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Molecular adaptations to endurance exercise and skeletal muscle fibre plasticity
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Whenever ATP is used, its millimolar concentration decreases only by a few micromoles because the Lohmann and myokinase reactions rapidly stabilise the ATP concentration. The small decrease of ATP translates into a large relative increase in the concentration of ADP and AMP as these substances lie in the micromolar range at rest. Thus, a small relative drop in ATP (less than 1%) can translate into a doubling of ADP and AMP concentrations. ADP and AMP are sensed and regulate the activity of AMP-activated protein kinase (AMPK). AMPK is a protein kinase that functions as a heterotrimer (a complex of three different proteins): the α catalytic subunit (the actual kinase whose activity is regulated by Thr172 phosphorylation);the β subunit that holds the enzyme together and binds glycogen;the ɣ subunit which binds ATP, ADP or AMP.
Coronary Artery Disease
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2022
Other mTOR inhibitors include curcumin and resveratrol which are major nutraceuticals of the Mediterranean basin. Green tea, a typical beverage of Okinawa, is also a cardinal mTOR inhibitor. Citrus bergamot, mentioned previously, is also a cheerleader for autophagy and has a favorable impact on cholesterol and sugar metabolism. Berberine, a component of several plants, has shown great promise in lowering blood sugar. In fact, Metformin, the darling of many antiaging physicians in supporting metabolism while lowering blood sugar, is now being replaced by berberine. Berberine makes even more sense as it drives AMP-activated protein kinase (AMPK) in a preferential direction, thus supporting metabolic pathways. AMPK or 5’ adenosine monophosphate-activated protein kinase is a unique enzyme that plays a crucial role in energy homeostasis by activating glucose and fatty acid oxidation when cellular energy reserves are low.
Therapeutic Potential of Anthocyanin Against Diabetes
Published in Hafiz Ansar Rasul Suleria, Megh R. Goyal, Health Benefits of Secondary Phytocompounds from Plant and Marine Sources, 2021
Tawheed Amin, H. R. Naik, Bazila Naseer, Syed Zameer Hussain
AMPK, the most critical factor for the balance of cell energy, is being perceived as a potential remedial focus in the counteractive action and treatment of T2D [51, 64, 96]. It is an energy-sensing enzyme and conserved kinase, the activation of which elicits the insulin-sensitizing target for T2D. AMPK gets activated when the energy levels of cell are low, which in turn stimulates the uptake of glucose in the fatty acid oxidation, skeletal muscles, and reduces the production of hepatic glucose. The dysregulation of AMPK in T2D patients by way of activating AMPK (either pharmacologically or physiologically) can improve the insulin sensitivity and metabolic health [24].
Protective effect of omega-3 polyunsaturated fatty acids on sepsis via the AMPK/mTOR pathway
Published in Pharmaceutical Biology, 2023
Peng Liu, Ming Li, Wei Wu, Anjie Liu, Honglin Hu, Qin Liu, Chengzhi Yi
The AMPK pathway is activated when AMP and ADP cellular levels are elevated due to various physiological stresses or pharmacological inducers (Carling 2017). Once activated, AMPK regulates protein, lipid, and sugar metabolism as well as autophagy and mitochondrial homeostasis, covering almost the entire physiological and metabolic activities of living organisms (Fullerton 2016; Casanova et al. 2019). During conditions of nutrient deficiency, AMPK is a metabolic checkpoint that inhibits cell growth (Zhang FJ, Zhang, et al. 2015; Jellusova 2020). This mechanism is achieved by inhibition of the mTORC1 pathway (Xu et al. 2019). AMPK can directly block the ability of the mTOR kinase complex to phosphorylate its substrates (Inoki et al. 2012). The mTOR signaling pathway, as a central coordinator of cell growth, is closely related to the development of liver fibrosis (Wang et al. 2019). In sepsis, upregulated p-AMPK and downregulated p-mTOR were observed in the CLP model (Zhang J et al. 2017; Zhao et al. 2018; Liu, Li, et al. 2020; Liu, Xu, et al. 2020). Meanwhile, DHA, a component of ω-3 PUFAs, was found to regulate the AMPK/mTOR signaling pathway in cancer cells (Jing et al. 2011). In the present study, we injected parenteral ω-3 PUFA solutions along with AMPK inhibitor Compound C and mTOR agonist MHY1485 into CLP-induced rats with sepsis. The results indicated that Compound C or MHY1485 could partially reverse the ameliorated inflammation response and multi-organ injury induced by ω-3 PUFAs in sepsis, indicating that ω-3 PUFAs protected against sepsis by directly regulating the AMPK/mTOR pathway.
Combination of mTOR inhibitor PP242 and AMPK activator metformin exerts enhanced inhibitory effects on colorectal carcinoma cells in vitro by blocking multiple kinase pathways
Published in Journal of Chemotherapy, 2023
Cuicui Sun, Xiaoyan Yang, Zhi Jin, Zuhua Gao
AMPK is a heterotrimeric serine/threonine kinase complex that functions as part of an evolutionarily conserved energy-sensing pathway. It has been demonstrated that AMPK plays a role in linking metabolic syndrome and cancer [26]. AMPK is a downstream effector of LKB1 and carries out many of its key tumour suppressor functions. AMPK could be suppressed in cancer cells with loss-of-function mutations of LKB1 or active mutations of B-Raf, or in cancers associated with metabolic syndrome. It is at a crossroad between upstream (p53, LKB1) and downstream (TSC2) tumour suppressors. It inhibits anabolic processes, including mTORC1 dependent protein biosynthesis and cell proliferation, through p53 activation. Metformin activates AMPK and exhibits an antiproliferative effect on several cancer cell lines [27]. Furthermore, metformin and the allosteric AMPK activator A-769662 both delay spontaneous tumour development in Pten+/− mice [28]. It is also reported that metformin can drive angiogenesis and accelerate the in vivo growth of BRAFV600E-driven melanoma by upregulating VEGFA mRNA and protein levels [29]. Metformin might be an attractive and safe anticancer drug for monotherapy or use in combination with chemotherapeutic or targeted agents. To date, no randomized control trials have been conducted for exploring the potential of metformin as a chemotherapeutic agent; however, pre-clinical evidence suggests that metformin may enhance chemotherapy response [30, 31].
Research progress on related mechanisms of uric acid activating NLRP3 inflammasome in chronic kidney disease
Published in Renal Failure, 2022
Miao Wang, Xin Lin, Xiaoming Yang, Yanlang Yang
AMPK (AMP-activated protein kinase) is a key regulatory pathway of cell energy metabolism. Serum uric acid can regulate AMPK-mTOR (mammalian target of rapamycin)-mitochondrial reactive oxygen species, and the HIF-1α (hypoxia inducible factor-1α) pathway mediates the enhancement of the inflammatory process [59]. A decrease in uric acid levels will lead to the activation of AMPK to reduce inflammation [60]. Hyperuricemia will further cause inflammation, autophagy, and mitochondrial dysfunction through damage to sodium-potassium pump signal transduction and eventually lead to cell damage. The AMPK-mTOR pathway is abundant in renal tubular epithelial cells [52]. Hyperuricemia can stimulate the activation of AMPK in proximal tubular epithelial cells, in this study, they found that UA stimulates AMPK activity as a protective mechanism; however, soon AMPK activity decreases, leading to the impairment of Na+-K+-ATPase signaling, which further triggers inflammation autophagy, and mitochondrial dysfunction and leads to cell injury. Sustained treatment with an AMPK activator significantly alleviated UA-induced alterations [61].