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Mara Lorenzi - One of the best experts on this subject based on the ideXlab platform.
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the Polyol Pathway as a mechanism for diabetic retinopathy attractive elusive and resilient
Experimental Diabetes Research, 2007Co-Authors: Mara LorenziAbstract:The Polyol Pathway is a two-step metabolic Pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the Pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the Pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of Polyol Pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the Polyol Pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the Polyol Pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the Polyol Pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered.
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ReviewArticle The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient
2007Co-Authors: Mara LorenziAbstract:Received 26 February 2007; Accepted 24 April 2007Recommended by Subrata ChakrabartiThe Polyol Pathway is a two-step metabolic Pathway in which glucose is reduced to sorbitol, which is then converted to fructose.It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemiabecause (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in humantissuesandorgansthataresitesofdiabeticcomplications,and(iii)theproductsofthePathwayandthealteredbalanceofcofactorsgenerate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase,the first and rate-limiting enzyme in the Pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but theresults of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators ofPolyol Pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accuratelytissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glialand neuronal abnormalities, which in experimental animals are mediated by the Polyol Pathway. The endothelial cells of humanretinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductasegene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindledinterest in a possible role of the Polyol Pathway in diabetic retinopathy and in methodological investigation that may prepare newclinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possibleto learn if the resilience of the Polyol Pathway means that it has a role in human diabetic retinopathy that should not have goneundiscovered.Copyright © 2007 Mara Lorenzi.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Studies of Rat and Human Retinas Predict a Role for the Polyol Pathway in Human Diabetic Retinopathy
Diabetes, 2004Co-Authors: Zeina Dagher, Veronica Asnaghi, Chiara Gerhardinger, Todd Hoehn, Yong Seek Park, Mara LorenziAbstract:The Polyol (sorbitol) Pathway of glucose metabolism is activated in many cell types when intracellular glucose concentrations are high, and it can generate cellular stress through several mechanisms. The role of the Polyol Pathway in the pathogenesis of diabetic retinopathy has remained uncertain, in part because it has been examined preferentially in galactose-induced retinopathy and in part because inhibition studies may not have achieved full blockade of the Pathway. Having observed that the streptozotocin-induced diabetic rat accurately models many cellular processes characteristic of human diabetic retinopathy, we tested in the diabetic rat if documented inhibition of the Polyol Pathway prevents a sequence of retinal vascular abnormalities also present in human diabetes. An inhibitor of aldose reductase, the rate-limiting enzyme in the Pathway, prevented the early activation of complement in the wall of retinal vessels and the decreased levels of complement inhibitors in diabetic rats, as well as the later apoptosis of vascular pericytes and endothelial cells and the development of acellular capillaries. Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat. Excess aldose reductase activity can be a mechanism for human diabetic retinopathy.
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a role for the Polyol Pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat
Diabetes, 2003Co-Authors: Veronica Asnaghi, Chiara Gerhardinger, Todd Hoehn, Abidemi Adeboje, Mara LorenziAbstract:We tested the hypothesis that the apoptosis of inner retina neurons and increased expression of glial fibrillary acidic protein (GFAP) observed in the rat after a short duration of diabetes are mediated by Polyol Pathway activity. Rats with 10 weeks of streptozotocin-induced diabetes and GHb levels of 16 ± 2% (mean ± SD) showed increased retinal levels of sorbitol and fructose, attenuation of GFAP immunostaining in astrocytes, appearance of prominent GFAP expression in Muller glial cells, and a fourfold increase in the number of apoptotic neurons when compared with nondiabetic rats. The cells undergoing apoptosis were immunoreactive for aldose reductase. Sorbinil, an inhibitor of aldose reductase, prevented all abnormalities. Intensive insulin treatment also prevented most abnormalities, despite reducing GHb only to 12 ± 1%. Diabetic mice, known to have much lower aldose reductase activity in other tissues when compared with rats, did not accumulate sorbitol and fructose in the retina and were protected from neuronal apoptosis and GFAP changes in the presence of GHb levels of 14 ± 2%. This work documents discrete cellular consequences of Polyol Pathway activity in the retina, and it suggests that activation of the Pathway and “retinal neuropathy” require severe hyperglycemia and/or high activity of aldose reductase. These findings have implications for how to evaluate the role of the Polyol Pathway in diabetic retinopathy.
Stephen S. M. Chung - One of the best experts on this subject based on the ideXlab platform.
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Polyol Pathway impairs the function of SERCA and RyR in ischemic-reperfused rat hearts by increasing oxidative modifications of these proteins
Journal of Molecular and Cellular Cardiology, 2010Co-Authors: Wh Tang, Tak Ming Wong, Sookja K. Chung, Gennadi M. Kravtsov, Martina Sauert, Xiao Yong Tong, Xiu Yun Hou, Stephen S. M. ChungAbstract:A number of studies have shown that the Polyol Pathway, consisting of aldose reductase (AR) and sorbitol dehydrogenase (SDH), contributes to ischemia-reperfusion (I/R)-induced myocardial infarction due to depletion of ATP. In this report we show that the Polyol Pathway in I/R heart also contributes to the impairment of sacro/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and ryanodine receptor (RyR), two key players in Ca(2+) signaling that regulate cardiac contraction. Rat hearts were isolated and retrogradely perfused with either Krebs' buffer containing 1 microM AR inhibitor, zopolrestat, or 200 nM SDH inhibitor, CP-170,711, and challenged by 30 min of regional ischemia and 45 min of reperfusion. We found that post-ischemic contractile function of the isolated perfused hearts was improved by pharmacological inhibition of the Polyol Pathway. I/R-induced contractile dysfunction is most likely due to impairment in Ca(2+) signaling and the activities of SERCA and RyR. All these abnormalities were significantly ameliorated by treatment with ARI or SDI. We showed that the Polyol Pathway activities increase the level of peroxynitrite, which enhances the tyrosine nitration of SERCA and irreversibly modifies it to form SERCAC674-SO(3)H. This leads to reduced level of S-glutathiolated SERCA, contributing to its inactivation. The Polyol Pathway activities also deplete the level of GSH, leading to decreased active RyR, the S-glutathiolated RyR. Thus, in I/R heart, inhibition of Polyol Pathway improved the function of SERCA and RyR by protecting them from irreversible oxidation.
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The role of the Polyol Pathway in acute kidney injury caused by hindlimb ischaemia in mice
The Journal of Pathology, 2009Co-Authors: Soroku Yagihashi, Sookja K. Chung, Hiroki Mizukami, Saori Ogasawara, Shin-ichiro Yamagishi, Hitoshi Nukada, Noriaki Kato, Chihiro Hibi, Stephen S. M. ChungAbstract:The Polyol Pathway, a collateral glycolytic process, previously considered to be active in high glucose milieu, has recently been proposed to play a crucial role in ischaemia/reperfusion tissue injury. In this study, we explored the role of the Polyol Pathway in acute kidney injury (AKI), a life-threatening condition, caused by hindlimb ischaemia, and determined if inhibition of the Polyol Pathway by aldose reductase (AR) inhibitor is beneficial for this serious disorder. Mice 8 weeks of age rendered hindlimb ischaemic for 3 h by the clipping of major supporting arteries revealed marked muscle necrosis with accumulation of sorbitol and fructose in ischaemic muscles. Serum concentrations of blood urea nitrogen (BUN), creatinine phosphokinase (CPK), creatinine, tumour necrosis factor (TNF)-α as well as interleukin (IL)-6 were all elevated in these mice. Treatment with AR inhibitor (ARI) effectively suppressed muscle necrosis and accompanying inflammatory reactions and prevented renal failure. Similar to ARI-treated mice, AR-deficient mice were protected from severe ischaemic limb injury and renal failure, showing only modest muscle necrosis and significant suppression of serum markers of renal failure and inflammation. Thus, these findings suggest that the Polyol Pathway is implicated in AKI caused by ischaemic limb injury and that AR may be a potential therapeutic target for this condition. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Polyol Pathway mediates iron-induced oxidative injury in ischemic-reperfused rat heart
Free Radical Biology and Medicine, 2008Co-Authors: Wh Tang, Tak Ming Wong, Sookja K. Chung, Stephen S. M. ChungAbstract:Abstract Recent studies have shown that the Polyol Pathway is involved in ischemia–reperfusion (I/R)-induced myocardial infarction, but the mechanism is unclear. We previously found that lack of aldose reductase (AR), the first enzyme of the Polyol Pathway, attenuated the increase in transferrin (Tf) level in I/R brain, suggesting that AR contributes to iron-catalyzed free radical-induced damage. We therefore investigated if this mechanism occurs in I/R hearts. We found that inhibition of AR or sorbitol dehydrogenase (SDH), the second enzyme of the Polyol Pathway, both attenuated the I/R-mediated increases in HIF-1α, Tf, TfR, and intracellular iron content and reduced the I/R-induced infarct area of the heart. Further, administration of niacin, which replenishes NAD+, the cofactor for SDH, also normalized TfR and HIF-1α levels in I/R hearts. These results suggest that during I/R Polyol Pathway activity increases the cytosolic NADH/NAD+ ratio. This activates HIF-1α that induces the expression of TfR, which in turn increases Tf uptake and iron accumulation and exacerbates oxidative damage that increases the lipid peroxidation. This was confirmed by the fact that administration of the iron chelator deferoxamine attenuated the I/R-induced myocardial infarction.
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Interaction between the Polyol Pathway and non-enzymatic glycation on mesangial cell gene expression.
Nephron Experimental Nephrology, 2004Co-Authors: Qinghong Dan, Sookja K. Chung, Stephen S. M. Chung, Rachel L.c. Wong, Shinan Yin, Karen S L LamAbstract:Background/Aims: Both activation of the Polyol Pathway and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic glomerulopathy. We investigated the
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Interaction between the Polyol Pathway and non-enzymatic glycation on aortic smooth muscle cell migration and monocyte adhesion.
Life Sciences, 2004Co-Authors: Qinghong Dan, Sookja K. Chung, Stephen S. M. Chung, Rachel L.c. Wong, Karen S L LamAbstract:We investigated for the interaction between the Polyol Pathway and enhanced non-enzymatic glycation, both implicated in the pathogenesis of diabetic atherosclerosis, in the activation of aortic smooth muscle cell (SMC) function. Mouse aortas and primary cultures of SMCs from wildtype (WT) mice and transgenic (TG) mice expressing human aldose reductase (AR) were studied regarding changes in AR activity, and SMC gene activation, migration and monocyte adhesion, in response to advanced glycation end-product modified BSA (AGE-BSA). Results showed that AGE-BSA increased AR activity in both WT and TG aortas, with greater increments (p < 0.05) in TG aortas which, basally, had elevated AR activity (2.8 fold of WT). These increments were attenuated by zopolrestat, an AR inhibitor. Similar AGE-induced increments in AR activity were observed in primary cultures of aortic SMCs from WT and TG mice (60% and 100%, respectively, P < 0.01). Such increments were accompanied by increases in intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels (both P < 0.05), activation of membrane-associated PKC-β1 (P < 0.05) as well as increased SMC migration and Tamm-Horsfall protein (THP)-1 monocyte adhesion to SMCs (both p < 0.01), with all changes being significantly greater in TG SMCs (P < 0.05) and suppressible by either zopolrestat or transfection with an AR antisense oligonucleotide. Our findings suggest that the effects of AGEs on SMC activation, migration and monocyte adhesion are mediated partly through the Polyol Pathway and, possibly, PKC activation. The greater AGE-induced changes in the TG SMCs have provided further support for the dependency of such changes on Polyol Pathway hyperactivity.
Sookja K. Chung - One of the best experts on this subject based on the ideXlab platform.
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Polyol Pathway impairs the function of SERCA and RyR in ischemic-reperfused rat hearts by increasing oxidative modifications of these proteins
Journal of Molecular and Cellular Cardiology, 2010Co-Authors: Wh Tang, Tak Ming Wong, Sookja K. Chung, Gennadi M. Kravtsov, Martina Sauert, Xiao Yong Tong, Xiu Yun Hou, Stephen S. M. ChungAbstract:A number of studies have shown that the Polyol Pathway, consisting of aldose reductase (AR) and sorbitol dehydrogenase (SDH), contributes to ischemia-reperfusion (I/R)-induced myocardial infarction due to depletion of ATP. In this report we show that the Polyol Pathway in I/R heart also contributes to the impairment of sacro/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and ryanodine receptor (RyR), two key players in Ca(2+) signaling that regulate cardiac contraction. Rat hearts were isolated and retrogradely perfused with either Krebs' buffer containing 1 microM AR inhibitor, zopolrestat, or 200 nM SDH inhibitor, CP-170,711, and challenged by 30 min of regional ischemia and 45 min of reperfusion. We found that post-ischemic contractile function of the isolated perfused hearts was improved by pharmacological inhibition of the Polyol Pathway. I/R-induced contractile dysfunction is most likely due to impairment in Ca(2+) signaling and the activities of SERCA and RyR. All these abnormalities were significantly ameliorated by treatment with ARI or SDI. We showed that the Polyol Pathway activities increase the level of peroxynitrite, which enhances the tyrosine nitration of SERCA and irreversibly modifies it to form SERCAC674-SO(3)H. This leads to reduced level of S-glutathiolated SERCA, contributing to its inactivation. The Polyol Pathway activities also deplete the level of GSH, leading to decreased active RyR, the S-glutathiolated RyR. Thus, in I/R heart, inhibition of Polyol Pathway improved the function of SERCA and RyR by protecting them from irreversible oxidation.
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The role of the Polyol Pathway in acute kidney injury caused by hindlimb ischaemia in mice
The Journal of Pathology, 2009Co-Authors: Soroku Yagihashi, Sookja K. Chung, Hiroki Mizukami, Saori Ogasawara, Shin-ichiro Yamagishi, Hitoshi Nukada, Noriaki Kato, Chihiro Hibi, Stephen S. M. ChungAbstract:The Polyol Pathway, a collateral glycolytic process, previously considered to be active in high glucose milieu, has recently been proposed to play a crucial role in ischaemia/reperfusion tissue injury. In this study, we explored the role of the Polyol Pathway in acute kidney injury (AKI), a life-threatening condition, caused by hindlimb ischaemia, and determined if inhibition of the Polyol Pathway by aldose reductase (AR) inhibitor is beneficial for this serious disorder. Mice 8 weeks of age rendered hindlimb ischaemic for 3 h by the clipping of major supporting arteries revealed marked muscle necrosis with accumulation of sorbitol and fructose in ischaemic muscles. Serum concentrations of blood urea nitrogen (BUN), creatinine phosphokinase (CPK), creatinine, tumour necrosis factor (TNF)-α as well as interleukin (IL)-6 were all elevated in these mice. Treatment with AR inhibitor (ARI) effectively suppressed muscle necrosis and accompanying inflammatory reactions and prevented renal failure. Similar to ARI-treated mice, AR-deficient mice were protected from severe ischaemic limb injury and renal failure, showing only modest muscle necrosis and significant suppression of serum markers of renal failure and inflammation. Thus, these findings suggest that the Polyol Pathway is implicated in AKI caused by ischaemic limb injury and that AR may be a potential therapeutic target for this condition. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Polyol Pathway mediates iron-induced oxidative injury in ischemic-reperfused rat heart
Free Radical Biology and Medicine, 2008Co-Authors: Wh Tang, Tak Ming Wong, Sookja K. Chung, Stephen S. M. ChungAbstract:Abstract Recent studies have shown that the Polyol Pathway is involved in ischemia–reperfusion (I/R)-induced myocardial infarction, but the mechanism is unclear. We previously found that lack of aldose reductase (AR), the first enzyme of the Polyol Pathway, attenuated the increase in transferrin (Tf) level in I/R brain, suggesting that AR contributes to iron-catalyzed free radical-induced damage. We therefore investigated if this mechanism occurs in I/R hearts. We found that inhibition of AR or sorbitol dehydrogenase (SDH), the second enzyme of the Polyol Pathway, both attenuated the I/R-mediated increases in HIF-1α, Tf, TfR, and intracellular iron content and reduced the I/R-induced infarct area of the heart. Further, administration of niacin, which replenishes NAD+, the cofactor for SDH, also normalized TfR and HIF-1α levels in I/R hearts. These results suggest that during I/R Polyol Pathway activity increases the cytosolic NADH/NAD+ ratio. This activates HIF-1α that induces the expression of TfR, which in turn increases Tf uptake and iron accumulation and exacerbates oxidative damage that increases the lipid peroxidation. This was confirmed by the fact that administration of the iron chelator deferoxamine attenuated the I/R-induced myocardial infarction.
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Interaction between the Polyol Pathway and non-enzymatic glycation on mesangial cell gene expression.
Nephron Experimental Nephrology, 2004Co-Authors: Qinghong Dan, Sookja K. Chung, Stephen S. M. Chung, Rachel L.c. Wong, Shinan Yin, Karen S L LamAbstract:Background/Aims: Both activation of the Polyol Pathway and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic glomerulopathy. We investigated the
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Interaction between the Polyol Pathway and non-enzymatic glycation on aortic smooth muscle cell migration and monocyte adhesion.
Life Sciences, 2004Co-Authors: Qinghong Dan, Sookja K. Chung, Stephen S. M. Chung, Rachel L.c. Wong, Karen S L LamAbstract:We investigated for the interaction between the Polyol Pathway and enhanced non-enzymatic glycation, both implicated in the pathogenesis of diabetic atherosclerosis, in the activation of aortic smooth muscle cell (SMC) function. Mouse aortas and primary cultures of SMCs from wildtype (WT) mice and transgenic (TG) mice expressing human aldose reductase (AR) were studied regarding changes in AR activity, and SMC gene activation, migration and monocyte adhesion, in response to advanced glycation end-product modified BSA (AGE-BSA). Results showed that AGE-BSA increased AR activity in both WT and TG aortas, with greater increments (p < 0.05) in TG aortas which, basally, had elevated AR activity (2.8 fold of WT). These increments were attenuated by zopolrestat, an AR inhibitor. Similar AGE-induced increments in AR activity were observed in primary cultures of aortic SMCs from WT and TG mice (60% and 100%, respectively, P < 0.01). Such increments were accompanied by increases in intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels (both P < 0.05), activation of membrane-associated PKC-β1 (P < 0.05) as well as increased SMC migration and Tamm-Horsfall protein (THP)-1 monocyte adhesion to SMCs (both p < 0.01), with all changes being significantly greater in TG SMCs (P < 0.05) and suppressible by either zopolrestat or transfection with an AR antisense oligonucleotide. Our findings suggest that the effects of AGEs on SMC activation, migration and monocyte adhesion are mediated partly through the Polyol Pathway and, possibly, PKC activation. The greater AGE-induced changes in the TG SMCs have provided further support for the dependency of such changes on Polyol Pathway hyperactivity.
Massimo Porta - One of the best experts on this subject based on the ideXlab platform.
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regulation of intracellular glucose and Polyol Pathway by thiamine and benfotiamine in vascular cells cultured in high glucose
Journal of Biological Chemistry, 2006Co-Authors: Elena Berrone, Elena Beltramo, Carmela Solimine, Massimo PortaAbstract:Abstract Hyperglycemia is a causal factor in the development of the vascular complications of diabetes. One of the biochemical mechanisms activated by excess glucose is the Polyol Pathway, the key enzyme of which, aldose reductase, transforms d-glucose into d-sorbitol, leading to imbalances of intracellular homeostasis. We aimed at verifying the effects of thiamine and benfotiamine on the Polyol Pathway, transketolase activity, and intracellular glucose in endothelial cells and pericytes under high ambient glucose. Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/liter) or high (28 mmol/liter) glucose, with or without thiamine or benfotiamine 50 or 100 μmol/liter. Transketolase and aldose reductase mRNA expression was determined by reverse transcription-PCR, and their activity was measured spectrophotometrically; sorbitol concentrations were quantified by gas chromatography-mass spectrometry and intracellular glucose concentrations by fluorescent enzyme-linked immunosorbent assay method. Thiamine and benfotiamine reduce aldose reductase mRNA expression, activity, sorbitol concentrations, and intracellular glucose while increasing the expression and activity of transketolase, for which it is a coenzyme, in human endothelial cells and bovine retinal pericytes cultured in high glucose. Thiamine and benfotiamine correct Polyol Pathway activation induced by high glucose in vascular cells. Activation of transketolase may shift excess glycolytic metabolites into the pentose phosphate cycle, accelerate the glycolytic flux, and reduce intracellular free glucose, thereby preventing its conversion to sorbitol. This effect on the Polyol Pathway, together with other beneficial effects reported for thiamine in high glucose, could justify testing thiamine as a potential approach to the prevention and/or treatment of diabetic complications.
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Regulation of Intracellular Glucose and Polyol Pathway by Thiamine and Benfotiamine in Vascular Cells Cultured
2006Co-Authors: Elena Berrone, Elena Beltramo, Carmela Solimine, Alessandro Ubertalli Ape, Massimo PortaAbstract:Hyperglycemia is a causal factor in the development of the vascular complications of diabetes. One of the biochemical mechanisms activated by excess glucose is the Polyol Pathway, the key enzyme of which, aldose reductase, transforms D-glucose into D-sorbitol, leading to imbalances of intracellular homeostasis. We aimed at verifying the effects of thiamine and benfotiamine on the Polyol Pathway, transketolase activity, and intracellular glucose in endothelial cells and pericytes under high ambient glucose. Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/liter) or high (28 mmol/liter) glucose, with or without thiamine or benfotiamine 50 or 100 mol/liter. Transketolase and aldose reductase mRNA expression was determined by reverse transcriptionPCR, and their activity was measured spectrophotometrically; sorbitol concentrations were quantified by gas chromatographymass spectrometry and intracellular glucose concentrations by fluorescent enzyme-linked immunosorbent assay method. Thiamine and benfotiamine reduce aldose reductase mRNA expression, activity, sorbitol concentrations, and intracellular glucose while increasing the expression and activity of transketolase, for which it is a coenzyme, in human endothelial cells and bovine retinal pericytes cultured in high glucose. Thiamine and benfotiamine correct Polyol Pathway activation induced by high glucose in vascular cells. Activation of transketolase may shift excess glycolytic metabolites into the pentose phosphate cycle, accelerate the glycolytic flux, and reduce intracellular free glucose, thereby preventing its conversion to sorbitol. This effect on the Polyol Pathway, together with other beneficial effects reported for thiamine in high glucose, could justify testing thiamine as a potential approach to the prevention and/or treatment of diabetic complications.
Yuan Tian - One of the best experts on this subject based on the ideXlab platform.
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Polyol Pathway exacerbated ischemia reperfusion induced injury in steatotic liver
Oxidative Medicine and Cellular Longevity, 2014Co-Authors: Changhe Zhang, Changjun Huang, Yuan TianAbstract:Background. The Polyol Pathway, a bypass Pathway of glucose metabolism initiated by aldose reductase (AR), has been shown to play an important role in mediating tissue ischemia/reperfusion (I/R) impairment recently. Here, we investigated how and why this Pathway might affect the fatty liver following I/R. Methods. Two opposite models were created: mice with high-fat-diet-induced liver steatosis were treated with aldose reductase inhibition (ARI) and subsequent I/R; and AR-overexpressing L02 hepatocytes were sequentially subjected to steatosis and hypoxia/reoxygenation. We next investigated (a) the hepatic injuries, including liver function, histology, and hepatocytes apoptosis/necrosis; (b) the NAD(P)(H) contents, redox status, and mitochondrial function; and (c) the flux through the caspase-dependent apoptosis Pathway. Results. AR-inhibition in vivo markedly attenuated the I/R-induced liver injuries, maintained the homeostasis of NAD(P)(H) contents and redox status, and suppressed the caspase-dependent apoptosis Pathway. Correspondingly, AR overexpression in vitro presented the opposite effects. Conclusion. The flux through the Polyol Pathway may render steatotic liver greater vulnerability to I/R. Interventions targeting this Pathway might provide a novel adjunctive approach to protect fatty liver from ischemia.
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Polyol Pathway exacerbated ischemia/reperfusion-induced injury in steatotic liver.
Oxidative Medicine and Cellular Longevity, 2014Co-Authors: Changhe Zhang, Changjun Huang, Yuan TianAbstract:Background. The Polyol Pathway, a bypass Pathway of glucose metabolism initiated by aldose reductase (AR), has been shown to play an important role in mediating tissue ischemia/reperfusion (I/R) impairment recently. Here, we investigated how and why this Pathway might affect the fatty liver following I/R. Methods. Two opposite models were created: mice with high-fat-diet-induced liver steatosis were treated with aldose reductase inhibition (ARI) and subsequent I/R; and AR-overexpressing L02 hepatocytes were sequentially subjected to steatosis and hypoxia/reoxygenation. We next investigated (a) the hepatic injuries, including liver function, histology, and hepatocytes apoptosis/necrosis; (b) the NAD(P)(H) contents, redox status, and mitochondrial function; and (c) the flux through the caspase-dependent apoptosis Pathway. Results. AR-inhibition in vivo markedly attenuated the I/R-induced liver injuries, maintained the homeostasis of NAD(P)(H) contents and redox status, and suppressed the caspase-dependent apoptosis Pathway. Correspondingly, AR overexpression in vitro presented the opposite effects. Conclusion. The flux through the Polyol Pathway may render steatotic liver greater vulnerability to I/R. Interventions targeting this Pathway might provide a novel adjunctive approach to protect fatty liver from ischemia.