupplementCoordinator for this supplement was Cheryl D Toner. Supplement Coordinatordisclosure: Cheryl D Toner is the contracted Health Research Coordinator for the CIand a consultant to the CI and the CMC. Publication costs for this supplement weredefrayed in part by the payment of page charges. This publication must therefore behereby marked “advertisement” in accordance with 18 USC section 1734 solely toindicate this fact. The opinions expressed in this publication are those of the author(s)and are not attributable to the sponsors or the publisher, Editor, or Editorial Board ofAdvances in Nutrition.

↵2 Author disclosures: The Cranberry Institute (CI) provided travel expensereimbursement to all authors and provided an honorarium to each author except for JANovotny and CD Toner. CD Toner is a consultant to the CI and the CMC and formerlyto the Juice Products Association. JB Blumberg is a member of the Scientific AdvisoryBoard of the CI and the CMC and has received research support from the CI andOcean Spray Cranberries, Inc. CG Krueger, JD Reed, and A RodriguezMateos havereceived research support from the CI. JA Novotny has received research supportfrom Ocean Spray Cranberries, Inc.

↵3 This is a free access article, distributed under terms(http://www.nutrition.org/publications/guidelinesandpolicies/license/) that permitunrestricted noncommercial use, distribution, and reproduction in any medium,provided the original work is properly cited.

↵14 Abbreviations used: AIEC, adherentinvasive Escherichia coli; BP, bloodpressure; CAD, coronary artery disease; CEACAM, carcinoembryonic antigenrelatedcell adhesion molecule; CJC, cranberry juice cocktail; cPAC, cranberryproanthocyanidin standard; CRP, Creactive protein; CVD, cardiovascular disease; DP,degree of polymerization; EEN, elemental enteral nutrition; ExPEC, extraintestinalpathogenic Escherichia coli; FimH, protein FimH; FMD, flowmediated vasodilation;FWCP, freezedried wholecranberry powder; Muc2, mucin 2; Nrf2, nuclear factor E2related factor 2; PapG, fimbrial adhesin PapG; ProA2, procyanidin A2; sIgA, secretoryIgA; SRM, standard reference material; STAT6, signal transducers and activators oftranscription 6; Th2, Thelper 2; T2D, type 2 diabetes; UTI, urinary tract infection.

© 2016 American Society for Nutrition

This is a free access article, distributed under terms(http://www.nutrition.org/publications/guidelinesandpolicies/license/) that permitunrestricted noncommercial use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.

References

1. US Department of Health and Human Services; US Department of Agriculture.Scientific report of the 2015 Dietary Guidelines Advisory Committee [Internet]. USDepartment of Health and Human Services; 2015 [cited 2016 Jan 23]. Available from:http://health.gov/dietaryguidelines/2015scientificreport/.

2. Blumberg JB, Camesano TA, Cassidy A, KrisEtherton P, Howell A, Manach C,Ostertag LM, Sies H, SkulasRay A, Vita JA. Cranberries and their bioactiveconstituents in human health. Adv Nutr 2013;4:618–32. Abstract/FREE Full Text

3. Kaspar KL, Howell AB, Khoo C. A randomized, doubleblind, placebocontrolled trialto assess the bacterial antiadhesion effects of cranberry extract beverages. FoodFunct 2015;6:1212–7. Medline Google Scholar

4. Shmuely H, Yahav J, Samra Z, Chodick G, Koren R, Niv Y, Ofek I. Effect of cranberryjuice on eradication of Helicobacter pylori in patients treated with antibiotics and aproton pump inhibitor. Mol Nutr Food Res 2007;51:746–51. CrossRef MedlineGoogle Scholar

5. Zhang L, Ma J, Pan K, Go VLW, Chen J, You W. Efficacy of cranberry juice onHelicobacter pylori infection: a doubleblind, randomized placebocontrolled trial.Helicobacter 2005;10:139–45. CrossRef Medline Google Scholar

6. Shmuely H, Ofek I, Weiss EI, Rones Z, HouriHaddad Y. Cranberry components forthe therapy of infectious disease. Curr Opin Biotechnol 2012;23:148–52. CrossRef



Medline Google Scholar

7. Bodet C, Grenier D, Chandad F, Ofek I, Steinberg D, Weiss EI. Potential oral healthbenefits of cranberry. Crit Rev Food Sci Nutr 2008;48:672–80. CrossRef MedlineGoogle Scholar

8. Feldman M, Grenier D. Cranberry proanthocyanidins act in synergy with licochalconeA to reduce Porphyromonas gingivalis growth and virulence properties, and tosuppress cytokine secretion by macrophages: Synergy between proanthocyanidinsand licochalcone A. J Appl Microbiol 2012;113:438–47. CrossRef MedlineGoogle Scholar

9. LaPlante KL, Sarkisian SA, Woodmansee S, Rowley DC, Seeram NP. Effects ofcranberry extracts on growth and biofilm production of Escherichia coli andStaphylococcus species. Phytother Res 2012;26:1371–4. CrossRef MedlineGoogle Scholar

10. Ulrey RK, Barksdale SM, Zhou W, van Hoek ML. Cranberry proanthocyanidins haveantibiofilm properties against Pseudomonas aeruginosa. BMC Complement AlternMed 2014;14:499–510. Medline Google Scholar

11. Weiss EI, HouriHaddad Y, Greenbaum E, Hochman N, Ofek I, ZakayRones Z.Cranberry juice constituents affect influenza virus adhesion and infectivity. AntiviralRes 2005;66:9–12. CrossRef Medline Google Scholar

12. Patel KD, Scarano FJ, Kondo M, Hurta RAR, Neto CC. Proanthocyanidinrichextracts from cranberry fruit (Vaccinium macrocarpon Ait.) aelectively inhibit thegrowth of human pathogenic fungi Candida spp. and Cryptococcus neoformans. JAgric Food Chem 2011;59:12864–73. CrossRef Medline Google Scholar

13. Rane HS, Bernardo SM, Howell AB, Lee SA. Cranberryderived proanthocyanidinsprevent formation of Candida albicans biofilms in artificial urine through biofilm andadherencespecific mechanisms. J Antimicrob Chemother 2014;69:428–36.Abstract/FREE Full Text

14. Feliciano RP, Krueger CG, Reed JD. Methods to determine effects of cranberryproanthocyanidins on extraintestinal infections: relevance for urinary tract health. MolNutr Food Res 2015;59:1292–306. Medline Google Scholar

15. Feliciano RP, Meudt JJ, Shanmuganayagam D, Krueger CG, Reed JD. Ratio of “Atype” to “Btype” proanthocyanidin interflavan bonds affects extraintestinalpathogenic Escherichia coli invasion of gut epithelial cells. J Agric Food Chem2014;62:3919–25. CrossRef Google Scholar

16. SánchezPatán F, Barroso E, van de Wiele T, JiménezGirón A, MartínAlvarez PJ,MorenoArribas MV, MartínezCuesta MC, Peláez C, Requena T, Bartolomé B.Comparative in vitro fermentations of cranberry and grape seed polyphenols withcolonic microbiota. Food Chem 2015;183:273–82. Medline Google Scholar

17. Ou K, Sarnoski P, Schneider KR, Song K, Khoo C, Gu L. Microbial catabolism ofprocyanidins by human gut microbiota. Mol Nutr Food Res 2014;58:2196–205.Medline Google Scholar

18. Polak D, Naddaf R, Shapira L, Weiss EI, HouriHaddad Y. Protective potential of nondialyzable material fraction of cranberry juice on the virulence of P. gingivalis and F.nucleatum mixed infection. J Periodontol 2013;84:1019–25. CrossRef MedlineGoogle Scholar

19. Kim D, Hwang G, Liu Y, Wang Y, Singh AP, Vorsa N, Koo H. Cranberry flavonoidsmodulate cariogenic properties of mixedspecies biofilm through exopolysaccharidesmatrix disruption. PLOS ONE 2015;10:e0145844. Medline Google Scholar

20. PinzónArango P, Holguin K, Camesano T. Impact of cranberry juice andproanthocyanidins on the ability of Escherichia coli to form biofilms. Food SciBiotechnol 2011;20:1315–21. Google Scholar

21. Sun J, Marais J, Khoo C, LaPlante K, Vejbory R, Givskov M, TolkerNielsen T,Seeram N, Rowley D. Cranberry (Vaccinium macrocarpon) oligosaccharidesdecrease biofilm formation by uropathogenic Escherichia coli. J Funct Foods2015;17:235–42. Medline Google Scholar

22. Hotchkiss AT, Nuñez A, Strahan GD, Chau HK, White AK, Marais JPJ, Hom K,Vakkalanka MS, Di R, Yam KL, et al. Cranberry xyloglucan structure and inhibition ofEscherichia coli adhesion to epithelial cells. J Agric Food Chem 2015;63:5622–33.Google Scholar

23. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. Inhibitory activity of cranberry juice onadherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells.Antimicrob Agents Chemother 1989;33:92–8. Abstract/FREE Full Text

24. PinzónArango PA, Liu Y, Camesano TA. Role of cranberry on bacterial adhesionforces and implications for Escherichia coli–uroepithelial cell attachment. J Med Food2009;12:259–70. CrossRef Medline Google Scholar

25. Signoretto C, Canepari P, Stauder M, Vezzulli L, Pruzzo C. Functional foods andstrategies contrasting bacterial adhesion. Curr Opin Biotechnol 2012;23:160–7.CrossRef Medline Google Scholar

26. Liu Y, Black MA, Caron L, Camesano TA. Role of cranberry juice on molecularscalesurface characteristics and adhesion behavior of Escherichia coli. Biotechnol Bioeng

2006;93:297–305.



2006;93:297–305. CrossRef Medline Google Scholar

27. de Llano DG, EstebanFernández A, SánchezPatán F, Martínlvarez P,MorenoArribas M, Bartolomé B. Antiadhesive activity of cranberry phenoliccompounds and their microbialderived metabolites against uropathogenicEscherichia coli in bladder epithelial cell cultures. Int J Mol Sci 2015;16:12119–30.Medline Google Scholar

28. Pastorelli L, De Salvo C, Mercado JR, Vecchi M, Pizarro TT. Central role of the gutepithelial barrier in the pathogenesis of chronic intestinal inflammation: lessonslearned from animal models and human genetics. Front Immunol [Internet] 2013[cited 2016 Jan 26]. Available from:http://journal.frontiersin.org/article/10.3389/fimmu.2013.00280/abstract.

29. Wong X, CarrascoPozo C, Escobar E, Navarrete P, Blachier F, Andriamihaja M,Lan A, Tomé D, Cires MJ, Pastene E, et al. Deleterious effect of pCresol on humancolonic epithelial cells prevented by proanthocyanidincontaining polyphenol extractsfrom fruits and proanthocyanidin bacterial metabolites. J Agric Food Chem2016;64:3574–83. Google Scholar

30. Johansson MEV, Ambort D, Pelaseyed T, Schütte A, Gustafsson JK, Ermund A,Subramani DB, HolménLarsson JM, Thomsson KA, Bergström JH, et al.Composition and functional role of the mucus layers in the intestine. Cell Mol Life Sci2011;68:3635–41. CrossRef Medline Google Scholar

31. Yusuf S, Nok AJ, Ameh DA, Adelaiye AB, Balogun EO. Quantitative changes ingastric mucosal glycoproteins: effect of cholinergic agonist and vagal nervestimulation in the rat. Neurogastroenterol Motil 2004;16:613–9. CrossRef MedlineGoogle Scholar

32. Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, Fallon R, Smith P,McKenzie ANJ. IL4 induces characteristic Th2 responses even in the combinedabsence of IL5, IL9, and IL13. Immunity 2002;17:7–17. CrossRef MedlineGoogle Scholar

33. Finkelman FD, SheaDonohue T, Goldhill J, Sullivan CA, Morris SC, Madden KB,Gause WC, Urban JF. Cytokine regulation of host defense against parasiticgastrointestinal nematodes: lessons from studies with rodent models. Annu RevImmunol 1997;15:505–33. CrossRef Medline Google Scholar

34. McKenzie GJ, Bancroft A, Grencis RK, McKenzie AN. A distinct role for interleukin13in Th2cellmediated immune responses. Curr Biol 1998;8:339–42. CrossRefMedline Google Scholar

35. Birchenough GMH, Johansson ME, Gustafsson JK, Bergström JH, Hansson GC.New developments in goblet cell mucus secretion and function. Mucosal Immunol2015;8:712–9. CrossRef Medline Google Scholar

36. Pendyala S, Walker JM, Holt PR. A highfat diet is associated with endotoxemia thatoriginates from the gut. Gastroenterology 2012;142:1100–1.e2. CrossRef MedlineGoogle Scholar

37. MartinezMedina M, Denizot J, Dreux N, Robin F, Billard E, Bonnet R,DarfeuilleMichaud A, Barnich N. Western diet induces dysbiosis with increased E coliin CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut2014;63:116–24. Abstract/FREE Full Text

38. Piya MK, Harte AL, McTernan PG. Metabolic endotoxaemia: is it more than just a gutfeeling? Curr Opin Lipidol 2013;24:78–85. CrossRef Medline Google Scholar

39. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R.Changes in gut microbiota control metabolic endotoxemiainduced inflammation inhighfat dietinduced obesity and diabetes in mice. Diabetes 2008;57:1470–81.Abstract/FREE Full Text

40. MartinezMedina M, GarciaGil LJ. Escherichia coli in chronic inflammatory boweldiseases: an update on adherent invasive Escherichia coli pathogenicity. World JGastrointest Pathophysiol 2014;5:213–27. Medline Google Scholar

41. Anhê FF, Roy D, Pilon G, Dudonné S, Matamoros S, Varin T, Garofalo C, Moine Q,Desjardins Y, Levy E, et al. A polyphenolrich cranberry extract protects from dietinduced obesity, insulin resistance and intestinal inflammation in association withincreased Akkermansia spp. population in the gut microbiota of mice. Gut2015;64:872–83. Abstract/FREE Full Text

42. Denis MC, Desjardins Y, Furtos A, Marcil V, Dudonné S, Montoudis A, Garofalo C,Delvin E, Marette A, Levy E. Prevention of oxidative stress, inflammation andmitochondrial dysfunction in the intestine by different cranberry phenolic fractions.Clin Sci 2015;128:197–212. Medline Google Scholar

43. Pierre JF, Heneghan AF, Feliciano RP, Shanmuganayagam D, Krueger CG,Reed JD, Kudsk KA. Cranberry proanthocyanidins improve intestinal sIgA duringelemental enteral nutrition. JPEN J Parenter Enteral Nutr 2014;38:107–14.Abstract/FREE Full Text

44. Pierre JF, Heneghan AF, Feliciano RP, Shanmuganayagam D, Roenneburg DA,Krueger CG, Reed JD, Kudsk KA. Cranberry proanthocyanidins improve the gut

mucous layer morphology and function in mice receiving elemental enteral nutrition.



mucous layer morphology and function in mice receiving elemental enteral nutrition.JPEN Parenter Enteral Nutr 2013;37:401–9. Abstract/FREE Full Text

45. Hermsen JL, Gomez FE, Sano Y, Kang W, Maeshima Y, Kudsk KA. Parenteralfeeding depletes pulmonary lymphocyte populations. JPEN Parenter Enteral Nutr2009;33:535–40. Abstract/FREE Full Text

46. Kudsk KA, Gomez FE, Kang W, Ueno C. Enteral feeding of a chemically defined dietpreserves pulmonary immunity but not intestinal immunity: the role of lymphotoxinbeta receptor. JPEN J Parenter Enteral Nutr 2007;31:477–81.Abstract/FREE Full Text

47. Mosenthal AC, Xu D, Deitch EA. Elemental and intravenous total parenteral nutritiondietinduced gut barrier failure is intestinal site specific and can be prevented byfeeding nonfermentable fiber. Crit Care Med 2002;30:396–402. CrossRef MedlineGoogle Scholar

48. Wu Y, Kudsk KA, DeWitt RC, Tolley EA, Li J. Route and type of nutrition influenceIgAmediating intestinal cytokines. Ann Surg 1999;229:662–7; discussion: 667–8.CrossRef Medline Google Scholar

49. Nantz MP, Rowe CA, Muller C, Creasy R, Colee J, Khoo C, Percival SS.Consumption of cranberry polyphenols enhances human γδT cell proliferation andreduces the number of symptoms associated with colds and influenza: a randomized,placebocontrolled intervention study. Nutr J 2013;12:161–9. CrossRef MedlineGoogle Scholar

50. Diard M, Garry L, Selva M, Mosser T, Denamur E, Matic I. Pathogenicityassociatedislands in extraintestinal pathogenic Escherichia coli are fitness elements involved inintestinal colonization. J Bacteriol 2010;192:4885–93. Abstract/FREE Full Text

51. Johnson JR, Russo TA. Molecular epidemiology of extraintestinal pathogenic(uropathogenic) Escherichia coli. Int J Med Microbiol 2005;295:383–404. CrossRefMedline Google Scholar

52. Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol 2010;7:653–60.CrossRef Medline Google Scholar

53. Pitout JDD. Extraintestinal pathogenic Escherichia coli: a combination of virulencewith antibiotic resistance. Front Microbiol [Internet] 2012 [cited 2016 Jan 26].Available from:http://journal.frontiersin.org/article/10.3389/fmicb.2012.00009/abstract.

54. Mathison BD, Kimble LL, Kaspar KL, Khoo C, Chew BP. Consumption of cranberrybeverage improved endogenous antioxidant status and protected against bacteriaadhesion in healthy humans: a randomized controlled trial. Nutr Res 2014;34:420–7.CrossRef Medline Google Scholar

55. Takahashi S, Takahashi S, Hamasuna R, Yasuda M, Arakawa S, Tanaka K,Ishikawa K, Hayami H, Yamamoto S, Kubo T, et al. A randomized clinical trial toevaluate the preventive effect of cranberry juice (UR65) for patients with recurrenturinary tract infection. J Infect Chemother 2013;19:112–7. CrossRef MedlineGoogle Scholar

56. Foxman B, Cronenwett AEW, Spino C, Berger MB, Morgan DM. Cranberry juicecapsules and urinary tract infection after surgery: results of a randomized trial. Am JObstet Gynecol 2015;213:194.e1–8. Google Scholar

57. Krueger CG, Reed JD, Feliciano RP, Howell AB. Quantifying and characterizingproanthocyanidins in cranberries in relation to urinary tract health. Anal Bioanal Chem2013;405:4385–95. CrossRef Medline Google Scholar

58. RodriguezMateos A, Vauzour D, Krueger CG, Shanmuganayagam D, Reed J, Calani L, Mena P, Del Rio D, Crozier A. Bioavailability, bioactivity and impact on health ofdietary flavonoids and related compounds: an update. Arch Toxicol 2014;88:1803–53.CrossRef Medline Google Scholar

59. Lee IT, Chan YC, Lin CW, Lee WJ, Sheu WHH. Effect of cranberry extracts on lipidprofiles in subjects with type 2 diabetes. Diabet Med 2008;25:1473–7. CrossRefMedline Google Scholar

60. Shidfar F, Heydari I, Hajimiresmaiel SJ, Hosseini S, Shidfar S, Amiri F. The effects ofcranberry juice on serum glucose, apoB, apoAI, Lp(a), and Paraoxonase1 activity intype 2 diabetic male patients. J Res Med Sci 2012;17:355–60. MedlineGoogle Scholar

61. Novotny JA, Baer DJ, Khoo C, Gebauer SK, Charron CS. Cranberry juiceconsumption lowers markers of cardiometabolic risk, including blood pressure andcirculating Creactive protein, triglyceride, and glucose concentrations in adults. JNutr 2015;145:1185–93. Abstract/FREE Full Text

62. Basu A, Betts NM, Ortiz J, Simmons B, Wu M, Lyons TJ. Lowenergy cranberry juicedecreases lipid oxidation and increases plasma antioxidant capacity in women withmetabolic syndrome. Nutr Res 2011;31:190–6. CrossRef Medline Google Scholar

63. Dohadwala MM, Holbrook M, Hamburg NM, Shenouda SM, Chung WB, Titas M,Kluge MA, Wang N, Palmisano J, Milbury PE, et al. Effects of cranberry juiceconsumption on vascular function in patients with coronary artery disease. Am J ClinNutr 2011;93:934–40. Abstract/FREE Full Text



64. Flammer AJ, Martin EA, Gössl M, Widmer RJ, Lennon RJ, Sexton JA, Loeffler D,Khosla S, Lerman LO, Lerman A. Polyphenolrich cranberry juice has a neutral effecton endothelial function but decreases the fraction of osteocalcinexpressingendothelial progenitor cells. Eur J Nutr 2013;52:289–96. CrossRef MedlineGoogle Scholar

65. Ruel G, Lapointe A, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C.Evidence that cranberry juice may improve augmentation index in overweight men.Nutr Res 2013;33:41–9. CrossRef Medline Google Scholar

66. Ruel G, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C. Favourableimpact of lowcalorie cranberry juice consumption on plasma HDLcholesterolconcentrations in men. Br J Nutr 2006;96:357–64. CrossRef MedlineGoogle Scholar

67. Ruel G, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C. Lowcaloriecranberry juice supplementation reduces plasma oxidized LDL and cell adhesionmolecule concentrations in men. Br J Nutr 2008;99:352–9. Medline Google Scholar

68. Ruel G, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C. Plasmamatrix metalloproteinase (MMP)9 levels are reduced following lowcalorie cranberryjuice supplementation in men. J Am Coll Nutr 2009;28:694–701. CrossRef MedlineGoogle Scholar

69. Ruel G, Pomerleau S, Couture P, Lamarche B, Couillard C. Changes in plasmaantioxidant capacity and oxidized lowdensity lipoprotein levels in men after shortterm cranberry juice consumption. Metabolism 2005;54:856–61. CrossRef MedlineGoogle Scholar

70. Wilson T, Meyers SL, Singh AP, Limburg PJ, Vorsa N. Favorable glycemic responseof type 2 diabetics to lowcalorie cranberry juice. J Food Sci 2008;73:H241–5.CrossRef Medline Google Scholar

71. Wilson T, Luebke JL, Morcomb EF, Carrell EJ, Leveranz MC, Kobs L, Schmidt TP,Limburg PJ, Vorsa N, Singh AP. Glycemic responses to sweetened dried and rawcranberries in humans with type 2 diabetes. J Food Sci 2010;75:H218–23.CrossRef Medline Google Scholar

72. Simão TNC, Lozovoy MAB, Simão ANC, Oliveira SR, Venturini D, Morimoto HK,Miglioranza LHS, Dichi I. Reducedenergy cranberry juice increases folic acid andadiponectin and reduces homocysteine and oxidative stress in patients with themetabolic syndrome. Br J Nutr 2013;110:1885–94. Medline Google Scholar

73. RodriguezMateos A, Heiss C, Borges G, Crozier A. Berry (poly)phenols andcardiovascular health. J Agric Food Chem 2014;62:3842–51. Google Scholar

74. Kim MJ, Ohn J, Kim JH, Kwak HK. Effects of freezedried cranberry powder onserum lipids and inflammatory markers in lipopolysaccharide treated rats fed anatherogenic diet. Nutr Res Pract 2011;5:404–11. CrossRef MedlineGoogle Scholar

75. Kim MJ, Chung JY, Kim JH, Kwak HK. Effects of cranberry powder on biomarkers ofoxidative stress and glucose control in db/db mice. Nutr Res Pract 2013;7:430–8.CrossRef Medline Google Scholar

76. Kim MJ, Kim JH, Kwak HK. Antioxidant effects of cranberry powder inlipopolysaccharide treated hypercholesterolemic rats. Prev Nutr Food Sci2014;19:75–81. Medline Google Scholar

77. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA,Deanfield J, Drexler H, GerhardHerman M, Herrington D, et al. Guidelines for theultrasound assessment of endothelialdependent flowmediated vasodilation of thebrachial artery: a report of the International Brachial Artery Reactivity Task Force. JAm Coll Cardiol 2002;39:257–65. Medline Google Scholar

78. Feliciano RP, Boeres A, Massaccesi L, Istas G, Ventura R, Nunes dos Santos C,Heiss C, RodriguezMateos A. Identification and quantification of novel cranberryderived plasma and urinary (poly)phenols. Arch Biochem Biophys . In press.Google Scholar

79. RodriguezMateos A, Feliciano RP, Boeres A, Weber T, Dos Santos CN, Ventura MR,Heiss C. Cranberry (poly)phenol metabolites correlate with improvements in vascularfunction: A doubleblind, randomized, controlled, doseresponse, crossover study.Mol Nutr Food Res 2016. (Epub ahead of print; DOI: 10.1002/mnfr.201600250).Google Scholar

80. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular eventsand allcause mortality with arterial stiffness. J Am Coll Cardiol 2010;55:1318–27.CrossRef Medline Google Scholar

81. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, StruijkerBoudier H, et al. Expert consensusdocument on arterial stiffness: methodological issues and clinical applications. EurHeart J 2006;27:2588–605. Abstract/FREE Full Text

82. Nürnberger J, KefliogluScheiber A, Opazo Saez AM, Wenzel RR, Philipp T, Schäfers RF. Augmentation index is associated with cardiovascular risk. J Hypertens2002;20:2407–14. CrossRef Medline Google Scholar



83. McDougall GJ, Kulkarni NN, Stewart D. Current developments on the inhibitoryeffects of berry polyphenols on digestive enzymes. Biofactors 2008;34:73–80.Medline Google Scholar

84. Hanhineva K, Törrönen R, BondiaPons I, Pekkinen J, Kolehmainen M, Mykkänen H,Poutanen K. Impact of dietary polyphenols on carbohydrate metabolism. Int J Mol Sci2010;11:1365–402. CrossRef Medline Google Scholar

85. Pinto M da S, Ghaedian R, Shinde R, Shetty K. Potential of cranberry powder formanagement of hyperglycemia using in vitro models. J Med Food 2010;13:1036–44.Medline Google Scholar

86. Bozzetto L, Annuzzi G, Pacini G, Costabile G, Vetrani C, Vitale M, Griffo E, Giacco A,De Natale C, Cocozza S, et al. Polyphenolrich diets improve glucose metabolism inpeople at high cardiometabolic risk: a controlled randomised intervention trial.Diabetologia 2015;58:1551–60. Medline Google Scholar

87. Dragan S, Andrica F, Serban MC, Timar R. Polyphenolsrich natural products fortreatment of diabetes. Curr Med Chem 2015;22:14–22. Medline Google Scholar

88. Hartstra AV, Bouter KEC, Bäckhed F, Nieuwdorp M. Insights into the role of themicrobiome in obesity and type 2 diabetes. Diabetes Care 2015;38:159–65.Abstract/FREE Full Text

89. Chambers BK, Camire ME. Can cranberry supplementation benefit adults with type 2diabetes? Diabetes Care 2003;26:2695–6. FREE Full Text

90. Törrönen R, Sarkkinen E, Tapola N, Hautaniemi E, Kilpi K, Niskanen L. Berriesmodify the postprandial plasma glucose response to sucrose in healthy subjects. Br JNutr 2010;103:1094–7. Medline Google Scholar

91. Basu A, Lyons TJ. Strawberries, blueberries, and cranberries in the metabolicsyndrome: clinical perspectives. J Agric Food Chem 2012;60:5687–92. CrossRefGoogle Scholar

92. Duffey KJ, Sutherland L. Adult cranberry beverage consumers have healthiermacronutrient intakes and measures of body composition compared to nonconsumers: National Health and Nutrition Examination Survey (NHANES) 2005–2008. Nutrients 2013;5:4938–49. CrossRef Medline Google Scholar

93. Duffey KJ, Sutherland LA. Adult consumers of cranberry juice cocktail have lower Creactive protein levels compared with nonconsumers. Nutr Res 2015;35:118–26.CrossRef Medline Google Scholar

94. Martín MA, Ramos S, Mateos R, Marais JPJ, BravoClemente L, Khoo C, Goya L.Chemical characterization and chemoprotective activity of cranberry phenolicpowders in a model cell culture: response of the antioxidant defenses and regulationof signaling pathways. Food Res Int 2015;71:68–82. CrossRef Google Scholar

95. US Highbush Blueberry Council. USHBC blueberry placebo and blueberry powderpolicy [Internet]. US Highbush Blueberry Council; 2010. [cited 2016 Feb 24]. Availablefrom: http://www.blueberry.org/research/research2010/researchpolicy2010.pdf.

96. California Table Grape Commission. Guidelines for use of California grape powder inresearch studies [Internet]. California Table Grape Commission; 2015. [cited 2016Feb 24]. Available from:http://www.grapesfromcalifornia.com/docs/Grape_Powder_Usage_Guidelines_10–21–15.pdf.

97. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections.Cochrane Database Syst Rev [Internet] 2012 [cited 2016 Jan 26]. Available from:http://doi.wiley.com/10.1002/14651858.CD001321.pub5.

98. Pappas E, Schaich KM. Phytochemicals of cranberries and cranberry products:characterization, potential health effects, and processing stability. Crit Rev Food SciNutr 2009;49:741–81. CrossRef Medline Google Scholar

99. White BL, Howard LR, Prior RL. Impact of different stages of juice processing on theanthocyanin, flavonol, and procyanidin contents of cranberries. J Agric Food Chem2011;59:4692–8. CrossRef Medline Google Scholar

100. Grace MH, Massey AR, Mbeunkui F, Yousef GG, Lila MA. Comparison of healthrelevant flavonoids in commonly consumed cranberry products. J Food Sci2012;77:H176–83. CrossRef Medline Google Scholar

101. Grace MH, Guzman I, Roopchand DE, Moskal K, Cheng DM, Pogrebnyak N,Raskin I, Howell A, Lila MA. Stable binding of alternative proteinenriched foodmatrices with concentrated cranberry bioflavonoids for functional food applications. JAgric Food Chem 2013;61:6856–64. Google Scholar

102. Ribnicky DM, Roopchand DE, Oren A, Grace M, Poulev A, Lila MA, Havenaar R,Raskin I. Effects of a high fat meal matrix and protein complexation on thebioaccessibility of blueberry anthocyanins using the TNO gastrointestinal model (TIM1). Food Chem 2014;142:349–57. CrossRef Medline Google Scholar

103. Feliciano RP, Krueger CG, Shanmuganayagam D, Vestling MM, Reed JD.Deconvolution of matrixassisted laser desorption/ionization timeofflight massspectrometry isotope patterns to determine ratios of Atype to Btype interflavan

bonds in cranberry proanthocyanidins. Food Chem 2012;135:1485–93.



bonds in cranberry proanthocyanidins. Food Chem 2012;135:1485–93. CrossRefMedline Google Scholar

104. Reed JD, Krueger CG, Vestling MM. MALDITOF mass spectrometry of oligomericfood polyphenols. Phytochemistry 2005;66:2248–63. CrossRef MedlineGoogle Scholar

105. Krueger CG, Chesmore N, Chen X, Parker J, Khoo C, Marais JPJ,Shanmuganayagam D, Crump P, Reed JD. Critical reevaluation of the 4(dimethylamino)cinnamaldehyde assay: cranberry proanthocyanidin standard issuperior to procyanidin A2 dimer for accurate quantification of proanthocyanidins incranberry products. J Funct Foods 2016;22:13–9. CrossRef Google Scholar

106. Prior RL, Fan E, Ji H, Howell A, Nio C, Payne MJ, Reed J. Multilaboratory validationof a standard method for quantifying proanthocyanidins in cranberry powders. J SciFood Agric 2010;90:1473–8. CrossRef Medline Google Scholar

107. Feliciano RP, Shea MP, Shanmuganayagam D, Krueger CG, Howell AB, Reed JD.Comparison of isolated cranberry (Vaccinium macrocarpon Ait.) proanthocyanidins tocatechin and procyanidins A2 and B2 for use as standards in the 4(dimethylamino)cinnamaldehyde assay. J Agric Food Chem 2012;60:4578–85.CrossRef Medline Google Scholar

108. The Cranberry Institute. Freezedried whole cranberry powder [Internet]. TheCranberry Institute; 2015. [cited 2016 Feb 24]. Available from:http://www.cranberryinstitute.org/health_research/FWCP%20Specifications%20Sheet%2010%201%2015.pdf.

109. The Cranberry Institute. Placebo for freezedried whole cranberry powder [Internet].The Cranberry Institute; 2015. [cited 2016 Feb 24]. Available from:http://www.cranberryinstitute.org/health_research/FWCP%20Placebo%20Specifications%20Sheet%2010%201%2015.pdf.

110. Zhang K, Zuo Y. GCMS determination of flavonoids and phenolic and benzoic acidsin human plasma after consumption of cranberry juice. J Agric Food Chem2004;52:222–7. CrossRef Medline Google Scholar

111. Milbury PE, Vita JA, Blumberg JB. Anthocyanins are bioavailable in humans followingan acute dose of cranberry juice. J Nutr 2010;140:1099–104.Abstract/FREE Full Text

112. Iswaldi I, ArráezRomán D, GómezCaravaca AM, Contreras M del M, Uberos J,SeguraCarretero A, FernándezGutiérrez A. Identification of polyphenols and theirmetabolites in human urine after cranberrysyrup consumption. Food Chem Toxicol2013;55:484–92. Medline Google Scholar

113. McKay DL, Chen CYO, Zampariello CA, Blumberg JB. Flavonoids and phenolicacids from cranberry juice are bioavailable and bioactive in healthy older adults. FoodChem 2015;168:233–40. CrossRef Medline Google Scholar

114. Walsh JM, Ren X, Zampariello C, Polasky DA, McKay DL, Blumberg JB, Chen CYO.Liquid chromatography with tandem mass spectrometry quantification of urinaryproanthocyanin A2 dimer and its potential use as a biomarker of cranberry intake:liquid chromatography. J Sep Sci 2016;39:342–9. Medline Google Scholar

115. Liu H, Garrett TJ, Tayyari F, Gu L. Profiling the metabolome changes caused bycranberry procyanidins in plasma of female rats using (1) H NMR and UHPLCQOrbitrapHRMS global metabolomics approaches. Mol Nutr Food Res 2015;59:2107–18. Medline Google Scholar

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