Ranirestat has a stronger inhibitory activity on aldose reductase and suppresses inflammatory reactions in high glucose–exposed endothelial cells

Ishibashi, Yuji; Matsui, Takanori; Matsumoto, Takafumi; Katô, Hiroshi; Yamagishi, Sho‐ichi

doi:10.1177/1479164116640220

Cited by 8 publications

(5 citation statements)

References 12 publications

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“…The genetic etiology of DR was investigated by a candidate gene approach, and the potential candidate genes in DR etiology were implicated [8,9]. Aldose reductase (AR), the rate-limiting enzyme in the sorbitol pathway, can catalyze the reduction of glucose to sorbito, and is implicated in the progression of diabetic complications [10]. Risk factors of DR have attracted much attention in recent years [11,12].…”

Section: Introductionmentioning

confidence: 99%

Association between Aldose Reductase Gene C(-106)T Polymorphism and Diabetic Retinopathy: A Systematic Review and Meta-Analysis

Lin¹,

Peng²,

Cao³

et al. 2020

Ophthalmic Res

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Controversial results regarding the associations between aldose reductase (AR) genetic polymorphisms and diabetic retinopathy (DR) have been reported for many years. The present meta-analysis was performed to clarify the effects of the AR gene C(-106)T polymorphism on DR risk. The PubMed, Web of Sciences, Cochrane library, EMBASE, Chinese National Knowledge Infrastructure, and Wan Fang databases were extensively searched in Chinese to select relevant studies with an updated date of April 25, 2018. The Newcastle-Ottawa Scale (NOS) was applied to assess quality. The randomeffects model was applied to calculate the pooled OR and 95% CI. This meta-analysis identified 23 studies with an average score of 7.52 for NOS analysis, including 4,313 DR cases and 5,128 diabetes mellitus (DM) control cases. In the overall analysis, a significant association between the AR gene C(-106)T polymorphism and DR susceptibility was found. In subgroups stratified by DM type and ethnicity, significantly increased risks for DR were found in DM type 1, East Asian populations, and Middle Eastern populations. Compared with DR control cases, the following associations were found: T vs. C: OR 0.91, 95% CI 0.85-0.97, I 2 = 72.9%; CT + TT vs. CC: OR 0.75, 95% CI 0.68-0.81, I 2 = 86.7%; and CT vs. CC: OR 0.86, 95% CI 0.78-0.94, I 2 = 70.5%. The results of this meta-analysis showed a significant association between the AR gene C(-106)T polymorphism and susceptibility to DR in DM patients. DM patients with allele T and CT+TT genotype of the AR gene may have a lower risk of DR.

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Section: Introductionmentioning

confidence: 99%

Association between Aldose Reductase Gene C(-106)T Polymorphism and Diabetic Retinopathy: A Systematic Review and Meta-Analysis

Lin¹,

Peng²,

Cao³

et al. 2020

Ophthalmic Res

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“…Luteolin has originally been described as a potent CBR1 inhibitor (Arai et al 2015 ) but is also a weak AKR1C3 inhibitor (Skarydova et al 2009 ). Ranirestat has been developed and described as a specific and potent AKR1B1 inhibitor (Kurono et al 2001 ; Ishibashi et al 2016 ; Bril et al 2004 ). Because our experiments did suggest that ranirestat is also an AKR1C3 inhibitor, we confirmed inhibition characteristics in HEK293 cells over-expressing AKR1C3.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of the reductive carbonyl idarubicin metabolism to evaluate inhibitors of the formation of cardiotoxic idarubicinol via carbonyl and aldo–keto reductases

Bajraktari-Sylejmani,

Oster,

Burhenne

et al. 2024

Arch Toxicol

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The most important dose-limiting factor of the anthracycline idarubicin is the high risk of cardiotoxicity, in which the secondary alcohol metabolite idarubicinol plays an important role. It is not yet clear which enzymes are most important for the formation of idarubicinol and which inhibitors might be suitable to suppress this metabolic step and thus would be promising concomitant drugs to reduce idarubicin-associated cardiotoxicity. We, therefore, established and validated a mass spectrometry method for intracellular quantification of idarubicin and idarubicinol and investigated idarubicinol formation in different cell lines and its inhibition by known inhibitors of the aldo–keto reductases AKR1A1, AKR1B1, and AKR1C3 and the carbonyl reductases CBR1/3. The enzyme expression pattern differed among the cell lines with dominant expression of CBR1/3 in HEK293 and MCF-7 and very high expression of AKR1C3 in HepG2 cells. In HEK293 and MCF-7 cells, menadione was the most potent inhibitor (IC50 = 1.6 and 9.8 µM), while in HepG2 cells, ranirestat was most potent (IC50 = 0.4 µM), suggesting that ranirestat is not a selective AKR1B1 inhibitor, but also an AKR1C3 inhibitor. Over-expression of AKR1C3 verified the importance of AKR1C3 for idarubicinol formation and showed that ranirestat is also a potent inhibitor of this enzyme. Taken together, our study underlines the importance of AKR1C3 and CBR1 for the reduction of idarubicin and identifies potent inhibitors of metabolic formation of the cardiotoxic idarubicinol, which should now be tested in vivo to evaluate whether such combinations can increase the cardiac safety of idarubicin therapies while preserving its efficacy.

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“…Diabetes is a greater risk for cardiovascular morbidity and mortality. Research showed that improving endothelial function and decreasing inflammation could lower cardiovascular disease risk of diabetes patients [19][20][21] . In the present study, we found that high glucose could increase the secretion of IL-1b, IL-6 and TNF-a in TAECs.…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates high glucose‐induced inflammatory injury through the reactive oxygen species–phosphoinositide 3‐kinase/protein kinase B–nuclear factor‐κB signaling pathway in rat thoracic aorta endothelial cells

Zhang

2017

J of Diabetes Invest

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Aims/IntroductionEndothelial cell inflammatory injury is likely required for barrier dysfunction under hyperglycemic conditions. Curcumin (CUR) is well known for its anti‐inflammatory effect. However, there have been few reports about the anti‐inflammatory effect of CUR induced by high glucose in endothelial cells. The aim of the present study was to investigate the inflammatory effect of high glucose and the anti‐inflammatory effect of CUR induced by high glucose in rat thoracic aorta endothelial cells (TAECs).Materials and MethodsWell characterized TAECs were established and cell viability was assayed by the cell counting kit‐8 method, messenger ribonucleic acid and protein expression were identified by real‐time polymerase chain reaction, western blot or enzyme‐linked immunosorbent assay, respectively. The production of reactive oxygen species was observed by a fluorescence microscope.ResultsHigh glucose (30 mmol/L) significantly decreased the cell viability of TAECs after being co‐cultivated for 12 h and showed a time‐dependent manner, and increased interleukin (IL)‐1β, IL‐6 and tumor necrosis factor‐α secretion in TAECs. The injury effect of high glucose was involved in the reactive oxygen species–phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)–nuclear factor (NF)‐κB signaling pathway. Anti‐oxidant N‐acetylcysteine, PI3K and NF‐κB‐specific pathway inhibitors can abolish the secretion of these inflammatory factors; pretreatment with anti‐oxidant N‐acetylcysteine significantly decreased PI3K expression, the level of phosphorylated AKT and nuclear NF‐κB; pretreatment of LY294002 can significantly decrease the NF‐κB level in nuclei. After treatment with CUR for 12 h, IL‐1β, IL‐6 and tumor necrosis factor‐α secretion were markedly decreased, and PI3K expression, the phosphorylation of AKT and nuclear NF‐κB level were also decreased.ConclusionCurcumin attenuates high glucose‐induced inflammatory injury through the reactive oxygen species–PI3K/AKT–NF‐κB signaling pathway in rat thoracic aorta endothelial cells.

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Ranirestat has a stronger inhibitory activity on aldose reductase and suppresses inflammatory reactions in high glucose–exposed endothelial cells

Cited by 8 publications

References 12 publications

Association between Aldose Reductase Gene C(-106)T Polymorphism and Diabetic Retinopathy: A Systematic Review and Meta-Analysis

Association between Aldose Reductase Gene C(-106)T Polymorphism and Diabetic Retinopathy: A Systematic Review and Meta-Analysis

In vitro evaluation of the reductive carbonyl idarubicin metabolism to evaluate inhibitors of the formation of cardiotoxic idarubicinol via carbonyl and aldo–keto reductases

Curcumin attenuates high glucose‐induced inflammatory injury through the reactive oxygen species–phosphoinositide 3‐kinase/protein kinase B–nuclear factor‐κB signaling pathway in rat thoracic aorta endothelial cells

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