Pyridostigmine regulates glucose metabolism and mitochondrial homeostasis to reduce myocardial vulnerability to injury in diabetic mice

Yang, Yang; Zhao, Ming; Yu, Xin; Liu, Longzhu; He, Xiaoqing; Deng, Juan; Zang, Weijin

doi:10.1152/ajpendo.00569.2018

Cited by 15 publications

(14 citation statements)

References 82 publications

(93 reference statements)

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“…Then, the product of pyruvate oxidation, acetyl CoA, enters the tricarboxylic acid cycle and is catalyzed by a key enzyme: CS [11]. It has been reported that the activity of these key enzymes, HK and PFK, decreases in STZ-induced T1DM animals and HFD-induced T2DM animals [4,5,25]. In accordance with those studies, we showed that the activity of HK and PFK in the liver decreased significantly in diabetic mice compared with that in normal control mice.…”

Section: Discussionsupporting

confidence: 88%

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Effect of long-term treatment of Carvacrol on glucose metabolism in Streptozotocin-induced diabetic mice

Mai

Qiu

et al. 2020

BMC Complement Med Ther

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Background: Carvacrol is a food additive with various bioactivities, including reducing the blood glucose level as well as improvement of heart function, in diabetic mice. We explored the antihyperglycemic effect of carvacrol and its effect on the key hepatic enzymes accounting for glucose metabolism. Methods: A streptozotocin (STZ)-induced diabetes-mellitus model in mice was used. Mice were divided randomly into a control group, diabetic group, low dose carvacrol-treated diabetic group (10 mg/kg body weight [BW]), and high dose carvacrol-treated diabetic group (20 mg/kg BW). Carvacrol was injected intraperitoneally (i.p.) in each carvacrol-treated group daily for 4 weeks and 6 weeks, respectively. The level of random plasma glucose, fasting plasma glucose, and plasma insulin was determined at 4 weeks and 6 weeks after carvacrol administration. The plasma level of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and the activity of hepatic key enzymes related to glucose metabolism were determined. Results: Carvacrol treatment decreased the levels of random plasma glucose and fasting plasma glucose, significantly in a dose-dependent manner. A significant improvement in glucose tolerance and a significant decrease in the plasma level of TG were observed in carvacrol-treated diabetic mice at a dose of 20 mg/kg BW compared with that in vehicle-treated diabetic mice. There was no significant difference in the plasma level of TC and insulin between vehicle-treated diabetic mice and carvacrol-treated diabetic mice. Carvacrol treatment at a dose of 20 mg/kg BW significantly reduced the plasma level of LDH but not AST, ALT, or ALP, compared with that in the vehicle-treated diabetic group. The activity of hexokinase (HK), 6-phosphofructokinase (PFK), and citrate synthetase (CS) was increased by carvacrol treatment in diabetic mice. Conclusions: Carvacrol exerted an anti-hyperglycemic effect in STZ-induced diabetic mice. This was achieved through regulating glucose metabolism by increasing the activity of the hepatic enzymes HK, PFK, and CS.

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Section: Discussionsupporting

confidence: 88%

“…A set of key enzymes control carbohydrate metabolism. For example, hexokinase (HK) and 6-phosphofructokinase (PFK) participate in anaerobic glycolysis [4,5]. Citrate synthetase (CS) is a key enzyme involved in aerobic oxidation [6].…”

Section: Introductionmentioning

confidence: 99%

Effect of long-term treatment of Carvacrol on glucose metabolism in Streptozotocin-induced diabetic mice

Mai

Qiu

et al. 2020

BMC Complement Med Ther

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“…Previous studies have shown that autonomic imbalance, as indicated by attenuated parasympathetic nerve tone and increased sympathetic nerve activity, is involved in the pathological processes of diabetes [23,24]. Some studies in this laboratory have shown that pyridostigmine increased vagal activity, improved cardiac damage in the diabetes and obesity models [14,25]. Consistent with these results, our study showed that pyridostigmine increased parameters of vagal activity, as evidenced by increased ACh, decreased AChE, higher SDNN and RMSSD in mice with diabetic cardiomyopathy.…”

Section: Discussionmentioning

confidence: 94%

“…Recent studies have revealed that autonomic imbalance and diminished vagus nerve activity occur frequently in humans with diabetes and in animal models of diabetes [13,14]. Autonomic imbalance participates in the pathological processes of many cardiovascular diseases [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…Autonomic imbalance participates in the pathological processes of many cardiovascular diseases [15,16]. Pyridostigmine, a cholinesterase inhibitor, improves vagal activity and regulates glucose metabolism to protect mitochondrial structure and function and decreases oxidative stress to reduce myocardial vulnerability to injury in diabetic mice [14]. However, thus far, no studies have analysed the protective effects of pyridostigmine on the intestinal barrier and gut microbiota homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Gut Microbiota and Branched-Chain Amino Acid Catabolism to Attenuate Mitochondria Dysfunction

Yang

Zhao

et al. 2020

Preprint

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Background: Recent studies have reported that disruption of gut microbes and their metabolites is associated with diabetic cardiomyopathy, but the mechanism by which gut microbes improve diabetic cardiomyopathy remains unclear. Method: Male C57BL/6J mice with high-fat diet and streptozotocin-induced diabetic cardiomyopathy were studied in comparison with control littermates. Diabetic mice were either untreated or subjected to daily intragastric of pyridostigmine. After 10 weeks of hyperglycaemia, vagus activity, cardiac function and cardiac structure were measured by heart rate variability assessment, echocardiography, and immunohistochemistry. The intestinal barrier and gut microbiota were evaluated by fluorescence in situ hybridization and high-throughput sequencing. Additionally, plasma and cardiac branched-chain amino acid (BCAA) distribution and cardiac BCAA catabolism were determined. The structure and respiratory function of mitochondria were measured to assess cardiac mitochondria performance. Results: Intestinal permeability and tight junctions were impaired, bacterial translocation was increased, vagal activity was decreased in mice with diabetic cardiomyopathy mice. Additionally, gut microbes in mice with diabetic cardiomyopathy were disrupted, especially key microbes related to diabetes and BCAA production. Pyridostigmine, which reversibly inhibits cholinesterase to improve autonomic imbalance, enhanced vagus nerve activity, improved insulin resistance and cardiac damage, and alleviated intestinal barrier injury and gut microbiota disruption. Specifically, pyridostigmine decreased the abundance of diabetes-non-protective microbes and increased that of diabetes-protective microbes and BCAA-producing microbes. Pyridostigmine decreased cardiac BCAA concentrations by impairing gut microbe-mediated BCAA production. Furthermore, pyridostigmine upregulated BCAT2 and PP2Cm expression and decreased P-BCKDHA/BCKDHA and BCKDK expression, thus improving cardiac BCAA catabolism. Interestingly, the mitochondrial structural and functional disruption in mice with diabetic cardiomyopathy was attenuated after pyridostigmine administration, which may indicate one of the mechanisms by which BCAAs reduce cardiac damage. Conclusions: In conclusion, intestinal barrier, gut microbiota and vagal activity were impaired in mice with diabetic cardiomyopathy. Pyridostigmine ameliorated insulin resistance and cardiomyopathy, with an effect related to regulated gut microbes and its metabolite BCAA catabolism to attenuate mitochondria dysfunction of heart. These results provide novel insights for the development of a therapeutic strategy for diabetes-induced cardiac damage that targets gut microbes and BCAA catabolism.

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Pyridostigmine attenuated high‐fat‐diet induced liver injury by the reduction of mitochondrial damage and oxidative stress via α7nAChR and M3AChR

Xue,

Wu,

Guo

et al. 2024

J Biochem & Molecular Tox

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Obesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous studies have shown that an imbalance in the autonomic nervous system is closely related to the pathogenesis of NAFLD. In this study, we investigated the effects of pyridostigmine (PYR), a cholinesterase (AChE) inhibitor, on HFD‐induced liver injury and explored the potential mechanisms involving mitochondrial damage and oxidative stress. A murine model of HFD‐induced obesity was established using the C57BL/6 mice, and PYR (3 mg/kg/d) or placebo was administered for 20 weeks. PYR reduced the body weight and liver weight of the HFD‐fed mice. Additionally, the serum levels of IL‐6, TNF‐α, cholesterol, and triglyceride were significantly lower in the PYR‐treated versus the untreated mice, corresponding to a decrease in hepatic fibrosis, lipid accumulation, and apoptosis in the former. Furthermore, the mitochondrial morphology improved significantly in the PYR‐treated group. Consistently, PYR upregulated ATP production and the mRNA level of the mitochondrial dynamic factors OPA1, Drp1 and Fis1, and the mitochondrial unfolded protein response (UPRmt) factors LONP1 and HSP60. Moreover, PYR treatment activated the Keap1/Nrf2 pathway and upregulated HO‐1 and NQO‐1, which mitigated oxidative injury as indicated by decreased 8‐OHDG, MDA and H2O2 levels, and increased SOD activity. Finally, PYR elevated acetylcholine (ACh) levels by inhibiting AChE, and upregulated the α7nAChR and M3AChR proteins in the HFD‐fed mice. PYR alleviated obesity‐induced hepatic injury in mice by mitigating mitochondrial damage and oxidative stress via α7nAChR and M3AChR.

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Pyridostigmine regulates glucose metabolism and mitochondrial homeostasis to reduce myocardial vulnerability to injury in diabetic mice

Cited by 15 publications

References 82 publications

Effect of long-term treatment of Carvacrol on glucose metabolism in Streptozotocin-induced diabetic mice

Effect of long-term treatment of Carvacrol on glucose metabolism in Streptozotocin-induced diabetic mice

Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Gut Microbiota and Branched-Chain Amino Acid Catabolism to Attenuate Mitochondria Dysfunction

Pyridostigmine attenuated high‐fat‐diet induced liver injury by the reduction of mitochondrial damage and oxidative stress via α7nAChR and M3AChR

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