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Presented ByDuquesne MarilynBelgium
3rd International Conference and Exhibition on Traditional & Alternative Medicine
August 03-05, 2015 Birmingham, UK
In Association with
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Introduction
Purpose of the
research
Method
Results
Conclusion
Herbal remedies : Natural but not unhazardous
Study cases of Aristolochic Acid intoxication
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Introduction
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 2
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Common term
Mixture of :
Aristolochic Acid I (AAI) Aristolochic Acid II (AAII)
&
nitrophenantrene carboxylic acid derivatives
What’s Aristolochic Acid ?
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 3
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Produced by :
Aristolochia Asarum
www.fr-academic.ru
Bragantia
www.afleurdepau.com etc.usf.edu
What’s Aristolochic Acid ?
Aristolochiaceae
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 4
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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
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 5
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Aristolochic acid toxicity
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 6
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Tubular atrophy
Interstitial fibrosis
Low molecular weight proteinuria
I) Nephrotoxicity
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 7
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I) Nephrotoxicity
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 8
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II) Carcinogenicity Induced by metabolisation of AA
Aristolochic acid I/IIAristolactam nitronium ion
R
NQO1CYP1A1CYP1A2
NQO1COXCPR
R
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 9
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II) Carcinogenicity
Properties of AA-DNA adducts
Cortex
Medulla
Localisation: Responsible for:
TP53
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 10
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TP53
Histochemistry
Genomic Proteomic
Metabonomic
α-1µglob.β-2µglob.
α-2 glycoprot.
INVASIVE METHOD
+
- NON INVASIVEMETHOD
INVASIVE METHOD
- NON INVASIVEMETHOD
- EARLY !!
- LATE
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 11
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Balkan Endemic Nephropathy (BEN)
Chronic Kidney disease
13
Pr. Grollman (thepoisongarden.co.uk)
Etiology: Dietary intoxication
Diseased or suspects : 25000
At risks : >100000
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Introduction 12
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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
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Metabonomic procedure
Method :
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Method 14
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What’s Metabonomic ?
Metabolites portrait
Mass spectro-metry
NMR
Temporal changes
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Method 15
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Samples collection
& preparation
4°C
Antibacterial
Phosphate buffer
External Reference (TSP)
Metabonomic procedure
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Method 16
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Metabonomic procedure
Spectroscopic analysis
NMR
Proton
electron
Magnetic field
Z
Y
X
O
Bo
RFTime
Intensity
Fourier transform
Frequency
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Method 17
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Spectroscopic analysis
Spectrum treatment &Multivariate analysis
Metabonomic procedure
PC1
PC2
SCORES plot
PC1
PC23.40
2.501.24
3.80
5.703.24 0.80
Observations Variables
PC1
LOADINGS plot
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Method 18
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Spectroscopic analysis
Spectrum treatment &Multivariate analysis
Biological interpretation
Metabonomic procedure
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication; Method 19
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Acute toxicity Chronic toxicity
- Diseased - Suspects- At risks
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results 20
Results
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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
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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
Results AA acute toxicity
I) Metabonomic results
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Acute toxicity (rats) 22
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Hippurate
GlucoseBetaine
Osmoprotectants Lactate & acetate
Results AA acute toxicity
I) Metabonomic results
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Acute toxicity (rats) 23
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↘ Hippurate
↗ Glucose
GlomerulusProximal
tubuleDistaltubule
↘ Cycle Krebs components
↗ Osmoprotectants
↗ Betaine ↗ Lactate & acetate
Results AA acute toxicity
Biological interpretation
Cortex
Medulla
↗↗ Bun↗ Ser. Creat.
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Acute toxicity (rats) 24
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↗ Nitrogenous waste in blood↗ Osmoprotectants in urine
Plasma
↘ Reabs. Glucose
AAHippurate
Results AA acute toxicity
Biological interpretation
OAT1 ↘ Hippurate
Deficient cycle Krebs
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Acute toxicity (rats) 25
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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
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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
Results AA chronic toxicity
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Chronic toxicity ( Humans) 27
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HealthyModerate renal injurySevere renal injury
Comparison of the different metabonomic profiles : healthy , moderale and severe renal injury
Renal damage severity
Results AA chronic toxicity
Herbal remedies : natural but not unhazardous. Study cases of AA intoxication Results : Chronic toxicity ( Humans) 28
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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,…)
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Perspectives & Conclusion
Metabonomic
- NON INVASIVEMETHOD
- EARLY Biomarkers
Lab. Human Biology & ToxicologyUMONS (Belgium)
High possibility of human AA intoxication cases !!
Preventive action
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Duquesne MarilynPhD student
Human Biology & Toxicology laboratoryUniversity of Mons(Belgium)
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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
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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
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Traditional Medicine-2016Website: http://traditionalmedicine.conferenceseries.com/
Meet the eminent gathering once again at
Traditional Medicine-2016London, UK
October 03-05, 2016