Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice

Cai, Haiyan; Wang, Ting; Zhao, Jian-chun; Sun, Peng; Yan, Guirui; Ding, Hong; Li, Yingxia; Wang, He-Yao; Zhu, Weiliang; Chen, Kaixian

doi:10.1038/aps.2013.97

Cited by 31 publications

(24 citation statements)

References 26 publications

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“…166 In addition, benzbromarone, a drug with uricosuric properties, was also identified as an inhibitor of FABP4 and can significantly reduce blood glucose in the db/db mouse model of obesity and type 2 diabetes mellitus. 167 The metabolic phenotypes generated by these molecules or their derivatives will be interesting to study, although in general the small molecule approach might be challenging due to issues of nonspecificity and off-target effects inherent with this therapeutic strategy. In addition, whether small molecule-mediated inhibition of both intracellular and extracellular FABP4 actions will be desirable therapeutically is unknown, as some intracellular actions might be important for normal adipocyte function.…”

Section: Therapeutic Implications Of Fabpsmentioning

confidence: 99%

Metabolic functions of FABPs—mechanisms and therapeutic implications

Hotamışlıgil¹,

2015

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Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were originally described as intracellular proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for immunometabolic diseases. In particular, genetic deficiency and small molecule-mediated inhibition of FABP4 (also known as aP2) and FABP5 can potently improve glucose homeostasis and reduce atherosclerosis in mouse models. Further research has shown that in addition to their intracellular roles, some FABPs are found outside the cells, and FABP4 undergoes regulated, vesicular secretion. The circulating form of FABP4 has crucial hormonal functions in systemic metabolism. In this Review we discuss the roles and regulation of both intracellular and extracellular FABP actions, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases.

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Section: Therapeutic Implications Of Fabpsmentioning

confidence: 99%

Metabolic functions of FABPs—mechanisms and therapeutic implications

Hotamışlıgil¹,

2015

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“…Allopurinol, a competitive inhibitor of xanthine oxidase that decreases UA production, protects isolated islets from neonatal rats against the cytotoxic effects of styreptozotocin, probably via decreasing intracellular UA levels [ 54 ]. Benzbromarone, an uricosuric drug, inhibits fatty acid-binding protein 4 and improves glucose tolerance in type 2 diabetic db/db mice [ 55 ]. Allopurinol improves endothelial function in hypertensive type 2 diabetic patients [ 56 ].…”

Section: Introductionmentioning

confidence: 99%

Uric acid‐induced pancreatic β-cell dysfunction

Ghasemi

2021

BMC Endocr Disord

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Hyperuricemia is associated with insulin resistance, pancreatic β-cell dysfunction and consequently with development of type 2 diabetes. Although a direct relationship between high levels of uric acid (UA) and the development of diabetes is still a controversial issue, there is some evidence that strongly points to pancreatic β-cells damage as a result of high serum UA levels. Here, the mechanisms underlying UA-induced β-cell damage are discussed. Available literature indicates that UA can decrease glucose-stimulated insulin secretion and cause β-cell death. The mechanisms underlying these effects are UA-induced oxidative stress and inflammation within the β-cells. UA also stimulates inducible nitric oxide (NO) synthase (iNOS) gene expression leading to NO-induced β-cell dysfunction. Thus hyperuricemia may potentially cause β-cell dysfunction, leading to diabetes. It may be hypothesized that in hyperuricemic subjects, UA-lowering drugs may be beneficial in preventing diabetes.

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“…Benzbromarone is a uricosuric agent used to treat gout [ 38 ]. In a non-exhaustive literature search we have only found circumstantial evidence relating benzbromarone with glucose blood levels [ 39 ]. On the other hand, folic acid (vitamin B 9 ) is an important biological cofactor necessary for DNA synthesis.…”

Section: Resultsmentioning

confidence: 99%

Benzbromarone, Quercetin, and Folic Acid Inhibit Amylin Aggregation

López

Varea

Navarro

et al. 2016

IJMS

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Human Amylin, or islet amyloid polypeptide (hIAPP), is a small hormone secreted by pancreatic β-cells that forms aggregates under insulin deficiency metabolic conditions, and it constitutes a pathological hallmark of type II diabetes mellitus. In type II diabetes patients, amylin is abnormally increased, self-assembled into amyloid aggregates, and ultimately contributes to the apoptotic death of β-cells by mechanisms that are not completely understood. We have screened a library of approved drugs in order to identify inhibitors of amylin aggregation that could be used as tools to investigate the role of amylin aggregation in type II diabetes or as therapeutics in order to reduce β-cell damage. Interestingly, three of the compounds analyzed—benzbromarone, quercetin, and folic acid—are able to slow down amylin fiber formation according to Thioflavin T binding, turbidimetry, and Transmission Electron Microscopy assays. In addition to the in vitro assays, we have tested the effect of these compounds in an amyloid toxicity cell culture model and we have found that one of them, quercetin, has the ability to partly protect cultured pancreatic insulinoma cells from the cytotoxic effect of amylin. Our data suggests that quercetin can contribute to reduce oxidative damage in pancreatic insulinoma β cells by modulating the aggregation propensity of amylin.

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Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice

Cited by 31 publications

References 26 publications

Metabolic functions of FABPs—mechanisms and therapeutic implications

Metabolic functions of FABPs—mechanisms and therapeutic implications

Uric acid‐induced pancreatic β-cell dysfunction

Benzbromarone, Quercetin, and Folic Acid Inhibit Amylin Aggregation

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