RARE DISEASE
Disorders of pentose/polyol metabolism
Disorders of pentose/polyol metabolism
Disorders of pentose/polyol metabolism
Drug discovery
0
drugs
With orphan designations
Overview
Disorders of pentose/polyol metabolism are rare inborn errors affecting the pentose phosphate pathway (PPP) or polyol metabolism, leading to toxic accumulation of sugars, polyols, and their derivatives. These defects disrupt NADPH/NADP+ balance and redox homeostasis, causing neurological manifestations (leukoencephalopathy, peripheral neuropathy) and hepatic complications (cirrhosis, steatosis). Diagnosis relies on elevated polyols (e.g., ribitol, D-arabitol) in body fluids and genetic confirmation of PPP enzyme deficiencies (e.g., ribose-5-phosphate isomerase, transaldolase) [1][2][11][14].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
24 drug discovery papers about Disorders of pentose/polyol metabolism, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
24 drug discovery papers about Disorders of pentose/polyol metabolism, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2023-11-28 | AKR1B1 drives hyperglycemia-induced metabolic reprogramming in MASLD-associated hepatocellular carcinoma
The mechanism behind the progressive pathological alteration in metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH)-associated hepatocellular carcinoma (HCC) is poorly understood. In the present study, we investigated the role of the polyol pathway enzyme AKR1B1 in metabolic switching associated with MASLD/MASH and in the progression of HCC. AKR1B1 expression was estimated in the tissue and plasma of patients with MASLD/MASH, HCC, and HCC with diabetes mellitus. The role of AKR1B1 in metabolic switching in vitro was assessed through media conditioning, lentiviral transfection, and pharmacological probes. A proteomic and metabolomic approach was applied for the in-depth investigation of metabolic pathways. Preclinically, mice were subjected to a high-fructose diet and diethylnitrosamine to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching characteristic of MASLD-HCC. A significant increase in the expression of AKR1B1 was observed in tissue and plasma samples from patients with MASLD/MASH, HCC, and HCC with diabetes mellitus compared to normal samples. Mechanistically, in vitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, the tricarboxylic acid cycle, and lipogenesis to promote hyperglycemia-mediated MASLD and cancer progression. A pathological increase in the expression of AKR1B1 was observed in experimental MASLD-HCC, and expression was positively correlated with high blood glucose levels. High-fructose diet + diethylnitrosamine-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. AKR1B1 inhibition with epalrestat or NARI-29 inhibited cellular metabolism in in vitro and in vivo models. Pathological AKR1B1 modulates hepatic metabolism to promote MASLD-associated hepatocarcinogenesis. Aldose reductase inhibition modulates the glycolytic pathway to prevent precancerous hepatocyte formation. This research work highlights AKR1B1 as a druggable target in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), which could provide the basis for the development of new chemotherapeutic agents. Moreover, our results indicate the potential of plasma AKR1B1 levels as a prognostic marker and diagnostic test for MASLD and associated HCC. Additionally, a major observation in this study was that AKR1B1 is associated with the promotion of the Warburg effect in HCC.
2023-06-29 | Screening Effect of Amino Acid on Xylitol Production By Recombinant Escherichia coli System
Numerical studies have been conducted to sources for safer biological methods to produce xylitol. In view of these concerns and the benefits of xylitol, a fermentation process that is formulated to yield highest xylitol is both favourable and profitable. In this study, recovery of xylitol production from xylose by recombinant Escherichia coli system was conducted by modulating both carbon source and amino acid composition of the media for the relative growth delay of the strain. The key enzyme for xylitol production in this recombinant system is xylose reductase, XR which utilize NADPH to reduce D-xylose to xylitol. By adding 20 types of amino acids individually and substituting glycerol as the carbon source each time, showed an increase of xylitol to 5.24 g/L and yield biomass production to 1.536. It is hypothesize that supply of single amino acid act as a tool to enhance (NAD(P)H)/(NADP+) ratio. Reduced NAD(P)H competition from other bioprocesses help the cell replenishes the reduced cofactor pool. Xylitol has a remarkable benefits as a healthy replacement of table sugar. Therefore, the success of this study will definitely bring forward advance in the production technology and act as a reference for future research.
2023-01-11 | AKR1B1 drives hyperglycemia-induced metabolic reprogramming in NAFLD-associated carcinogenesis and progression of hepatocellular carcinoma
Abstract Objective Emergent epidemiological evidence suggests that the progression of NAFLD/NASH-associated HCC positively correlates with the patient's glycemic index. However, the mechanism behind this progressive pathological alteration is poorly understood. It has shown that the polyol pathway master regulator, AKR1B1 is over-expressed in hyperglycemia and responsible for most of diabetic complications. Hence in the present study, we have investigated the role of AKR1B1 in metabolic switching associated with NAFLD/NASH and in the progression of HCC. Methods The expression of AKR1B1 in NAFL/NASH, HCC, and HCC with diabetes mellitus patient's liver and plasma were estimated. The role of AKR1B1 in the metabolic switching of HCC cell lines was assessed through media conditioning and lentiviral transfection. Standard inhibitor epalrestat or investigational drug NARI-29 (4-((Z)-5-((Z)-2-Cyano-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl) benzoic acid) was utilized to elucidate the effect of AKR1B1 inhibition in hepatocarcinogenesis. A proteomic approach was applied for an in-depth investigation of the involved metabolic pathway and to evaluate the therapeutic efficacy of pharmacological inhibitors. Preclinically, a high fructose diet (HFrD) fed in combination with a diethyl nitrosamine (DEN) induced mouse model was developed to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching in the pathobiology of NAFLD and its progression to HCC. Results A significant increase in the expression of AKR1B1 was observed in NAFL/NASH, HCC, and HCC-DM tissue samples compared to non-involved adjacent tissues indicating its role in the disease progression. Moreover, a statistically significant elevation of AKR1B1 was observed in NAFLD, NAFLD-associated HCC, and HCC-DM plasma samples compared to normal control. Mechanistically, Invitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, TCA cycle, and lipogenesis to promote hyperglycemia-mediated fatty liver and cancer progression. A pathologically increased expression of AKR1B1 was observed in experimental NAFL-HCC, and expression was positively correlated with high blood glucose levels. HFrD + DEN-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. However, AKR1B1 inhibition with EPS or NARI-29 has inhibited cellular metabolism in vitro and in vivo models. Conclusion Pathological AKR1B1 modulates hepatic glucose metabolism to promote NAFLD-associated hepato-carcinogenesis. Aldose reductase inhibition modulates glucose metabolism to prevent the pre-cancerous hepatocyte formation. Hence EPS and NARI-29 could be promising AKR1B1 inhibitors for controlling aberrant metabolism and treating NAFLD-associated HCC.
2022-04-29 | The potential of Ginkgo biloba in the treatment of human diseases and the relationship to Nrf2-mediated antioxidant protection.
This review summarises the current findings regarding the therapeutic effects of GBE and its active ingredients in relation to the Nrf2 antioxidant cascade, to provide scientific insights into the clinical applications of GBE in treating oxidative stress-induced diseases.We found that GBE or its active ingredients activate several signalling mechanisms in cells, including the Nrf2 pathway, which is the master controller of the antioxidant defence that detoxifies reactive oxygen species (ROS). ROS-mediated cell and tissue damage contributes to ageing and pathological conditions that underlie several important human diseases, such as diabetic nephropathy (DN), ischemic stroke and age-related macular degeneration (AMD).GBE or its component antioxidants could be applied for the treatment and/or prevention of DN, ischemic stroke and AMD due to their capacity to activate Nrf2 signalling. These strategies may also be applicable to the treatment of other similar conditions that are induced by oxidative stress. Thus, the therapeutic applications of GBE could be expanded.
2022-03-29 | α-Lipoic Acid Strengthens the Antioxidant Barrier and Reduces Oxidative, Nitrosative, and Glycative Damage, as well as Inhibits Inflammation and Apoptosis in the Hypothalamus but Not in the Cerebral Cortex of Insulin-Resistant Rats
The research determined the role of α-lipoic acid (ALA) in reducing the brain manifestations of insulin resistance. The mechanism of ALA action is mainly based on its ability to "scavenge" oxygen free radicals and stimulate biosynthesis of reduced glutathione (GSH), considered the most critical brain antioxidant. Although the protective effect of ALA is widely documented in various diseases, there are still no studies assessing the influence of ALA on brain metabolism in the context of insulin resistance and type 2 diabetes. The experiment was conducted on male Wistar rats fed a high-fat diet for ten weeks with intragastric administration of ALA for four weeks. We are the first to demonstrate that ALA improves the function of enzymatic and nonenzymatic brain antioxidant systems, but the protective effects of ALA were mainly observed in the hypothalamus of insulin-resistant rats. Indeed, ALA caused a significant increase in superoxide dismutase, catalase, peroxidase, and glutathione reductase activities, as well as GSH concentration and redox potential ([GSH]2/[GSSG]) in the hypothalamus of HFD-fed rats. A consequence of antioxidant barrier enhancement by ALA is the reduction of oxidation, glycation, and nitration of brain proteins, lipids, and DNA. The protective effects of ALA result from hypothalamic activation of the transcription factor Nrf2 and inhibition of NF-κB. In the hypothalamus of insulin-resistant rats, we demonstrated reduced levels of oxidation (AOPP) and glycation (AGE) protein products, 4-hydroxynoneal, 8-isoprostanes, and 3-nitrotyrosine and, in the cerebral cortex, lower levels of 8-hydroxydeoxyguanosine and peroxynitrite. In addition, we demonstrated that ALA decreases levels of proinflammatory TNF-α but also increases the synthesis of anti-inflammatory IL-10 in the hypothalamus of insulin-resistant rats. ALA also prevents neuronal apoptosis, confirming its multidirectional effects within the brain. Interestingly, we have shown no correlation between brain and serum/plasma oxidative stress biomarkers, indicating the different nature of redox imbalance at the central and systemic levels. To summarize, ALA improves antioxidant balance and diminishes oxidative/glycative stress, protein nitrosative damage, inflammation, and apoptosis, mainly in the hypothalamus of insulin-resistant rats. Further studies are needed to determine the molecular mechanism of ALA action within the brain.
small molecules
2023-11-28 | AKR1B1 drives hyperglycemia-induced metabolic reprogramming in MASLD-associated hepatocellular carcinoma
The mechanism behind the progressive pathological alteration in metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH)-associated hepatocellular carcinoma (HCC) is poorly understood. In the present study, we investigated the role of the polyol pathway enzyme AKR1B1 in metabolic switching associated with MASLD/MASH and in the progression of HCC. AKR1B1 expression was estimated in the tissue and plasma of patients with MASLD/MASH, HCC, and HCC with diabetes mellitus. The role of AKR1B1 in metabolic switching in vitro was assessed through media conditioning, lentiviral transfection, and pharmacological probes. A proteomic and metabolomic approach was applied for the in-depth investigation of metabolic pathways. Preclinically, mice were subjected to a high-fructose diet and diethylnitrosamine to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching characteristic of MASLD-HCC. A significant increase in the expression of AKR1B1 was observed in tissue and plasma samples from patients with MASLD/MASH, HCC, and HCC with diabetes mellitus compared to normal samples. Mechanistically, in vitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, the tricarboxylic acid cycle, and lipogenesis to promote hyperglycemia-mediated MASLD and cancer progression. A pathological increase in the expression of AKR1B1 was observed in experimental MASLD-HCC, and expression was positively correlated with high blood glucose levels. High-fructose diet + diethylnitrosamine-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. AKR1B1 inhibition with epalrestat or NARI-29 inhibited cellular metabolism in in vitro and in vivo models. Pathological AKR1B1 modulates hepatic metabolism to promote MASLD-associated hepatocarcinogenesis. Aldose reductase inhibition modulates the glycolytic pathway to prevent precancerous hepatocyte formation. This research work highlights AKR1B1 as a druggable target in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), which could provide the basis for the development of new chemotherapeutic agents. Moreover, our results indicate the potential of plasma AKR1B1 levels as a prognostic marker and diagnostic test for MASLD and associated HCC. Additionally, a major observation in this study was that AKR1B1 is associated with the promotion of the Warburg effect in HCC.
2023-06-29 | Screening Effect of Amino Acid on Xylitol Production By Recombinant Escherichia coli System
Numerical studies have been conducted to sources for safer biological methods to produce xylitol. In view of these concerns and the benefits of xylitol, a fermentation process that is formulated to yield highest xylitol is both favourable and profitable. In this study, recovery of xylitol production from xylose by recombinant Escherichia coli system was conducted by modulating both carbon source and amino acid composition of the media for the relative growth delay of the strain. The key enzyme for xylitol production in this recombinant system is xylose reductase, XR which utilize NADPH to reduce D-xylose to xylitol. By adding 20 types of amino acids individually and substituting glycerol as the carbon source each time, showed an increase of xylitol to 5.24 g/L and yield biomass production to 1.536. It is hypothesize that supply of single amino acid act as a tool to enhance (NAD(P)H)/(NADP+) ratio. Reduced NAD(P)H competition from other bioprocesses help the cell replenishes the reduced cofactor pool. Xylitol has a remarkable benefits as a healthy replacement of table sugar. Therefore, the success of this study will definitely bring forward advance in the production technology and act as a reference for future research.
2023-01-11 | AKR1B1 drives hyperglycemia-induced metabolic reprogramming in NAFLD-associated carcinogenesis and progression of hepatocellular carcinoma
Abstract Objective Emergent epidemiological evidence suggests that the progression of NAFLD/NASH-associated HCC positively correlates with the patient's glycemic index. However, the mechanism behind this progressive pathological alteration is poorly understood. It has shown that the polyol pathway master regulator, AKR1B1 is over-expressed in hyperglycemia and responsible for most of diabetic complications. Hence in the present study, we have investigated the role of AKR1B1 in metabolic switching associated with NAFLD/NASH and in the progression of HCC. Methods The expression of AKR1B1 in NAFL/NASH, HCC, and HCC with diabetes mellitus patient's liver and plasma were estimated. The role of AKR1B1 in the metabolic switching of HCC cell lines was assessed through media conditioning and lentiviral transfection. Standard inhibitor epalrestat or investigational drug NARI-29 (4-((Z)-5-((Z)-2-Cyano-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl) benzoic acid) was utilized to elucidate the effect of AKR1B1 inhibition in hepatocarcinogenesis. A proteomic approach was applied for an in-depth investigation of the involved metabolic pathway and to evaluate the therapeutic efficacy of pharmacological inhibitors. Preclinically, a high fructose diet (HFrD) fed in combination with a diethyl nitrosamine (DEN) induced mouse model was developed to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching in the pathobiology of NAFLD and its progression to HCC. Results A significant increase in the expression of AKR1B1 was observed in NAFL/NASH, HCC, and HCC-DM tissue samples compared to non-involved adjacent tissues indicating its role in the disease progression. Moreover, a statistically significant elevation of AKR1B1 was observed in NAFLD, NAFLD-associated HCC, and HCC-DM plasma samples compared to normal control. Mechanistically, Invitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, TCA cycle, and lipogenesis to promote hyperglycemia-mediated fatty liver and cancer progression. A pathologically increased expression of AKR1B1 was observed in experimental NAFL-HCC, and expression was positively correlated with high blood glucose levels. HFrD + DEN-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. However, AKR1B1 inhibition with EPS or NARI-29 has inhibited cellular metabolism in vitro and in vivo models. Conclusion Pathological AKR1B1 modulates hepatic glucose metabolism to promote NAFLD-associated hepato-carcinogenesis. Aldose reductase inhibition modulates glucose metabolism to prevent the pre-cancerous hepatocyte formation. Hence EPS and NARI-29 could be promising AKR1B1 inhibitors for controlling aberrant metabolism and treating NAFLD-associated HCC.
2022-04-29 | The potential of Ginkgo biloba in the treatment of human diseases and the relationship to Nrf2-mediated antioxidant protection.
This review summarises the current findings regarding the therapeutic effects of GBE and its active ingredients in relation to the Nrf2 antioxidant cascade, to provide scientific insights into the clinical applications of GBE in treating oxidative stress-induced diseases.We found that GBE or its active ingredients activate several signalling mechanisms in cells, including the Nrf2 pathway, which is the master controller of the antioxidant defence that detoxifies reactive oxygen species (ROS). ROS-mediated cell and tissue damage contributes to ageing and pathological conditions that underlie several important human diseases, such as diabetic nephropathy (DN), ischemic stroke and age-related macular degeneration (AMD).GBE or its component antioxidants could be applied for the treatment and/or prevention of DN, ischemic stroke and AMD due to their capacity to activate Nrf2 signalling. These strategies may also be applicable to the treatment of other similar conditions that are induced by oxidative stress. Thus, the therapeutic applications of GBE could be expanded.
2022-03-29 | α-Lipoic Acid Strengthens the Antioxidant Barrier and Reduces Oxidative, Nitrosative, and Glycative Damage, as well as Inhibits Inflammation and Apoptosis in the Hypothalamus but Not in the Cerebral Cortex of Insulin-Resistant Rats
The research determined the role of α-lipoic acid (ALA) in reducing the brain manifestations of insulin resistance. The mechanism of ALA action is mainly based on its ability to "scavenge" oxygen free radicals and stimulate biosynthesis of reduced glutathione (GSH), considered the most critical brain antioxidant. Although the protective effect of ALA is widely documented in various diseases, there are still no studies assessing the influence of ALA on brain metabolism in the context of insulin resistance and type 2 diabetes. The experiment was conducted on male Wistar rats fed a high-fat diet for ten weeks with intragastric administration of ALA for four weeks. We are the first to demonstrate that ALA improves the function of enzymatic and nonenzymatic brain antioxidant systems, but the protective effects of ALA were mainly observed in the hypothalamus of insulin-resistant rats. Indeed, ALA caused a significant increase in superoxide dismutase, catalase, peroxidase, and glutathione reductase activities, as well as GSH concentration and redox potential ([GSH]2/[GSSG]) in the hypothalamus of HFD-fed rats. A consequence of antioxidant barrier enhancement by ALA is the reduction of oxidation, glycation, and nitration of brain proteins, lipids, and DNA. The protective effects of ALA result from hypothalamic activation of the transcription factor Nrf2 and inhibition of NF-κB. In the hypothalamus of insulin-resistant rats, we demonstrated reduced levels of oxidation (AOPP) and glycation (AGE) protein products, 4-hydroxynoneal, 8-isoprostanes, and 3-nitrotyrosine and, in the cerebral cortex, lower levels of 8-hydroxydeoxyguanosine and peroxynitrite. In addition, we demonstrated that ALA decreases levels of proinflammatory TNF-α but also increases the synthesis of anti-inflammatory IL-10 in the hypothalamus of insulin-resistant rats. ALA also prevents neuronal apoptosis, confirming its multidirectional effects within the brain. Interestingly, we have shown no correlation between brain and serum/plasma oxidative stress biomarkers, indicating the different nature of redox imbalance at the central and systemic levels. To summarize, ALA improves antioxidant balance and diminishes oxidative/glycative stress, protein nitrosative damage, inflammation, and apoptosis, mainly in the hypothalamus of insulin-resistant rats. Further studies are needed to determine the molecular mechanism of ALA action within the brain.
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