Presented By Duquesne Marilyn Belgium Presented By Duquesne Marilyn Belgium 3 rd International Conference and Exhibition on Traditional & Alternative Medicine

Presented ByDuquesne MarilynBelgium

3rd International Conference and Exhibition on Traditional & Alternative Medicine

August 03-05, 2015 Birmingham, UK

In Association with

Introduction

Purpose of the

research

Method

Results

Conclusion

Herbal remedies : Natural but not unhazardous

Study cases of Aristolochic Acid intoxication

Introduction

Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 2

Common term

Mixture of :

Aristolochic Acid I (AAI) Aristolochic Acid II (AAII)

&

nitrophenantrene carboxylic acid derivatives

What’s Aristolochic Acid ?


Produced by :

Aristolochia Asarum

www.fr-academic.ru

Bragantia

www.afleurdepau.com etc.usf.edu

What’s Aristolochic Acid ?

Aristolochiaceae


found in :

>> >

What’s Aristolochic Acid ?Medicinal properties of Aristolochia

Rhizomes : - Gastric stimulant- Fevers treatment- Malaria

Roots:- Type 2 diabetes- Snakebites

Leaves : - Skin disorders- Dyspepsia - Leishmania

Stems:- Anti-inflammatory- Diuretic- Circulation stimulating

Fruits : - Respiratory diseases- Skin wounds- Malaria

Seeds:- Biliousness- Abdominal pain

Flowers : - Diuretic- Hypoglycaemic effect


Aristolochic acid toxicity


Tubular atrophy

Interstitial fibrosis

Low molecular weight proteinuria

I) Nephrotoxicity


I) Nephrotoxicity


II) Carcinogenicity Induced by metabolisation of AA

Aristolochic acid I/IIAristolactam nitronium ion

R

NQO1CYP1A1CYP1A2

NQO1COXCPR

R


Jean-Marie COLET

est-ce bien nitrium ion pas nitronium??

II) Carcinogenicity

Properties of AA-DNA adducts

Cortex

Medulla

Localisation: Responsible for:

TP53


TP53

Histochemistry

Genomic Proteomic

Metabonomic

α-1µglob.β-2µglob.

α-2 glycoprot.

INVASIVE METHOD

+

- NON INVASIVEMETHOD

INVASIVE METHOD


- EARLY !!

- LATE


Balkan Endemic Nephropathy (BEN)

Chronic Kidney disease

13

Pr. Grollman (thepoisongarden.co.uk)

Etiology: Dietary intoxication

Diseased or suspects : 25000

At risks : >100000


Purpose of research

Metabonomic

Mechanism of toxicity

Exposure

AbsorptionDistributionmetabolism

Primary target

Target cell damage

Target organ

Damage to organism

Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Purpose of research 13

BEN

Metabonomic procedure

Method :

Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Method 14

What’s Metabonomic ?

Metabolites portrait

Mass spectro-metry

NMR

Temporal changes


Samples collection

& preparation

4°C

Antibacterial

Phosphate buffer

External Reference (TSP)




Spectroscopic analysis

NMR

Proton

electron

Magnetic field

Z

Y

X

O

Bo

RFTime

Intensity

Fourier transform

Frequency



Spectrum treatment &Multivariate analysis


PC1

PC2

SCORES plot

PC1

PC23.40

2.501.24

3.80

5.703.24 0.80

Observations Variables

PC1

LOADINGS plot



Spectrum treatment &Multivariate analysis

Biological interpretation



Acute toxicity Chronic toxicity

- Diseased - Suspects- At risks

Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results 20

Results

Physiological data AAI AAI/AAII AAI AAI/AAII AAI AAI/AAII

Body Weight

Food intake

Water intake

Urinary volume

+ +

N.D

+

+ +

- -

-

+

+ +

+

N.D

+

+ +

- - -

- -

-

N.D

-

-

- - +

+ +

- - - -

- - -

- -

+

Clinical chemistry AAI AAI/AAII AAI AAI/AAII AAI AAI/AAII

BUN

Sr. Creatinine

Albumin

≠

≠

≠

+ + +

++≠

+ +

+≠

+ + + +

+++≠

+ +

+≠

+ + + +

+++≠

50mg/kg 75mg/kg 100mg/kg

↘

Polyuria

↗↗ ↗

75 100

AAII

- - - - -

- - - -

- - - - -

- - - -

+ + + +

+++≠

+ + + +

+ + +≠

Toxicity : AAI < AAI/AAII ? AAII ?

Results AA acute toxicity

I) Physiological Parameters

AAI AAI/AAII AAI AAI/AAII AAI AAI/AAII

Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Acute toxicity (rats) 21

A 50 mg/kg AAIB 75 mg/kg AAIC 100 mg/kg AAID 50 mg/kg AAI/AAIIE 75 mg/kg AAI/AAIIF 100 mg/kg AAI/AAII


I) Metabonomic results


Hippurate

GlucoseBetaine

Osmoprotectants Lactate & acetate


I) Metabonomic results


↘ Hippurate

↗ Glucose

GlomerulusProximal

tubuleDistaltubule

↘ Cycle Krebs components

↗ Osmoprotectants

↗ Betaine ↗ Lactate & acetate



Cortex

Medulla

↗↗ Bun↗ Ser. Creat.


↗ Nitrogenous waste in blood↗ Osmoprotectants in urine

Plasma

↘ Reabs. Glucose

AAHippurate



OAT1 ↘ Hippurate

Deficient cycle Krebs


Metabonomic profile reflecting the severity of renal damage in proximal tubules and/or interstitial tissue:

Psihogios, N ; Kalaitzidis, R ; Dimou, S ; Seferiadis,K ; Siamopoulos, K ; and Bairaktari, E. Evaluation of Tubulointerstitial lesions severity in patients with glomerulonephritides : An NMR-based metabonomic study . J.Proteome Res. 2007, 6, 3760-3770

Results AA chronic toxicity

Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Chronic toxicity ( Humans) 26

Creatinine filtration : VHippurate secretion : VGlucose reabsorption : V

Creatinine filtration : XHippurate secretion: XGlucose reabsorption : X

Metabonomic profile : Healthy

Creatinine filtration : XHippurate secretion : XGlucose reabsorption : V

Metabonomic profile:Moderate renal injury

Metabonomic profile:Severe renal injury

Metabonomic comparison diseased, suspects, at risks, others , NEN with Belgium control samples.

Metabonomics: on the Road to Detect Diagnostic Biomarkers in Endemic (Balkan) Nephropathy. Evaluation in a Retrospective Pilot Project. Duquesne et al., J Cancer Sci Ther 2012



HealthyModerate renal injurySevere renal injury

Comparison of the different metabonomic profiles : healthy , moderale and severe renal injury

Renal damage severity



Perspectives & Conclusions

Acute toxicity model

Chronic toxicity model

In process

Metabolites identification : early & easily biomarkers ( ↗ Glucose, betaine, osmoprotectants ; ↘ hippurate, cycle Krebs components )

New samples

BEN

Biological hypotheses ( renal functions, transport injuries,…)

Perspectives & Conclusion

Metabonomic


- EARLY Biomarkers

Lab. Human Biology & ToxicologyUMONS (Belgium)

High possibility of human AA intoxication cases !!

Preventive action

Duquesne MarilynPhD student

Human Biology & Toxicology laboratoryUniversity of Mons(Belgium)

Profile : Familial history

Proteinuria : ACR, alpha-1

Azotemia (serum

creatinine)

anemia 15 years in EN

Diseased v v v v

v v v v

v v v v

Suspects v v

v v

At risks v

Others : x x x x

http://biology-igcse.weebly.com/dialysis.htmlhttp://www.nuhospitals.com/renal-kidney-transplant.html

https://sites.google.com/a/montessori.edu.co/biology-projects/dna-vocabulary-2/_draft_post-12http://www.medicinenet.com/kidney_infection/article.htm

http://carcin.oxfordjournals.org/content/24/10/1695/F1.large.jpghttp://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=&

url=http%3A%2F%2Fwww.ayurvedindia.in%2FOthers%2FLiver-Disorders%2F961&ei=inE3VeL7GdbsaMyxgYAE&psig=AFQjCNFvJDXErveYz2GG_VmWaQIoHQKqeA&ust=1429783307048964

https://www.flickr.com/photos/14179358@N05/3678083407/

WWW.stjude.comtutocours.fr

www.michigananimalhospital.comwww.vcahospitals.com

www.riversideonline.comwww.mhhe.com

hyperphysics.phy-astr.gsu.edu

Herbal remedies : natural but unhazardous. Study cases of AA intoxication ; Introduction

http://biology-igcse.weebly.com/dialysis.html

http://www.nuhospitals.com/renal-kidney-transplant.html

https://sites.google.com/a/montessori.edu.co/biology-projects/dna-vocabulary-2/_draft_post-12

http://carcin.oxfordjournals.org/content/24/10/1695/F1.large.jpg

http://carcin.oxfordjournals.org/content/24/10/1695/F1.large.jpg

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=&url=http://www.ayurvedindia.in/Others/Liver-Disorders/961&ei=inE3VeL7GdbsaMyxgYAE&psig=AFQjCNFvJDXErveYz2GG_VmWaQIoHQKqeA&ust=1429783307048964



http://www.stjude.com/

http://www.michigananimalhospital.com/

http://www.vcahospitals.com/main/pet-health-information/article/animal-health/serum-electrolytes/369

http://www.riversideonline.com/

http://www.mhhe.com/

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=0CAYQjB0&url=http://hyperphysics.phy-astr.gsu.edu/hbase/nuclear/nmr.html&ei=cJ5AVfPGCo_paMKkgPgC&psig=AFQjCNEzJgPUs81Ajj-JdlXhLC-Ys8x5HA&ust=1430384613820089

Traditional Medicine-2016Website: http://traditionalmedicine.conferenceseries.com/

Meet the eminent gathering once again at

Traditional Medicine-2016London, UK

October 03-05, 2016

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Presented By Duquesne Marilyn Belgium Presented By Duquesne Marilyn Belgium 3 rd International Conference and Exhibition on Traditional & Alternative Medicine