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Satish K. Srivastava - One of the best experts on this subject based on the ideXlab platform.
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abstract 1682 combined treatment of aldose reductase inhibitor Fidarestat and anti pd1 antibodies synergistically prevents t cell and nk cell mediated colon cancer growth in murine models
Immunology, 2018Co-Authors: Ashish Saxena, Himangshu Sonowal, Satish K. Srivastava, Kota V. RamanaAbstract:Immune checkpoint inhibitors such as anti-programmed death 1 (PD1) and anti-PD-L1 monoclonal antibodies though have great potential for cancer immunotherapy, the acquired drug resistance and unwanted immune side effects limit their use. However, the combination therapy using conventional drugs and immune checkpoint inhibitors not only synergistically increase anti-tumor responses but it also reduces immune-associated adverse events. In our earlier studies, we have shown that inhibition of polyol pathway enzyme, aldose reductase (AR) prevents colon cancer growth and metastasis in culture as well as in mouse models. In this study, we investigated whether Fidarestat, a potent AR inhibitor that has already gone through Phase-III clinical trial for diabetic neuropathy and found to safe for human use, can synergize with anti PD-1 to increase antitumor activity and decrease immune-associated adverse effects. Mice bearing syngeneic CT26 colon carcinoma tumors were treated with anti PD-1 alone or in combination with Fidarestat, and the tumor growth was monitored. Our results indicate that Fidarestat in combination with anti-PD1 synergistically increases tumor regression within 28 days of treatment. Further, a combination of Fidarestat and anti-PD1 significantly increased the CD8+ T cells and natural killer (NK) cells and decreased the Myeloid-derived suppressor cells (MDSCs) at tumor milieu. Fidarestat plus anti-PD1 also increased CD8+ T cell and NK cell effector functions as determined by IFNg and granzyme B. Systemically, combination therapy also increased the number of CD8+ T cells and NK cells and decreased MDSCs in the mouse spleens. Further, the effector functions of CD8+ T cells and NK cells were increased with the combination treatment in mice spleens. Moreover, the levels of various inflammatory cytokines and chemokines in the serum and liver were significantly less in Fidarestat plus anti-PD1 -treated mice as compared to anti-PD1 alone -treated mice indicating that Fidarestat rescues immune-mediated adverse events in various organs. Thus, our results suggest that by regulating the number as well as effector function of CD8+ T cells, NK cells and MDSCs, AR inhibitor in combination with anti-PD1 would not only regress the tumor growth but would also provide a long-lasting specific immunity against colon cancer, which would decrease the chances of tumor recurrence. Citation Format: Ashish Saxena, Himangshu Sonowal, Satish K. Srivastava, Kota V. Ramana. Combined treatment of aldose reductase inhibitor, Fidarestat, and anti-PD1 antibodies synergistically prevents T cell- and NK cell-mediated colon cancer growth in murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1682.
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aldose reductase inhibitor Fidarestat prevents doxorubicin induced endothelial cell death and dysfunction
Biochemical Pharmacology, 2018Co-Authors: Himangshu Sonowal, Satish K. Srivastava, Pabitra Bikash Pal, Kirtikar Shukla, Ashish Saxena, Kota V. RamanaAbstract:Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, Fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy. However, the efficacy of Fidarestat in the prevention of Dox-induced endothelial dysfunction, a pathological event critical to cardiovascular complications, is not known. Here, we have examined the effect of Fidarestat on Dox-induced endothelial cell toxicity and dysfunction in vitro and in vivo. Incubation of human umbilical vein endothelial cells (HUVECs) with Dox significantly increased the endothelial cell death, and pre-treatment of Fidarestat prevented it. Further, Fidarestat prevented the Dox-induced oxidative stress, formation of reactive oxygen species (ROS) and activation of Caspase-3 in HUVECs. Fidarestat also prevented Dox-induced monocyte adhesion to HUVECs and expression of ICAM-1 and VCAM-1. Fidarestat pre-treatment to HUVECs restored the Dox-induced decrease in the Nitric Oxide (NO)-levels and eNOS expression. Treatment of HUVECs with Dox caused a significant increase in the activation of NF-κB and expression of various inflammatory cytokines and chemokines which were prevented by Fidarestat pre-treatment. Most importantly, Fidarestat prevented the Dox-induced mouse cardiac cell hypertrophy and expression of eNOS, iNOS, and 3-Nitrotyrosine in the aorta tissues. Further, Fidarestat blunted the Dox-induced expression of various inflammatory cytokines and chemokines in vivo. Thus, our results suggest that by preventing Dox-induced endothelial cytotoxicity and dysfunction, AR inhibitors could avert cardiotoxicity associated with anthracycline chemotherapy.
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aldose reductase inhibitor Fidarestat regulates mitochondrial biogenesis via nrf2 ho 1 ampk pathway in colon cancer cells
Cancer Letters, 2017Co-Authors: Kirtikar Shukla, Kota V. Ramana, Himangshu Sonowal, Ashish Saxena, Satish K. SrivastavaAbstract:Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, Fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, Fidarestat augmented the EGF-induced expression of Nrf2 in CRC cells. Fidarestat also increased the Nrf2 -DNA binding activity as well as expression of HO-1 and NQO1 and activation of SOD and catalase in SW480 cells. Similarly, in nude mice xenograft tumor tissues, Nrf2 and HO-1 levels were significantly higher in Fidarestat-treated mice compared to controls. Further, stimulation of CRC cells with EGF in the presence of Fidarestat increased the mRNA levels of PGC-1α, Nrf1 and TFAM and protein levels of PGC-1α, TFAM and COX-IV and decreased the mitochondrial DNA damage as measured by 8-hydroxy-2'-deoxyguanosine levels. AR inhibitor also modulated the phosphorylations of AMPK and mTOR and expression of p53 in EGF-treated cells. Collectively, our results indicate that AR inhibitor prevents CRC growth by increasing mitochondrial biogenesis via increasing the expression of Nrf2/HO-1/AMPK/p53 and decreasing the mitochondrial DNA damage.
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aldose reductase inhibitor Fidarestat prevents high fat diet induced intestinal polyps in apcmin mice
Current Cancer Drug Targets, 2017Co-Authors: Ashish Saxena, Kota V. Ramana, Ravinder Tammali, Satish K. SrivastavaAbstract:Background Recent epidemiological and experimental studies have shown that obesity is a major risk factor for Colorectal Cancer (CRC). Regular intake of high fat-containing diet can promote obesity and metabolic syndrome by increasing the insulin resistance and inflammatory response which contribute to carcinogenesis. Previously, we have shown that inhibition of polyol pathway enzyme aldose reductase (AR) prevents carcinogens- and inflammatory growth factorsinduced CRC. However, the effect of AR inhibition on a high-fat diet (HFD)-induced formation of intestinal polyps in Apc-deficient Min (multiple intestinal neoplasia; ApcMin/+) mice is not known. Methods We examined the effect of AR inhibitor, Fidarestat on the HFD-induced formation of preneoplastic intestinal polyps in ApcMin/+ mice which is an excellent model of colon cancer. Results APCMin/+ mice fed for 12 weeks of HFD caused a significant increase in the formation of polyps in the small and large intestines and Fidarestat given along with the HFD prevented the number of intestinal polyps. Fidarestat also decreased the size of the polyps in the intestines of HFDtreated APC Min mice. Further, the expression levels of beta-catenin, PCNA, PKC-β2, P-AKT, Pp65, COX-2, and iNOS in the small and large intestines of HFD-treated mice significantly increased, and AR inhibitor prevented it. Conclusion Our results thus suggest that Fidarestat could be used as a potential chemopreventive drug for intestinal cancers due to APC gene mutations.
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aldose reductase inhibitor protects against hyperglycemic stress by activating nrf2 dependent antioxidant proteins
Experimental Diabetes Research, 2017Co-Authors: Kirtikar Shukla, Himangshu Sonowal, Satish K. Srivastava, Pabitra Bikash Pal, Kota V. RamanaAbstract:We have shown earlier that pretreatment of cultured cells with aldose reductase (AR) inhibitors prevents hyperglycemia-induced mitogenic and proinflammatory responses. However, the effects of AR inhibitors on Nrf2-mediated anti-inflammatory responses have not been elucidated yet. We have investigated how AR inhibitor Fidarestat protects high glucose- (HG-) induced cell viability changes by increasing the expression of Nrf2 and its dependent phase II antioxidant enzymes. Fidarestat pretreatment prevents HG (25 mM)-induced Thp1 monocyte viability. Further, treatment of Thp1 monocytes with Fidarestat caused a time-dependent increase in the expression as well as the DNA-binding activity of Nrf2. In addition, Fidarestat augmented the HG-induced Nrf2 expression and activity and also upregulated the expression of Nrf2-dependent proteins such as hemeoxygenase-1 (HO1) and NQO1 in Thp1 cells. Similarly, treatment with AR inhibitor also induced the expression of Nrf2 and HO1 in STZ-induced diabetic mice heart and kidney tissues. Further, AR inhibition increased the HG-induced expression of antioxidant enzymes such as SOD and catalase and activation of AMPK-α1 in Thp1 cells. Our results thus suggest that pretreatment with AR inhibitor prepares the monocytes against hyperglycemic stress by overexpressing the Nrf2-dependent antioxidative proteins.
Kota V. Ramana - One of the best experts on this subject based on the ideXlab platform.
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abstract 1682 combined treatment of aldose reductase inhibitor Fidarestat and anti pd1 antibodies synergistically prevents t cell and nk cell mediated colon cancer growth in murine models
Immunology, 2018Co-Authors: Ashish Saxena, Himangshu Sonowal, Satish K. Srivastava, Kota V. RamanaAbstract:Immune checkpoint inhibitors such as anti-programmed death 1 (PD1) and anti-PD-L1 monoclonal antibodies though have great potential for cancer immunotherapy, the acquired drug resistance and unwanted immune side effects limit their use. However, the combination therapy using conventional drugs and immune checkpoint inhibitors not only synergistically increase anti-tumor responses but it also reduces immune-associated adverse events. In our earlier studies, we have shown that inhibition of polyol pathway enzyme, aldose reductase (AR) prevents colon cancer growth and metastasis in culture as well as in mouse models. In this study, we investigated whether Fidarestat, a potent AR inhibitor that has already gone through Phase-III clinical trial for diabetic neuropathy and found to safe for human use, can synergize with anti PD-1 to increase antitumor activity and decrease immune-associated adverse effects. Mice bearing syngeneic CT26 colon carcinoma tumors were treated with anti PD-1 alone or in combination with Fidarestat, and the tumor growth was monitored. Our results indicate that Fidarestat in combination with anti-PD1 synergistically increases tumor regression within 28 days of treatment. Further, a combination of Fidarestat and anti-PD1 significantly increased the CD8+ T cells and natural killer (NK) cells and decreased the Myeloid-derived suppressor cells (MDSCs) at tumor milieu. Fidarestat plus anti-PD1 also increased CD8+ T cell and NK cell effector functions as determined by IFNg and granzyme B. Systemically, combination therapy also increased the number of CD8+ T cells and NK cells and decreased MDSCs in the mouse spleens. Further, the effector functions of CD8+ T cells and NK cells were increased with the combination treatment in mice spleens. Moreover, the levels of various inflammatory cytokines and chemokines in the serum and liver were significantly less in Fidarestat plus anti-PD1 -treated mice as compared to anti-PD1 alone -treated mice indicating that Fidarestat rescues immune-mediated adverse events in various organs. Thus, our results suggest that by regulating the number as well as effector function of CD8+ T cells, NK cells and MDSCs, AR inhibitor in combination with anti-PD1 would not only regress the tumor growth but would also provide a long-lasting specific immunity against colon cancer, which would decrease the chances of tumor recurrence. Citation Format: Ashish Saxena, Himangshu Sonowal, Satish K. Srivastava, Kota V. Ramana. Combined treatment of aldose reductase inhibitor, Fidarestat, and anti-PD1 antibodies synergistically prevents T cell- and NK cell-mediated colon cancer growth in murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1682.
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aldose reductase inhibitor Fidarestat prevents doxorubicin induced endothelial cell death and dysfunction
Biochemical Pharmacology, 2018Co-Authors: Himangshu Sonowal, Satish K. Srivastava, Pabitra Bikash Pal, Kirtikar Shukla, Ashish Saxena, Kota V. RamanaAbstract:Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, Fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy. However, the efficacy of Fidarestat in the prevention of Dox-induced endothelial dysfunction, a pathological event critical to cardiovascular complications, is not known. Here, we have examined the effect of Fidarestat on Dox-induced endothelial cell toxicity and dysfunction in vitro and in vivo. Incubation of human umbilical vein endothelial cells (HUVECs) with Dox significantly increased the endothelial cell death, and pre-treatment of Fidarestat prevented it. Further, Fidarestat prevented the Dox-induced oxidative stress, formation of reactive oxygen species (ROS) and activation of Caspase-3 in HUVECs. Fidarestat also prevented Dox-induced monocyte adhesion to HUVECs and expression of ICAM-1 and VCAM-1. Fidarestat pre-treatment to HUVECs restored the Dox-induced decrease in the Nitric Oxide (NO)-levels and eNOS expression. Treatment of HUVECs with Dox caused a significant increase in the activation of NF-κB and expression of various inflammatory cytokines and chemokines which were prevented by Fidarestat pre-treatment. Most importantly, Fidarestat prevented the Dox-induced mouse cardiac cell hypertrophy and expression of eNOS, iNOS, and 3-Nitrotyrosine in the aorta tissues. Further, Fidarestat blunted the Dox-induced expression of various inflammatory cytokines and chemokines in vivo. Thus, our results suggest that by preventing Dox-induced endothelial cytotoxicity and dysfunction, AR inhibitors could avert cardiotoxicity associated with anthracycline chemotherapy.
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aldose reductase inhibitor Fidarestat regulates mitochondrial biogenesis via nrf2 ho 1 ampk pathway in colon cancer cells
Cancer Letters, 2017Co-Authors: Kirtikar Shukla, Kota V. Ramana, Himangshu Sonowal, Ashish Saxena, Satish K. SrivastavaAbstract:Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, Fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, Fidarestat augmented the EGF-induced expression of Nrf2 in CRC cells. Fidarestat also increased the Nrf2 -DNA binding activity as well as expression of HO-1 and NQO1 and activation of SOD and catalase in SW480 cells. Similarly, in nude mice xenograft tumor tissues, Nrf2 and HO-1 levels were significantly higher in Fidarestat-treated mice compared to controls. Further, stimulation of CRC cells with EGF in the presence of Fidarestat increased the mRNA levels of PGC-1α, Nrf1 and TFAM and protein levels of PGC-1α, TFAM and COX-IV and decreased the mitochondrial DNA damage as measured by 8-hydroxy-2'-deoxyguanosine levels. AR inhibitor also modulated the phosphorylations of AMPK and mTOR and expression of p53 in EGF-treated cells. Collectively, our results indicate that AR inhibitor prevents CRC growth by increasing mitochondrial biogenesis via increasing the expression of Nrf2/HO-1/AMPK/p53 and decreasing the mitochondrial DNA damage.
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aldose reductase inhibitor Fidarestat prevents high fat diet induced intestinal polyps in apcmin mice
Current Cancer Drug Targets, 2017Co-Authors: Ashish Saxena, Kota V. Ramana, Ravinder Tammali, Satish K. SrivastavaAbstract:Background Recent epidemiological and experimental studies have shown that obesity is a major risk factor for Colorectal Cancer (CRC). Regular intake of high fat-containing diet can promote obesity and metabolic syndrome by increasing the insulin resistance and inflammatory response which contribute to carcinogenesis. Previously, we have shown that inhibition of polyol pathway enzyme aldose reductase (AR) prevents carcinogens- and inflammatory growth factorsinduced CRC. However, the effect of AR inhibition on a high-fat diet (HFD)-induced formation of intestinal polyps in Apc-deficient Min (multiple intestinal neoplasia; ApcMin/+) mice is not known. Methods We examined the effect of AR inhibitor, Fidarestat on the HFD-induced formation of preneoplastic intestinal polyps in ApcMin/+ mice which is an excellent model of colon cancer. Results APCMin/+ mice fed for 12 weeks of HFD caused a significant increase in the formation of polyps in the small and large intestines and Fidarestat given along with the HFD prevented the number of intestinal polyps. Fidarestat also decreased the size of the polyps in the intestines of HFDtreated APC Min mice. Further, the expression levels of beta-catenin, PCNA, PKC-β2, P-AKT, Pp65, COX-2, and iNOS in the small and large intestines of HFD-treated mice significantly increased, and AR inhibitor prevented it. Conclusion Our results thus suggest that Fidarestat could be used as a potential chemopreventive drug for intestinal cancers due to APC gene mutations.
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aldose reductase inhibitor protects against hyperglycemic stress by activating nrf2 dependent antioxidant proteins
Experimental Diabetes Research, 2017Co-Authors: Kirtikar Shukla, Himangshu Sonowal, Satish K. Srivastava, Pabitra Bikash Pal, Kota V. RamanaAbstract:We have shown earlier that pretreatment of cultured cells with aldose reductase (AR) inhibitors prevents hyperglycemia-induced mitogenic and proinflammatory responses. However, the effects of AR inhibitors on Nrf2-mediated anti-inflammatory responses have not been elucidated yet. We have investigated how AR inhibitor Fidarestat protects high glucose- (HG-) induced cell viability changes by increasing the expression of Nrf2 and its dependent phase II antioxidant enzymes. Fidarestat pretreatment prevents HG (25 mM)-induced Thp1 monocyte viability. Further, treatment of Thp1 monocytes with Fidarestat caused a time-dependent increase in the expression as well as the DNA-binding activity of Nrf2. In addition, Fidarestat augmented the HG-induced Nrf2 expression and activity and also upregulated the expression of Nrf2-dependent proteins such as hemeoxygenase-1 (HO1) and NQO1 in Thp1 cells. Similarly, treatment with AR inhibitor also induced the expression of Nrf2 and HO1 in STZ-induced diabetic mice heart and kidney tissues. Further, AR inhibition increased the HG-induced expression of antioxidant enzymes such as SOD and catalase and activation of AMPK-α1 in Thp1 cells. Our results thus suggest that pretreatment with AR inhibitor prepares the monocytes against hyperglycemic stress by overexpressing the Nrf2-dependent antioxidative proteins.
N Kato - One of the best experts on this subject based on the ideXlab platform.
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amelioration of acute kidney injury in lipopolysaccharide induced systemic inflammatory response syndrome by an aldose reductase inhibitor Fidarestat
PLOS ONE, 2012Co-Authors: Kazunori Takahashi, N Kato, Hiroki Mizukami, Kosuke Kamata, Wataru Inaba, Chihiro Hibi, Soroku YagihashiAbstract:Background Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. Methods Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. Results Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. Conclusion AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality.
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aldose reductase inhibitor Fidarestat prevents diabetic ocular complications in spontaneously diabetic torii rats
The Open Diabetes Journal, 2011Co-Authors: Akihiro Kakehashi, N Kato, Masanobu Kawakami, Mikiko Takezawa, Fumihiko Toyoda, Nozomi Kinoshita, Chiho Kambara, Hiroko Yamagami, Sane Ishikawa, Yasunori KanazawaAbstract:We evaluated the effect of an aldose reductase inhibitor, Fidarestat, on diabetic retinopathy (DR) and cataract in spontaneously diabetic Torii (SDT) rats. Four rat groups were included: untreated, low- and high-dose (8 and 32 mg/kg/day) Fidarestat-treated SDT rats, and nondiabetic control Sprague-Dawley rats. DR and cataract were evaluated and retinal and lens sorbitol, reduced glutathione (GSH), ocular fluid vascular endothelial growth factor (VEGF), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured. The incidence rates of DR and cataract were significantly lower in the low- and high-dose Fidarestat groups vs the untreated group (p<0.001/p<0.001). Retinal and lens sorbitol levels were lower in the control (1.1±0.1/3.1±0.2 nmol/mg protein) (p<0.05/p<0.01) and low- (2.7±1.1/30.0±3.3 nmol/mg protein) (p<0.01/p<0.01) and high-dose groups (0.7±0.2/5.9±0.6 nmol/mg protein) (p<0.001/p<0.001) vs the untreated group (23.2±4.7/123.9±29.6 nmol/mg protein). Retinal and lens GSH levels were higher in the nondiabetic control (52.2±5.8/29.0±2.7 � mol/mg protein) (p<0.01/p<0.001) and the low- (46.8±8.2/24.7±2.8 � mol/mg protein) (not significant (NS)/p<0.001) and high-dose groups (63.3±14.6/26.9±3.6 � mol/mg protein) (p<0.05/p<0.001) vs the untreated group (30.3±2.0/1.6±0.4 � mol/mg protein). VEGF levels were lower in the nondiabetic control (40.4±10.0 pg/ml) (p<0.01) and low- (65.3±4.5 pg/ml) (p<0.05) and high-dose groups (47.7±10 pg/ml) (p<0.001) vs the untreated group (324.7±76.4 pg/ml). 8-OHdG levels were lower in the nondiabetic control (0.73±0.11 ng/mg creatinine) (p<0.01) and low- (4.57±0.42 ng/mg creatinine) (NS) and high-dose groups (3.58±0.70 ng/mg creatinine) (NS) vs the untreated group (6.04±1.28 ng/ml). Fidarestat inhibited activation of the polyol pathway, reduced oxidative stress and VEGF, and prevented DR and cataract in SDT rats.
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effect of the aldose reductase inhibitor Fidarestat on experimental diabetic neuropathy in the rat
Diabetologia, 2006Co-Authors: Yoshimasa Kuzumoto, Susumu Kusunoki, N KatoAbstract:Aims/hypothesis Fidarestat, an aldose reductase inhibitor (ARI), has been reported to improve clinical symptoms and nerve conduction deficits in human diabetic neuropathy. We evaluated the dose-dependency and some of the mechanisms of the drug action in experimental diabetic neuropathy (EDN).
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long term treatment with Fidarestat suppresses the development of diabetic retinopathy in stz induced diabetic rats
Journal of Diabetes and Its Complications, 2003Co-Authors: N Kato, Satomi Yashima, Takeshi Suzuki, Yukiharu Nakayama, Takahito JomoriAbstract:It is important to suppress retinal vascular changes for prevention of the onset and progression of diabetic retinopathy. In the present study, we investigated the dose-response effect of an aldose reductase (AR) inhibitor, Fidarestat, on retinal vascular changes in the retinas of streptozotocin (STZ)-induced diabetic rats. Fidarestat (0.5, 1, and 2 mg/kg) was administered once a day, from 4 days after STZ injection, for 15 months. Microaneurysms and thickness of the basement membrane were frequently observed in the untreated diabetic group as compared to the nondiabetic control group. In addition, the number of pericytes decreased in the untreated diabetic group. Fidarestat diminished the prevalence rate of microaneurysms, basement membrane thickness and decrease in the number of pericytes, and complete suppression was observed at a dose of 2 mg/kg. Fidarestat also dose-dependently inhibited sorbitol accumulation in the retina. Furthermore, a close correlation was observed between the prevalence rate of microaneurysms and the decrease in the number of pericytes, which indicated that damage to pericytes triggers retinal vascular changes. These results suggest that Fidarestat, by virtue of its long-term correction of the accelerated polyol pathway, has a potential role in preventing the progression of diabetic retinopathy.
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sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes
Biochemical and Biophysical Research Communications, 2002Co-Authors: Shinjiro Amano, Mitsuhiro Makino, N Kato, Hiroko Hirooka, Kaori Taniko, Takahito Jomori, Shoichi Yamagishi, Yosuke Inagaki, Tamami Okamoto, Masayoshi TakeuchiAbstract:The polyol pathway consists of two enzymes, aldose reductase (AR) and sorbitol dehydrogenase (SDH). There is a growing body of evidence to suggest that acceleration of the polyol pathway is implicated in the pathogenesis of diabetic vascular complications. However, a functional role remains to be elucidated for SDH in the development and progression of diabetic retinopathy. In this study, cultured bovine retinal capillary pericytes were used to investigate the effects of SDH overexpression on glucose toxicity. High glucose modestly increased reactive oxygen species (ROS) generation, decreased DNA synthesis, and up-regulated vascular endothelial growth factor (VEGF) mRNA levels in cultured pericytes. SDH overexpression was found to significantly stimulate ROS generation in high glucose-exposed pericytes and subsequently potentiate the cytopathic effects of glucose. Fidarestat, a newly developed AR inhibitor, and N-acetylcysteine, an antioxidant, completely prevented these deleterious effects of SDH overexpression on pericytes. Furthermore, Fidarestat administration was found to significantly prevent vascular hyperpermeability, the characteristic changes of the early phase of diabetic retinopathy, in streptozotocin-induced diabetic rats. Our present results suggest that SDH-mediated conversion of sorbitol to fructose and the resultant ROS generation may play an active role in the pathogenesis of diabetic retinopathy. Blockage of sorbitol formation by Fidarestat could be a promising therapeutic strategy for the treatment of early phase of diabetic retinopathy.
Soroku Yagihashi - One of the best experts on this subject based on the ideXlab platform.
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Amelioration of Acute Kidney Injury in Lipopolysaccharide-Induced Systemic Inflammatory Response Syndrome by an Aldose Reductase Inhibitor,
2013Co-Authors: Kazunori Takahashi, Hiroki Mizukami, Kosuke Kamata, Wataru Inaba, Chihiro Hibi, Noriaki Kato, Soroku YagihashiAbstract:Background: Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. Methods: Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1b, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-a) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. Results: Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation
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amelioration of acute kidney injury in lipopolysaccharide induced systemic inflammatory response syndrome by an aldose reductase inhibitor Fidarestat
PLOS ONE, 2012Co-Authors: Kazunori Takahashi, N Kato, Hiroki Mizukami, Kosuke Kamata, Wataru Inaba, Chihiro Hibi, Soroku YagihashiAbstract:Background Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. Methods Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. Results Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. Conclusion AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality.
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aldose reductase deficient mice are protected from delayed motor nerve conduction velocity increased c jun nh2 terminal kinase activation depletion of reduced glutathione increased superoxide accumulation and dna damage
Diabetes, 2006Co-Authors: Karen S L Lam, Soroku Yagihashi, Shinichiro Yamagishi, Yuk Shan Chen, Johnny C W Yip, Meena Arvindakshan, Peter J Oates, Craig A Ellery, Stephen S M Chung, Sookja K ChungAbstract:The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR −/− ) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR +/+ ) and AR −/− mice. Under short-term diabetic conditions, AR −/− mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR +/+ mice. Sorbitol levels in the sciatic nerves of diabetic AR +/+ mice were increased significantly, whereas sorbitol levels in the diabetic AR −/− mice were significantly lower than those in diabetic AR +/+ mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH 2 -terminal kinase (JNK), depletion of reduced glutathione, increase of superoxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR +/+ mice were not observed in the diabetic AR −/− mice, indicating that the diabetic AR −/− mice were protected from oxidative stress in the sciatic nerve. The diabetic AR −/− mice also excreted less 8-hydroxy-2′-deoxyguanosine in urine than diabetic AR +/+ mice. The structural abnormalities observed in the sural nerve of diabetic AR +/+ mice were less severe in the diabetic AR −/− mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI Fidarestat in diabetic AR +/+ nerves, similar to those in diabetic AR −/− mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage.
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effects of polyol pathway hyperactivity on protein kinase c activity nociceptive peptide expression and neuronal structure in dorsal root ganglia in diabetic mice
Diabetes, 2004Co-Authors: Kenji Uehara, Shinichiro Yamagishi, Saori Otsuki, Shyunsuke Chin, Soroku YagihashiAbstract:We explored the specific impact of polyol pathway hyperactivity on dorsal root ganglia (DRG) using transgenic mice that overexpress human aldose reductase because DRG changes are crucial for the development of diabetic sensory neuropathy. Littermate mice served as controls. Half of the animals were made diabetic by streptozotocin injection and followed for 12 weeks. After diabetes onset, diabetic transgenic mice showed a significant elevation of pain sensation threshold after transient decrease and marked slowing of motor and sensory nerve conduction at the end of the study, while these changes were modest in diabetic littermate mice. Protein kinase C (PKC) activities were markedly reduced in diabetic transgenic mice, and the changes were associated with reduced expression of membrane PKC-α isoform that was translocated to cytosol. Membrane PKC-βII isoform expression was contrariwise increased. Calcitonin gene-related peptide–and substance P–positive neurons were reduced in diabetic transgenic mice and less severely so in diabetic littermate mice. Morphometric analysis disclosed neuronal atrophy only in diabetic transgenic mice. Treatment with an aldose reductase inhibitor (Fidarestat 4 mg · kg −1 · day −1 , orally) corrected all of the changes detected in diabetic transgenic mice. These findings underscore the pathogenic role of aldose reductase in diabetic sensory neuropathy through the altered cellular signaling and peptide expressions in DRG neurons.
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differential influence of increased polyol pathway on protein kinase c expressions between endoneurial and epineurial tissues in diabetic mice
Journal of Neurochemistry, 2003Co-Authors: Shinichiro Yamagishi, Kenji Uehara, Saori Otsuki, Soroku YagihashiAbstract:To explore the relationship between polyol pathway and protein kinase C (PKC), we examined PKC activities and expressions of PKC isoforms separately in endoneurial and vessel-rich epineurial tissues in diabetic mice transgenic for human aldose reductase (Tg). Tg and littermate control mice (Lm) were made diabetic by streptozotocin at 8 weeks of age and treated orally with aldose reductase inhibitor (ARI) (Fidarestat 3-5 mg/kg/day) or placebo for 12 weeks. At the end, compared with non-diabetic state, sorbitol contents were increased 6.4-fold in endoneurium and 5.1-fold in epineurium in diabetic Tg, whereas the increase was detected only in endoneurium in diabetic Lm. Endoneurial PKC activity was significantly reduced in diabetic Tg. By contrast, epineurial PKC activity was increased in both diabetic Lm and diabetic Tg and there was no significant difference between the two groups. These changes were all corrected by ARI treatment. Consistent with the changes of PKC activities, diabetic Tg showed decreased expression of PKC alpha in endoneurium, whereas there was an increased expression of PKC beta II in epineurium in both diabetic Tg and diabetic Lm. These findings suggest the presence of dichotomous metabolic pathway between neural and vascular tissues in the polyol-PKC-related pathogenesis of diabetic neuropathy.
Irina G Obrosova - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the aldose reductase inhibitor Fidarestat on ischemia reperfusion injury in rat retina
International Journal of Molecular Medicine, 2010Co-Authors: Irina G Obrosova, Pal Pacher, Yury Maksimchyk, Elisabet Agardh, Majlis Smith, Azza B Elremessy, Carldavid AgardhAbstract:This study evaluated the effects of retinal ischemia-reperfusion (IR) injury and pre-treatment with the potent and specific aldose reductase inhibitor Fidarestat on apoptosis, aldose reductase and sorbitol dehydrogenase expression, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress. Female Wistar rats were pre-treated with either vehicle (N-methyl-D-elucamine) or Fidarestat, 32 mg kg(-1)d(-1) for both, in the right jugular vein, for 3 consecutive days. A group of vehicle- and Fidarestat-treated rats were subjected to 45-min retinal ischemia followed by 24-h reperfusion. Ischemia was induced 30 min after the last vehicle or Fidarestat administration. Retinal IR resulted in a remarkable increase in retinal cell death. The number of TUNEL-positive nuclei increased 48-fold in the IR group compared with non-ischemic controls (p<0.01), and this increase was partially prevented by Fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p<0.05), and this increase was prevented by Fidarestat. Sorbitol dehydrogenase and nitrated protein expressions were similar among all experimental groups. Retinal sorbitol concentrations tended to increase in the ER group but the difference with non-ischemic controls did not achieve statistical significance (p=0.08). Retinal fructose concentrations were 2.2-fold greater in the IR group than in the non-ischemic controls (p<0.05). Fidarestat pre-treatment of rats subjected to IR reduced retinal sorbitol concentration to the levels in non-ischemic controls. Retinal fructose concentrations were reduced by 41% in Fidarestat-pre-treated IR group vs. untreated ischemic controls (p=0.0517), but remained 30% higher than in the non-ischemic control group. In conclusion, IR injury to rat retina is associated with a dramatic increase in cell death. elevated AR expression and sorbitol pathway intermediate accumulation. These changes were prevented or alleviated by the AR inhibitor Fidarestat. The results identify AR as an important therapeutic target for diseases involving IR injury, and provide the rationale for development of Fidarestat and other AR inhibitors. (Less)
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the aldose reductase inhibitor Fidarestat suppresses ischemia reperfusion induced inflammatory response in rat retina
Pharmacology, 2009Co-Authors: Carldavid Agardh, Irina G Obrosova, Elisabet Agardh, Majlis SmithAbstract:Recent studies suggest that increased aldose reductase (AR) activity plays an important role in ischemia-reperfusion injury in the retina. The mechanisms are not completely understood, but may be linked to inflammation. In the present study, we investigated whether the AR inhibitor Fidarestat suppressed the retinal inflammatory response induced by ischemia-reperfusion in a rat model. The inflammatory response was manifested by increased gene expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 (ICAM-1) as well as elevated protein levels of soluble ICAM-1. This response was partially suppressed by the AR inhibitor Fidarestat. The findings may reveal beneficial effects of AR inhibition on retinal inflammation associated with ischemia-reperfusion and are in agreement with recent developments in pharmacological research suggesting that pathological conditions other than diabetes may benefit from AR inhibitors.
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aldose reductase inhibitor Fidarestat counteracts diabetes associated cataract formation retinal oxidative nitrosative stress glial activation and apoptosis
International Journal of Molecular Medicine, 2008Co-Authors: Viktor R Drel, Pal Pacher, Azza B Elremessy, T K Ali, Jeho Shin, U Julius, Irina G ObrosovaAbstract:This study was aimed at evaluating the potent and specific aldose reductase inhibitor Fidarestat, on diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis. Control and streptozotocin-diabetic rats were treated with or without Fidarestat (16 mg kg(-1)d(-1)) for 10 weeks after an initial 2-week period without treatment. Lens changes were evaluated by indirect ophthalmoscopy and portable slit lamp. Nitrotyrosine, poly(ADP-ribose), and glial fibrillary acidic protein expression were assessed by immunohistochemistry. The rate of apoptosis was quantified in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. To dissect the effects of high glucose exposure in retinal microvascular cells, primary bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without Fidarestat (10 microM) for 3-14 days. Apoptosis was assessed by TUNEL assay, nitrotyrosine and poly(ADP-ribose) by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Fidarestat treatment prevented diabetic cataract formation and counteracted retinal nitrosative stress, and poly(ADP-ribose) polymerase activation, as well as glial activation. The number of TUNEL-positive nuclei (mean +/- SEM) was increased approximately 4-fold in diabetic rats vs. controls (207+/-33 vs. 49+/-4, p<0.01), and this increase was partially prevented by Fidarestat (106+/-34, p<0.05 vs. untreated diabetic group). The apoptotic cell number increased with the prolongation of exposure of both pericytes and endothelial cells to high glucose levels. Fidarestat counteracted nitrotyrosine and poly(ADP-ribose) accumulation and apoptosis in both cell types. Antiapoptotic effect of Fidarestat in high glucose-exposed retinal pericytes was not associated with the inhibition of Bax or increase in Bcl-2 expression. In conclusion, the findings, i) support an important role for aldose reductase in diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis, and ii) provide a rationale for the development of aldose reductase inhibitors, and, in particular, Fidarestat, for the prevention and treatment of diabetic ocular complications.
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high fat diet induced neuropathy of pre diabetes and obesity effects of healthy diet and aldose reductase inhibition
Diabetes, 2007Co-Authors: Irina G Obrosova, Nazar Mashtalir, Olga Ilnytska, Valeriy V Lyzogubov, Ivan A Pavlov, Jerry L Nadler, Viktor R DrelAbstract:OBJECTIVE— Subjects with dietary obesity and pre-diabetes have an increased risk for developing both nerve conduction slowing and small sensory fiber neuropathy. Animal models of this type of neuropathy have not been described. This study evaluated neuropathic changes and their amenability to dietary and pharmacological interventions in mice fed a high-fat diet (HFD), a model of pre-diabetes and alimentary obesity. RESEARCH DESIGN AND METHODS— Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks. RESULTS— HFD-fed mice developed obesity, increased plasma FFA and insulin concentrations, and impaired glucose tolerance. They also had motor and sensory nerve conduction deficits, tactile allodynia, and thermal hypoalgesia in the absence of intraepidermal nerve fiber loss or axonal atrophy. Despite the absence of overt hyperglycemia, the mice displayed augmented sorbitol pathway activity in the peripheral nerve, as well as 4-hydroxynonenal adduct nitrotyrosine and poly(ADP-ribose) accumulation and 12/15-lipoxygenase overexpression in peripheral nerve and dorsal root ganglion neurons. A 6-week feeding with normal chow after 16 weeks on HFD alleviated tactile allodynia and essentially corrected thermal hypoalgesia and sensory nerve conduction deficit without affecting motor nerve conduction slowing. Normal chow containing the aldose reductase inhibitor Fidarestat (16 mg · kg−1· day −1) corrected all functional changes of HFD-induced neuropathy. CONCLUSIONS— Similar to human subjects with pre-diabetes and obesity, HFD-fed mice develop peripheral nerve functional, but not structural, abnormalities and, therefore, are a suitable model for evaluating dietary and pharmacological approaches to halt progression and reverse diabetic neuropathy at the earliest stage of the disease.
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the leptin deficient ob ob mouse a new animal model of peripheral neuropathy of type 2 diabetes and obesity
Diabetes, 2006Co-Authors: Viktor R Drel, Jeho Shin, Nazar Mashtalir, Olga Ilnytska, Valeriy V Lyzogubov, Irina G ObrosovaAbstract:Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocin-induced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice ( approximately 11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable ( approximately 78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with Fidarestat (16 mg . kg(-1) . d(-1)), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)-positive nuclei in sciatic nerve, spinal cord, and DRGs of Fidarestat-treated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes.