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Jean-pierre Cosyns - One of the best experts on this subject based on the ideXlab platform.

  • Aristolochic Acid and ‘Chinese Herbs Nephropathy’
    Drug Safety, 2003
    Co-Authors: Jean-pierre Cosyns
    Abstract:

    Chinese Herbs nephropathy (CHN) is a rapidly progressive interstitial nephropathy reported after the introduction of Chinese Herbs in a slimming regimen followed by young Belgian women. It is characterised by early, severe anaemia, mild tubular proteinuria and initially normal arterial blood pressure in half of the patients. Renal histology shows unusual extensive, virtually hypocellular cortical interstitial fibrosis associated with tubular atrophy and global sclerosis of glomeruli decreasing from the outer to the inner cortex. Urothelial malignancy of the upper urinary tract develops subsequently in almost half of the patients. Suspicion that the disease was due to the recent introduction of Chinese Herbs in the slimming regimen was reinforced by identification in the slimming pills of the nephrotoxic and carcinogenic aristolochic acid (AA) extracted from species of Aristolochia. This hypothesis was substantiated by the identification of premutagenic AA-DNA adducts in the kidney and ureteric tissues of CHN patients. Finally, induction of the clinical features (interstitial fibrosis and upper urothelial malignancy) typical of CHN in rodents given AA alone removed any doubt on the causal role of this phytotoxin in CHN, now better called aristolochic acid nephropathy (AAN). AAN is not restricted to the Belgian cases. Similar cases have been observed throughout the world, but AA is sometimes incriminated on the basis of the known content of AA in the Herbs. The possibility remains that in some individuals in whom AA has not been demonstrated, other phytotoxins might be implicated. Biological and morphological features of AAN are strikingly similar to those reported in another fibrosing interstitial nephropathy of still unknown aetiology, Balkan endemic nephropathy (BEN). Interestingly, AA was incriminated as the cause of BEN many years ago, a hypothesis yet to be fully explored. The intake of AA and the presence of tissular AA-DNA adducts in patients with an unequivocal diagnosis of BEN remains to be demonstrated. The tragic phenomenon of CHN, recognised only 10 years ago, has been at the root of significant research and progress both in nephrology and oncology. It has provided a fascinating opportunity to understand the link between a fibrosing interstitial nephropathy and urothelial carcinoma. It allows the categorisation of interstitial nephritis on the basis of histological findings, of initiating toxic substances and of associated clinical features. Finally, it has led to the withdrawal in several countries of a previously unsuspected carcinogenic and nephrotoxic substance.

  • aristolochic acid and Chinese Herbs nephropathy a review of the evidence to date
    Drug Safety, 2003
    Co-Authors: Jean-pierre Cosyns
    Abstract:

    Chinese Herbs nephropathy (CHN) is a rapidly progressive interstitial nephropathy reported after the introduction of Chinese Herbs in a slimming regimen followed by young Belgian women. It is characterised by early, severe anaemia, mild tubular proteinuria and initially normal arterial blood pressure in half of the patients. Renal histology shows unusual extensive, virtually hypocellular cortical interstitial fibrosis associated with tubular atrophy and global sclerosis of glomeruli decreasing from the outer to the inner cortex. Urothelial malignancy of the upper urinary tract develops subsequently in almost half of the patients. Suspicion that the disease was due to the recent introduction of Chinese Herbs in the slimming regimen was reinforced by identification in the slimming pills of the nephrotoxic and carcinogenic aristolochic acid (AA) extracted from species of Aristolochia. This hypothesis was substantiated by the identification of premutagenic AA-DNA adducts in the kidney and ureteric tissues of CHN patients. Finally, induction of the clinical features (interstitial fibrosis and upper urothelial malignancy) typical of CHN in rodents given AA alone removed any doubt on the causal role of this phytotoxin in CHN, now better called aristolochic acid nephropathy (AAN). AAN is not restricted to the Belgian cases. Similar cases have been observed throughout the world, but AA is sometimes incriminated on the basis of the known content of AA in the Herbs. The possibility remains that in some individuals in whom AA has not been demonstrated, other phytotoxins might be implicated. Biological and morphological features of AAN are strikingly similar to those reported in another fibrosing interstitial nephropathy of still unknown aetiology, Balkan endemic nephropathy (BEN). Interestingly, AA was incriminated as the cause of BEN many years ago, a hypothesis yet to be fully explored. The intake of AA and the presence of tissular AA-DNA adducts in patients with an unequivocal diagnosis of BEN remains to be demonstrated. The tragic phenomenon of CHN, recognised only 10 years ago, has been at the root of significant research and progress both in nephrology and oncology. It has provided a fascinating opportunity to understand the link between a fibrosing interstitial nephropathy and urothelial carcinoma. It allows the categorisation of interstitial nephritis on the basis of histological findings, of initiating toxic substances and of associated clinical features. Finally, it has led to the withdrawal in several countries of a previously unsuspected carcinogenic and nephrotoxic substance.

  • aristolochic acid nephropathy in a Chinese patient time to abandon the term Chinese Herbs nephropathy
    American Journal of Kidney Diseases, 2001
    Co-Authors: Gaelle Gillerot, M. Jadoul, Heinz H Schmeiser, Christian A Bieler, Charles Van Ypersele De Strihou, Volker M Arlt, Jean-pierre Cosyns
    Abstract:

    The causal role of aristolochic acid (AA) in the so-called Chinese Herbs nephropathy (CHN) has been conclusively demonstrated only in the Belgian epidemic. We report a biopsy-proven hypocellular interstitial fibrosing nephropathy in a Chinese patient who had ingested a Chinese herbal preparation bought in Shanghai. The identification of AA in the preparation and of AA-DNA adducts in the kidney tissue unequivocally demonstrates, for the first time, the causal role of AA outside the Belgian epidemic. Because the ingested preparation is very popular in China as an over-the-counter product, our observation raises the possibility that many such cases due to AA might be currently unrecognized in China. AA should be banned from herbal preparations worldwide. All cases of the so-called CHN, in which the causal role of AA has been thoroughly documented, should be further identified as aristolochic acid nephropathy (AAN). The term phytotherapy-associated interstitial nephritis (PAIN) might refer to the other cases associated with phytotherapy without identification, as yet, of the causal agent.

  • chronic aristolochic acid toxicity in rabbits a model of Chinese Herbs nephropathy
    Kidney International, 2001
    Co-Authors: Jean-pierre Cosyns, Jeanpaul Dehoux, Yves Guiot, R M Goebbels, Annie Robert, Alfred Bernard, Charles Van Ypersele De Strihou
    Abstract:

    BACKGROUND: Chinese Herbs nephropathy (CHN) is a new type of subacute interstitial nephritis that is attributed to aristolochic acid (AA), which inadvertently has been included in slimming pills. The contribution of other simultaneously prescribed drugs remains disputed. In the present study, the effects of a chronic intake of AA given as a single drug was evaluated through renal histology and function in rabbits. METHODS: Female New Zealand White rabbits were injected intraperitoneally with either 0.1 mg AA/kg or with saline 5 days a week for 17 to 21 months. Body weight, renal function, and urinary excretion of glucose and low molecular weight proteins were monitored prior to sacrifice at the end of the study period. RESULTS: All animals given AA developed renal hypocellular interstitial fibrosis, which was classified into three patterns. Fibrosis was confined to medullary rays (MRs) in pattern I (N = 3), extended to the outer cortical labyrinth (OCL) in pattern II (N = 2), and eventually to the inner cortical labyrinth (ICL) in pattern III (N = 6). Fibrosis in MR and OCL was associated with mainly proximal tubular epithelial cell flattening. All treated animals displayed urothelial atypia. Three of them also developed tumors of the urinary tract. No significant pathologic changes were found in control rabbits. AA-treated animals differed from controls by an impaired growth, increased serum creatinine, glucosuria, tubular proteinuria, and anemia. CONCLUSION: The observed pattern of renal histopathological lesions and disorders of the renal function, as well as urothelial atypia and malignancy, are very reminiscent of CHN. Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy.

  • detection of dna adducts formed by aristolochic acid in renal tissue from patients with Chinese Herbs nephropathy
    Cancer Research, 1996
    Co-Authors: Heinz H Schmeiser, Christian A Bieler, Manfred Wiessler, Charles Van Ypersele De Strihou, Jean-pierre Cosyns
    Abstract:

    A unique type of rapidly progressive renal fibrosis, designated Chinese Herbs nephropathy (CHN), has been described in young Belgian women who had followed a slimming regimen including recently introduced Chinese Herbs (Stephania tetrandra and Magnolia officinalis). Aristolochic acid (AA), a known nephrotoxin and carcinogen, was suspected as its causal factor, To substantiate this hypothesis, renal tissue from five patients with CHN and six patients with other renal diseases was analyzed for the presence of AA-derived DNA adducts, a described biomarker of AA exposure associated with its carcinogenic and mutagenic activity, Using the P-32-postlabeling method, a major distinct DNA adduct spot was found in all five cases of CHN and identified by cochromatographic analyses with authentic markers as the deoxyadenosine adduct of AA-I [7-(deoxyadenosin-N-6-yl)-aristolactam I], the major component of the plant extract AA, This DNA adduct was absent in the six control cases, The 7-(deoxyadenosin-N-6-yl) -aristolactam I adduct levels in CHN ranged from 0.7 to 5.3/10(7) nucleotides. Our data demonstrate that AA is implicated in CHN, They suggest a mechanism for the urothelial atypia and cancers observed in this disease and raise the possibility that a DNA mutation is responsible for the kidney-destructive fibrotic process.

Peter J Hylands - One of the best experts on this subject based on the ideXlab platform.

  • virtual screening of Chinese Herbs with random forest
    Journal of Chemical Information and Modeling, 2007
    Co-Authors: Thomas M Ehrman, Peter J Hylands
    Abstract:

    Random Forest, a form of multiple decision trees, has been used to screen a database of Chinese herbal constituents for potential inhibitors against several therapeutically important molecular targets. These comprise cyclic adenosine 3‘-5‘-monophosphate phosphodiesterases, protein kinase A, cyclooxygenases, lipoxygenases, aldose reductase, and three HIV targets-integrase, protease, and reverse transcriptase. In addition, compounds were identified which may inhibit the expression of inducible nitric oxide synthase and/or nitric oxide production in vivo. A total of 240 Chinese Herbs containing 8264 compounds were screened in silico, including many used on a regular basis in traditional Chinese medicine. Active compounds were selected from another database of 2597 phytochemicals and related natural products with known target affinities and covered a wide range of structural classes. Random Forest was found to perform well, even on highly unbalanced data characteristic of ligand-based screening where the comp...

Charles Van Ypersele De Strihou - One of the best experts on this subject based on the ideXlab platform.

  • aristolochic acid nephropathy in a Chinese patient time to abandon the term Chinese Herbs nephropathy
    American Journal of Kidney Diseases, 2001
    Co-Authors: Gaelle Gillerot, M. Jadoul, Heinz H Schmeiser, Christian A Bieler, Charles Van Ypersele De Strihou, Volker M Arlt, Jean-pierre Cosyns
    Abstract:

    The causal role of aristolochic acid (AA) in the so-called Chinese Herbs nephropathy (CHN) has been conclusively demonstrated only in the Belgian epidemic. We report a biopsy-proven hypocellular interstitial fibrosing nephropathy in a Chinese patient who had ingested a Chinese herbal preparation bought in Shanghai. The identification of AA in the preparation and of AA-DNA adducts in the kidney tissue unequivocally demonstrates, for the first time, the causal role of AA outside the Belgian epidemic. Because the ingested preparation is very popular in China as an over-the-counter product, our observation raises the possibility that many such cases due to AA might be currently unrecognized in China. AA should be banned from herbal preparations worldwide. All cases of the so-called CHN, in which the causal role of AA has been thoroughly documented, should be further identified as aristolochic acid nephropathy (AAN). The term phytotherapy-associated interstitial nephritis (PAIN) might refer to the other cases associated with phytotherapy without identification, as yet, of the causal agent.

  • chronic aristolochic acid toxicity in rabbits a model of Chinese Herbs nephropathy
    Kidney International, 2001
    Co-Authors: Jean-pierre Cosyns, Jeanpaul Dehoux, Yves Guiot, R M Goebbels, Annie Robert, Alfred Bernard, Charles Van Ypersele De Strihou
    Abstract:

    BACKGROUND: Chinese Herbs nephropathy (CHN) is a new type of subacute interstitial nephritis that is attributed to aristolochic acid (AA), which inadvertently has been included in slimming pills. The contribution of other simultaneously prescribed drugs remains disputed. In the present study, the effects of a chronic intake of AA given as a single drug was evaluated through renal histology and function in rabbits. METHODS: Female New Zealand White rabbits were injected intraperitoneally with either 0.1 mg AA/kg or with saline 5 days a week for 17 to 21 months. Body weight, renal function, and urinary excretion of glucose and low molecular weight proteins were monitored prior to sacrifice at the end of the study period. RESULTS: All animals given AA developed renal hypocellular interstitial fibrosis, which was classified into three patterns. Fibrosis was confined to medullary rays (MRs) in pattern I (N = 3), extended to the outer cortical labyrinth (OCL) in pattern II (N = 2), and eventually to the inner cortical labyrinth (ICL) in pattern III (N = 6). Fibrosis in MR and OCL was associated with mainly proximal tubular epithelial cell flattening. All treated animals displayed urothelial atypia. Three of them also developed tumors of the urinary tract. No significant pathologic changes were found in control rabbits. AA-treated animals differed from controls by an impaired growth, increased serum creatinine, glucosuria, tubular proteinuria, and anemia. CONCLUSION: The observed pattern of renal histopathological lesions and disorders of the renal function, as well as urothelial atypia and malignancy, are very reminiscent of CHN. Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy.

  • detection of dna adducts formed by aristolochic acid in renal tissue from patients with Chinese Herbs nephropathy
    Cancer Research, 1996
    Co-Authors: Heinz H Schmeiser, Christian A Bieler, Manfred Wiessler, Charles Van Ypersele De Strihou, Jean-pierre Cosyns
    Abstract:

    A unique type of rapidly progressive renal fibrosis, designated Chinese Herbs nephropathy (CHN), has been described in young Belgian women who had followed a slimming regimen including recently introduced Chinese Herbs (Stephania tetrandra and Magnolia officinalis). Aristolochic acid (AA), a known nephrotoxin and carcinogen, was suspected as its causal factor, To substantiate this hypothesis, renal tissue from five patients with CHN and six patients with other renal diseases was analyzed for the presence of AA-derived DNA adducts, a described biomarker of AA exposure associated with its carcinogenic and mutagenic activity, Using the P-32-postlabeling method, a major distinct DNA adduct spot was found in all five cases of CHN and identified by cochromatographic analyses with authentic markers as the deoxyadenosine adduct of AA-I [7-(deoxyadenosin-N-6-yl)-aristolactam I], the major component of the plant extract AA, This DNA adduct was absent in the six control cases, The 7-(deoxyadenosin-N-6-yl) -aristolactam I adduct levels in CHN ranged from 0.7 to 5.3/10(7) nucleotides. Our data demonstrate that AA is implicated in CHN, They suggest a mechanism for the urothelial atypia and cancers observed in this disease and raise the possibility that a DNA mutation is responsible for the kidney-destructive fibrotic process.

Thomas M Ehrman - One of the best experts on this subject based on the ideXlab platform.

  • virtual screening of Chinese Herbs with random forest
    Journal of Chemical Information and Modeling, 2007
    Co-Authors: Thomas M Ehrman, Peter J Hylands
    Abstract:

    Random Forest, a form of multiple decision trees, has been used to screen a database of Chinese herbal constituents for potential inhibitors against several therapeutically important molecular targets. These comprise cyclic adenosine 3‘-5‘-monophosphate phosphodiesterases, protein kinase A, cyclooxygenases, lipoxygenases, aldose reductase, and three HIV targets-integrase, protease, and reverse transcriptase. In addition, compounds were identified which may inhibit the expression of inducible nitric oxide synthase and/or nitric oxide production in vivo. A total of 240 Chinese Herbs containing 8264 compounds were screened in silico, including many used on a regular basis in traditional Chinese medicine. Active compounds were selected from another database of 2597 phytochemicals and related natural products with known target affinities and covered a wide range of structural classes. Random Forest was found to perform well, even on highly unbalanced data characteristic of ligand-based screening where the comp...

Ming Yu Lo - One of the best experts on this subject based on the ideXlab platform.

  • antihypertensive effects of tannins isolated from traditional Chinese Herbs as non specific inhibitors of angiontensin converting enzyme
    Life Sciences, 2003
    Co-Authors: Jen Chen Tsai, Paul Chan, Neil G Thomas, Brian Tomlinson, Ming Yu Lo
    Abstract:

    The tannins are natural polyphenols, able to precipitate water-soluble alkaloids and possess an inhibitory action on the angiotensin converting enzyme (ACE). We identified 18 polyphenolic compounds (tannins) from Chinese Herbs and examined the in vitro effects of these tannins on ACE activity, including determination of the 50% inhibitory concentrations (IC50), specificity and mode of inhibition. We also assessed the in vivo inhibitory effect of the tannins on angiotensin I-induced blood pressure elevation in spontaneously hypertensive rats (SHR). Nine tannins with an IC50 <200 μM for ACE inhibitors were identified belonging to three tannin classes: caffeoylquinates, flavan-3-ols and gallotannins. In vitro, we found caffeoylquinates chelate the ACE zinc cofactor. Two of the flavan-3-ols: epigallocatechin-3-O-gallate and epigallocatechin-3-O-methylgallate, and one of gallotannin: 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose were non-specific inhibitors because also reduced the activity of trypsin and chymotrypsin. The ACE inhibition of 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose was also reduced after addition of bovine serum albumin, suggesting a non-specific mode of action. In vivo, 1,2,3,6-tetra-O-galloyl-β-D-glucose and epigallocatechin-3-O-methylgallate had a strong dose-dependent hypotensive effect reducing the blood pressure significantly in the SHR with infusion of the angiotensin I. These findings indicate that some of the tannins isolated from Herbs inhibit ACE activity non-specifically. The ACE inhibitory effect of these tannins may explain the hypotensive effects of some traditional Chinese Herbs.