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The development and benefits of metformin in various diseases

《医学前沿（英文）》 2023年第17卷第3期页码 388-431 doi: 10.1007/s11684-023-0998-6

摘要： Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.

关键词： metformin metabolism cancer aging neurological disorder

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Antioxidative potential of metformin: Possible protective mechanism against generating OH radicals

Huibin Guo, Ning Wang, Xiang Li

《环境科学与工程前沿（英文）》 2021年第15卷第2期 doi: 10.1007/s11783-020-1313-2

摘要： Abstract • Metformin consumes O2−• and OH• induced by PM are proposed. • OH• dominated the oxidation of metformin compared with O2−• • Metformin can prevent the harm of ROS induced by PM to human health. • Antioxidative potential of metformin was first proposed to provide measures. Exposure to particulate matter (PM) can lead to the excessive accumulation of reactive oxygen species (ROS), which causes oxidative stress and endangers human health. In this study, the effects of metformin on PM-induced radicals were investigated, and the antioxidation reaction mechanism of metformin was analyzed by the density functional theory (DFT) method. The corresponding results revealed that the consumption rate of dithiothreitol (DTT) increased as the metformin concentration (0–40 mmol/L) increased under exposure to PM active components. Moreover, the OH radical content decreased as the metformin concentration increased. This result may be related to the consumption of PM-induced OH radicals by metformin, which promotes the DTT consumption rate. Additionally, because the initiation reaction has a high barrier, the oxidation reaction rate between metformin and •O2− is not very fast, although various catalysts may be present in the human environment. Importantly, we found that the barrier of metformin induced by OH radicals is only 9.6 kcal/mol while the barrier of metformin induced by oxygen is 57.9 kcal/mol, which shows that the rate of the •OH-initiated oxidative reaction of metformin is much faster and that this reaction path occurs more easily. By sample analysis, the mean OH radical generation was 55 nmol/min/g (ranging from 5 to 105 nmol/min/g) on haze days and 30 nmol/min/g (ranging from 10 to 50 nmol/min/g) on non-haze days. Moreover, OH radical generation was higher on haze days than on neighboring non-haze days. Taken together, all data suggest that metformin could consume the PM-induced radicals, such as OH radicals and •O2−, thereby providing health protection.

关键词： Antioxidative potential Metformin Mechanism OH radical Health protection.

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Metformin and metabolic diseases: a focus on hepatic aspects

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《医学前沿（英文）》 2015年第9卷第2期页码 173-186 doi: 10.1007/s11684-015-0384-0

摘要：

Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases.

关键词： metformin diabetes hepatic steatosis inflammatory response insulin resistance