bims-amsmem 2022-07-17 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022‒07‒17
24 papers selected by
Dipsikha Biswas, Københavns Universitet

Ginsenoside compound K reduces the progression of Huntington's disease via the inhibition of oxidative stress and overactivation of the ATM/AMPK pathway.
Parenteral Nutrition Associated Hepatic Steatosis and NAFLD Intersect at AMPK.
Metformin mitigates gas explosion-induced blast lung injuries through AMPK-mediated energy metabolism and NOX2-related oxidation pathway in rats.
Electroacupuncture improves follicular development and metabolism and regulates the expression of adiponectin, AMPK and ACC in an obese rat model of polycystic ovary syndrome.
Tamoxifen modulates mitochondrial dynamics through AMPK and MAPK during nutrition deprivation.
Targeted Proteomic Approaches for Proteome-Wide Characterizations of the AMP-Binding Capacities of Kinases.
Isoliquiritigenin attenuates pathological cardiac hypertrophy via regulating AMPKα in vivo and in vitro.
Crocetin Protected Human Hepatocyte LO2 Cell From TGF-β-Induced Oxygen Stress and Apoptosis but Promoted Proliferation and Autophagy via AMPK/m-TOR Pathway.
γ-Glutamylcysteine ameliorates D-gal-induced senescence in PC12 cells and mice via activating AMPK and SIRT1.
Glucose metabolism controls human γδ T-cell-mediated tumor immunosurveillance in diabetes.
Selenium deficiency aggravates bisphenol A-induced autophagy in chicken kidney through regulation of nitric oxide and adenosine monophosphate activated protein kinase/mammalian target of rapamycin signaling pathway.
LACC1 contributes to inflammation and cognitive disorder after stroke via the AMPK/NLRP3 pathway.
Epigallocatechin-3-gallate attenuates myocardial fibrosis in diabetic rats by activating autophagy.
Stachydrine alleviates lipid-induced skeletal muscle insulin resistance via AMPK/HO-1-mediated suppression of inflammation and endoplasmic reticulum stress.
Ginkgolide B Protects Against Ischemic Stroke via Targeting AMPK/PINK1.
AMPK regulates behavior and physiological plasticity of Haliotis discus hannai under different spectral compositions.
Hypoxic Tumor-Derived Exosomes Induce M2 Macrophage Polarization via PKM2/AMPK to Promote Lung Cancer Progression.
Systems modelling predicts chronic inflammation and genomic instability prevent effective mitochondrial regulation during biological ageing.
Upregulation of adiponectin by Ginsenoside Rb1 contributes to amelioration of hepatic steatosis induced by high fat diet.
Exogenous H2S Protects against Septic Cardiomyopathy by Inhibiting Autophagy through the AMPK/mTOR Pathway.
Isosteviol sodium attenuates high fat/high cholesterol-induced myocardial dysfunction by regulating the Sirt1/AMPK pathway.
Inverse correlation between the expression of AMPK/SIRT1 and NAMPT in psoriatic skin: A pilot study.
Adipose-derived mesenchymal stem cells reduced transient cerebral ischemia injury by modulation of inflammatory factors and AMPK signaling.
LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy.

J Ginseng Res. 2022 Jul;46(4): 572-584

Ginsenoside compound K reduces the progression of Huntington's disease via the inhibition of oxidative stress and overactivation of the ATM/AMPK pathway.

Kuo-Feng Hua, A-Ching Chao, Ting-Yu Lin, Wan-Tze Chen, Yu-Chieh Lee, Wan-Han Hsu, Sheau-Long Lee, Hsin-Min Wang, Ding-I Yang, Tz-Chuen Ju.

  Background: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of trinucleotide CAG repeat in the Huntingtin (Htt) gene. The major pathogenic pathways underlying HD involve the impairment of cellular energy homeostasis and DNA damage in the brain. The protein kinase ataxia-telangiectasia mutated (ATM) is an important regulator of the DNA damage response. ATM is involved in the phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK plays a critical role in response to DNA damage. Herein, we demonstrated that expression of polyQ-expanded mutant Htt (mHtt) enhanced the phosphorylation of ATM. Ginsenoside is the main and most effective component of Panax ginseng. However, the protective effect of a ginsenoside (compound K, CK) in HD remains unclear and warrants further investigation.Methods: This study used the R6/2 transgenic mouse model of HD and performed behavioral tests, survival rate, histological analyses, and immunoblot assays.
Results: The systematic administration of CK into R6/2 mice suppressed the activation of ATM/AMPK and reduced neuronal toxicity and mHTT aggregation. Most importantly, CK increased neuronal density and lifespan and improved motor dysfunction in R6/2 mice. Conversely, CK enhanced the expression of Bcl2 protected striatal cells from the toxicity induced by the overactivation of mHtt and AMPK.
Conclusions: Thus, the oral administration of CK reduced the disease progression and markedly enhanced lifespan in the transgenic mouse model (R6/2) of HD.

Keywords:  AMP-Activated protein kinase; Ataxia-telangiectasia mutated; Huntington's disease; Panax ginseng, ginsenoside

DOI:  https://doi.org/10.1016/j.jgr.2021.11.003
Cell Mol Gastroenterol Hepatol. 2022 Jul 07. pii: S2352-345X(22)00148-5. [Epub ahead of print]

Parenteral Nutrition Associated Hepatic Steatosis and NAFLD Intersect at AMPK.

Gregory Guthrie.

DOI: https://doi.org/10.1016/j.jcmgh.2022.06.005
Exp Ther Med. 2022 Aug;24(2): 529

Metformin mitigates gas explosion-induced blast lung injuries through AMPK-mediated energy metabolism and NOX2-related oxidation pathway in rats.

Miao Zhang, Yunzhe Sun, Chunjie Ding, Shan Hong, Ning Li, Yi Guan, Lin Zhang, Xinwen Dong, Jia Cao, Wu Yao, Wenjie Ren, Sanqiao Yao.

  Gas explosions are a recurrent event in coal mining that cause severe pulmonary damage due to shock waves, and there is currently no effective targeted treatment. To illustrate the mechanism of gas explosion-induced lung injury and to explore strategies for blast lung injury (BLI) treatment, the present study used a BLI rat model and supplementation with metformin (MET), an AMP-activated protein kinase (AMPK) activator, at a dose of 10 mg/kg body weight by intraperitoneal injection. Protein expression levels were detected by western blotting. Significantly decreased expression of phosphorylated (p)-AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and metabolic activity were observed in the BLI group compared with those in the control group. However, the mitochondrial stability, metabolic activity and expression of p-AMPK and PGC1α were elevated following MET treatment. These results suggested that MET could attenuate gas explosion-induced BLI by improving mitochondrial homeostasis. Meanwhile, high expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX2) and low expression of catalase (CAT) were observed in the BLI group. The expression levels of NOX2 and CAT were restored in the BLI + MET group relative to changes in the BLI group, and the accumulation of oxidative stress was successfully reversed following MET treatment. Overall, these findings revealed that MET could alleviate BLI by activating the AMPK/PGC1α pathway and inhibiting oxidative stress caused by NOX2 activation.

Keywords:  AMP-activated protein kinase; blast lung injury; gas explosion injury; metformin; mitochondria; nicotinamide adenine dinucleotide phosphate oxidase

DOI:  https://doi.org/10.3892/etm.2022.11456
Acupunct Med. 2022 Jul 13. 9645284221107690

Electroacupuncture improves follicular development and metabolism and regulates the expression of adiponectin, AMPK and ACC in an obese rat model of polycystic ovary syndrome.

Jing Zhou, Ping Yin, Qingyi Zhao, Zhihai Hu, Yi Wang, Guizhi Ma, Xinyi Wu, Lu Lu, Yin Shi.

  BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism and follicular arrest. Electroacupuncture (EA) has been shown to be effective at improving hyperandrogenism and follicular arrest in PCOS; however, its mechanism of action remains to be deciphered.OBJECTIVE: In this study, we investigated whether EA improved follicular development in an obese rat model of PCOS and regulated the expression of adiponectin, AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC).
METHODS: EA was administered at CV3, CV4 and ST40. Changes in body weight, paraovarian fat, estrus cycle, ovarian morphology, levels of related hormones, and glucose and lipid metabolism were evaluated. In addition, protein and mRNA expression of adiponectin, AMPK and ACC was measured.
RESULTS: The body weight and paraovarian fat of rats in the EA group were reduced, while estrus cyclicity and ovarian morphology improved. Levels of free fatty acids, triglycerides, total cholesterol and low-density lipoprotein cholesterol were significantly reduced in the EA group, as well as blood glucose levels. Furthermore, levels of testosterone and luteinizing hormone were reduced in the EA group, while estradiol levels were increased. Protein and mRNA expression of adiponectin, AMPKα1 and liver kinase B1 (LKB1) was found to be increased in the EA group, while protein and mRNA expression of ACC were significantly reduced.Conclusion: Our findings suggest that EA improved follicular development and metabolism and regulated expression levels of adiponectin, AMPKα1, LKB1 and ACC in our obese rat model of PCOS.

Keywords:  ACC; AMPK; adiponectin; electroacupuncture; metabolism; obesity; polycystic ovary syndrome

DOI:  https://doi.org/10.1177/09645284221107690
Cell Biol Int. 2022 Jul 12.

Tamoxifen modulates mitochondrial dynamics through AMPK and MAPK during nutrition deprivation.

Gangipangi Vijayakumar, Uppalapati S Swetha, Selvaraju Sudhagar.

  The interaction of cancer cells with their tumor microenvironment determines key events in the progression of the disease, therapeutic efficacy, and the development of drug resistance. Here, we presented evidence that tamoxifen support breast cancer growth during nutrition deprivation by modulating mitochondrial dynamics through AMPK and MAPK signaling. Tamoxifen enhances mitochondrial fusion under nutrition-deprived conditions by suppressing Drp1 ser616 phosphorylation and upregulating Mfn1 levels. Tamoxifen-induced mitochondrial fusion is mediated by the activation of AMPK as evident by the pharmacological inhibition of AMPK reverse mitochondrial fusion. Interestingly, JNK activation by tamoxifen controls the mitochondrial fusion morphology by downregulating Mfn2. Collectively, tamoxifen support cell growth by enhancing mitochondrial fusion by regulating stress kinase signaling under nutrition deprivation condition.

Keywords:  AMPK; MAPK; Tamoxifen; mitochondrial dynamics; nutrition deprivation

DOI:  https://doi.org/10.1002/cbin.11853
J Proteome Res. 2022 Jul 12.

Targeted Proteomic Approaches for Proteome-Wide Characterizations of the AMP-Binding Capacities of Kinases.

Weili Miao, Jiekai Yin, Douglas F Porter, Xiaogang Jiang, Paul A Khavari, Yinsheng Wang.

Kinases play important roles in cell signaling, and adenosine monophosphate (AMP) is known to modulate cellular energy homeostasis through AMP-activated protein kinase (AMPK). Here, we explored novel AMP-binding kinases by employing a desthiobiotin-conjugated AMP acyl-phosphate probe to enrich efficiently AMP-binding proteins. Together with a parallel-reaction monitoring-based targeted proteomic approach, we uncovered 195 candidate AMP-binding kinases. We also enriched desthiobiotin-labeled peptides from adenine nucleotide-binding sites of kinases and analyzed them using LC-MS/MS in the multiple-reaction monitoring mode, which resulted in the identification of 44 peptides derived from 43 kinases displaying comparable or better binding affinities toward AMP relative to adenosine triphosphate (ATP). Moreover, our proteomic data revealed a potential involvement of AMP in the MAPK pathway through binding directly to the relevant kinases, especially MEK2 and MEK3. Together, we revealed the AMP-binding capacities of a large number of kinases, and our work built a strong foundation for understanding how AMP functions as a second messenger to modulate cell signaling.

DOI: https://doi.org/10.1021/acs.jproteome.2c00225
J Mol Histol. 2022 Jul 14.

Isoliquiritigenin attenuates pathological cardiac hypertrophy via regulating AMPKα in vivo and in vitro.

Meiling Gao, Qiang Cai, Haichao Si, Si Shi, Huixia Wei, Miaomiao Lv, Xiaofan Wang, Tieli Dong.

  Isoliquiritigenin (ISL) is a type of flavonoid, derived from the root of the legume plant Glycyrrhiza, that has multiple pharmacological properties. However, its role in cardiac remodeling induced by pressure overload has yet to be fully elucidated. Aortic banding (AB) surgery was used to establish a cardiac hypertrophy model in male C57BL/6 mice. Mice were randomly divided into four groups (n = 20 per group) as follows: Sham + vehicle, sham + ISL, AB + vehicle and AB + ISL. ISL was administered to the mice intragastrically for 1 week after the operation. To evaluate the role of ISL in mice challenged with AB, echocardiography, histological analysis and molecular biochemistry examinations were performed. ISL treatment decreased cardiac hypertrophy and improved cardiac dysfunction induced by pressure overload. In addition, ISL decreased the cross-sectional area of cardiomyocytes. Furthermore, ISL reversed the AB-mediated increase in phosphorylated (p-)mTOR and p-ERK protein levels and further increased the protein expression of p-AMP-activated protein kinase (AMPK)α in response to AB, whereas knockout of AMPKα abolished the protective effects of ISL. The present study suggested that ISL could suppress pressure overload-induced cardiac hypertrophy through the activation of AMPKα. Therefore, ISL may serve as a therapeutic target for cardiac remodeling.

Keywords:  AMPKα; Cardiac remodeling; Hypertrophy; Isoliquiritigenin

DOI:  https://doi.org/10.1007/s10735-022-10090-w
Front Public Health. 2022 ;10 909125

Crocetin Protected Human Hepatocyte LO2 Cell From TGF-β-Induced Oxygen Stress and Apoptosis but Promoted Proliferation and Autophagy via AMPK/m-TOR Pathway.

Hongxing Guo, Chenyu Ruan, Xiuhong Zhan, Hao Pan, Yumei Luo, Ke Gao.

  Objective: To investigate the protective effects of crocetin against transforming growth factor-β (TGF-β)-induced injury in LO2 cells.Methods: Human hepatocyte LO2 cells were pre-treated with crocetin (10 μM) for 6, 12, and 24 h, and then induced by TGF-β. Proliferation, oxidative stress, apoptosis, autophagy, and related proteins were assessed.
Results: Crocetin pre-treating promoted proliferation but suppressed apoptosis in TGF-β-induced LO2 cells. Crocetin protected LO2 cells from TGF-β-induced inflammation and oxygen stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) but enhancing superoxide dismutase (SOD) and glutathione (GSH). Autophagy was suppressed in TGF-β but crocetin promoted autophagy in LO2 cells by mediating Adenosine 5'-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (m-TOR) signaling pathway via upregulating p-AMPK and p-Beclin-1 but downregulating p-mTOR.
Conclusions: Crocetin protected LO2 cells from TGF-β-induced damage by promoting proliferation and autophagy, and suppressing apoptosis and anti-inflammation via regulation of AMPK/m-TOR signaling pathway.

Keywords:  AMPK/m-TOR; apoptosis; autophagy; crocetin; inflammation; proliferation

DOI:  https://doi.org/10.3389/fpubh.2022.909125
Food Funct. 2022 Jul 11.

γ-Glutamylcysteine ameliorates D-gal-induced senescence in PC12 cells and mice via activating AMPK and SIRT1.

Shuai Lu, Jinyi Zhou, Chen Yang, Xiaoxue Zhang, Yingying Shi, Jie Liu, Xintong Yan, Juanjuan Liang, Xianli Liu, Lan Luo, Da Zhou, Zhimin Yin.

Aging is a natural process accompanied by inflammation and oxidative stress and is closely associated with age-related diseases. As a direct precursor of glutathione, γ-glutamylcysteine (γ-GC) possesses antioxidant and anti-inflammatory properties; however, whether γ-GC plays an important role in anti-aging remains unknown. Here, we investigated the protective effects and mechanisms of γ-GC in D-galactose (D-gal)-induced senescence in PC12 cells and aging mice. Our results showed that γ-GC treatment significantly reduced the percentage of senescence-associated-β-galactosidase (SA-β-Gal)-positive cells and inhibited D-gal-induced cell cycle arrest in PC12 cells. The results of Nissl and hematoxylin and eosin (H&E) staining in mouse brain showed that γ-GC treatment markedly reversed the damage in the hippocampus of D-gal-induced aging mice. Moreover, γ-GC increased the phosphorylation of AMP-activated protein kinase (AMPK) to promote the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) while inhibiting the nuclear translocation of deleted in breast cancer 1 (DBC1), which leads to the activation of sirtuin 1 (SIRT1) and deacetylation of p53 in the nucleus. Therefore, γ-GC may be a potential therapeutic candidate compound for the prevention and treatment of age-related diseases.

DOI: https://doi.org/10.1039/d2fo01246d
Cell Mol Immunol. 2022 Jul 11.

Glucose metabolism controls human γδ T-cell-mediated tumor immunosurveillance in diabetes.

Xiaofeng Mu, Zheng Xiang, Yan Xu, Jing He, Jianwen Lu, Yuyuan Chen, Xiwei Wang, Chloe Ran Tu, Yanmei Zhang, Wenyue Zhang, Zhinan Yin, Wing-Hang Leung, Yu-Lung Lau, Yinping Liu, Wenwei Tu.

  Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cancer. The effect of glucose metabolism on γδ T cells and their impact on tumor surveillance remain unknown. Here, we showed that high glucose induced Warburg effect type of bioenergetic profile in Vγ9Vδ2 T cells, leading to excessive lactate accumulation, which further inhibited lytic granule secretion by impairing the trafficking of cytolytic machinery to the Vγ9Vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro, in vivo and in patients. Strikingly, activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vγ9Vδ2 T cells. These results suggest that the impaired antitumor activity of Vγ9Vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.

Keywords:  AMPK; Glucose metabolism; Lactate; T2DM; Tumor surveillance; γδ T cells

DOI:  https://doi.org/10.1038/s41423-022-00894-x
Environ Toxicol. 2022 Jul 13.

Selenium deficiency aggravates bisphenol A-induced autophagy in chicken kidney through regulation of nitric oxide and adenosine monophosphate activated protein kinase/mammalian target of rapamycin signaling pathway.

Huijie Chen, Yue Zhang, Xue Qi, Xu Shi, Xiaodan Huang, Shi-Wen Xu.

  Bisphenol A (BPA), a phenolic compound, is harmful to humans and animals as its residue in the water threatens multiple organs, especially the kidney. Low selenium (Se) diets are consumed in many regions of the world, and poor Se status has exacerbating effect on toxicity of several environmental chemicals. Here, we described the discovery path of Se deficiency aggravation on autophagy in BPA treated chicken kidney through regulating nitric oxide (NO) and adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathways. The actual dietary Se intake for chickens was 0.30 mg/kg in control group and 0.03 mg/kg in Low-Se group, and BPA exposure concentration for chickens was 0.05 g/kg. Chicken embryo kidney (CEK) cells were used in vitro and the BPA exposure concentration for CEK cells was 150 nM. We found that BPA significantly increased levels of NO and inducible nitric oxide synthase, activated AMPK/mTOR signaling pathways, thereby triggering p62/LC3/Beclin1 signaling, resulting in formations of autophagosome and autolysosome, and finally stimulating autophagy in the chicken kidney. Additionally, Se deficiency promoted the occurrence of autophagy in BPA-treated kidneys. Altogether, our findings showed that Se deficiency exacerbates BPA-induced renal autophagy in chickens via regulation of NO and AMPK/mTOR signaling pathways. These findings will improve our understandings of the mechanisms of nephrotoxicity of BPA and detoxification by Se in chickens. In addition, further work is required to determine if Se status of exposed populations needs to be considered in future epidemiological assessments.

Keywords:  adenosine monophosphate activated protein kinase/mammalian target of rapamycin; autophagy; bisphenol A; nitric oxide; selenium deficiency

DOI:  https://doi.org/10.1002/tox.23613
Acta Neurobiol Exp (Wars). 2022 ;82(2): 207-212

LACC1 contributes to inflammation and cognitive disorder after stroke via the AMPK/NLRP3 pathway.

Junping Jiao, Shujuan Tian, Junqiang Bao, Zhiwei Wang, Xiongwei Xie, Guofeng Yang.

The current study aimed to investigate the effects of LACC1 on cognitive disorder due to stroke, as well as its underlying mechanism. LACC1 promoted inflammation and aggravated cognitive impairment in a mouse model of stroke. In an in vitro model of stroke, inhibition of LACC1 reduced inflammation and ROS‑induced oxidative stress by activating AMP‑activated protein kinase (AMPK) expression and suppressing NLPR3 expression. Furthermore, our studies revealed that inhibition of AMPK activity reduced the effects of si‑LACC1 on cognitive disorder in mice after stroke via the AMPK/NLPR3 pathway. AMPK activation also reduced the effects of LACC1 on inflammation and ROS‑induced oxidative stress via the NLPR3 pathway in the in vitro model that we evaluated. Our study suggests that LACC1‑aggravated inflammation causes cognitive impairment after stroke via the AMPK/NLRP3 pathway, which may provide a new therapeutic target for stroke and other neurological diseases and their associated complications. In sum, we identified an important role and regulatory mechanism for LACC1 in maintaining stroke‑induced cognitive disorder via the AMPK/NLRP3 pathway.

DOI: https://doi.org/10.55782/ane-2022-019
Exp Biol Med (Maywood). 2022 Jul 14. 15353702221110646

Epigallocatechin-3-gallate attenuates myocardial fibrosis in diabetic rats by activating autophagy.

Qiang Jia, Rui Yang, Shomaila Mehmood, Yan Li.

  Epigallocatechin-3-gallate (EGCG) possesses anti-fibrotic potential in diverse tissues; however, the molecular mechanisms underlying the impacts of EGCG on diabetes-induced myocardial fibrosis remain unclear. This present study aimed to unravel the anti-fibrotic effects of EGCG on the heart in type 2 diabetic rats and investigate its molecular mechanisms. Rats were randomly assigned to the following four groups: Normal (NOR), diabetic cardiomyopathy (DCM), DCM + 40 mg/kg EGCG, and DCM + 80 mg/kg EGCG groups. After 8 weeks of EGCG treatment, fasting blood glucose, left ventricular hemodynamic indices, heart index, and myocardial injury-related parameters were measured. Hematoxylin and eosin staining and Sirius Red staining were used to evaluate myocardial pathological alterations and collagen accumulation. The contents of myocardial hydroxyproline, collagen-I, collagen-III, transforming growth factor (TGF)-β1, matrix metalloprotease (MMP)-2, and MMP-9 were measured. The gene expression levels of myocardial TGF-β1, MMP-2, and MMP-9 were detected. Autophagic regulators, including adenosine 5'-monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), and autophagic markers, including microtubule-associated protein-1 light chain 3 and Beclin1 were estimated. The results indicated that diabetes significantly decreased cardiac contractile function and aggravated myocardial hypertrophy and injury. Furthermore, diabetes repressed the activation of autophagy in myocardial tissue and promoted cardiac fibrosis. Following ingestion with different doses of EGCG, myocardial contractile dysfunction, hypertrophy and injury were ameliorated; myocardial autophagy was activated, and myocardial fibrosis was alleviated in the EGCG treatment groups. In conclusion, these findings suggested that EGCG could attenuate cardiac fibrosis in type 2 diabetic rats, and its underlying mechanisms associated with activation of autophagy via modulation of the AMPK/mTOR pathway and then repression of the TGF-β/MMPs pathway.

Keywords:  AMPK/mTOR signaling pathway; Epigallocatechin-3-gallate; autophagy; diabetes mellitus; myocardial fibrosis; rat

DOI:  https://doi.org/10.1177/15353702221110646
J Endocrinol Invest. 2022 Jul 14.

Stachydrine alleviates lipid-induced skeletal muscle insulin resistance via AMPK/HO-1-mediated suppression of inflammation and endoplasmic reticulum stress.

T W Jung, H Kim, S Y Park, W Cho, H Oh, H J Lee, A M Abd El-Aty, A Hacimuftuoglu, J H Jeong.

  OBJECTIVE: Insulin resistance develops due to skeletal muscle inflammation and endoplasmic reticulum (ER) stress. Stachydrine (STA), extracted from Leonurus heterophyllus, has been shown to suppress proliferation and induce apoptosis in breast cancer cells and exert anti-inflammatory properties in the brain, heart, and liver. However, the roles of STA in insulin signaling in skeletal muscle remain unclear. Herein, we examined the impacts of STA on insulin signaling in skeletal muscle under hyperlipidemic conditions and its related molecular mechanisms.METHODS: Various protein expression levels were determined by Western blotting. Levels of mouse serum cytokines were measured by ELISA.
RESULTS: We found that STA-ameliorated inflammation and ER stress, leading to attenuation of insulin resistance in palmitate-treated C2C12 myocytes. STA dose-dependently enhanced AMPK phosphorylation and HO-1 expression. Administration of STA attenuated not only insulin resistance but also inflammation and ER stress in the skeletal muscle of high-fat diet (HFD)-fed mice. Additionally, STA-ameliorated glucose tolerance and insulin sensitivity, as well as serum TNFα and MCP-1, in mice fed a HFD. Small interfering (si) RNA-associated suppression of AMPK or HO-1 expression abolished the effects of STA in C2C12 myocytes.
CONCLUSIONS: These results suggest that STA activates AMPK/HO-1 signaling, resulting in reduced inflammation and ER stress, thereby improving skeletal muscle insulin resistance. Using STA as a natural ingredient, this research successfully treated insulin resistance and type 2 diabetes.

Keywords:  AMPK; ER stress; HO-1; Inflammation; Insulin resistance; Stachydrine

DOI:  https://doi.org/10.1007/s40618-022-01866-8
Front Pharmacol. 2022 ;13 941094

Ginkgolide B Protects Against Ischemic Stroke via Targeting AMPK/PINK1.

Yile Cao, Lei Yang, Hong Cheng.

  Introduction: Ginkgolide B (GB), which is an active constituent derived from Ginkgo biloba leaves, has been reported to ameliorate Alzheimer's disease (AD), ischemic stroke, as well as other neurodegenerative diseases due to its viable immunosuppressive and anti-inflammatory functions. However, it has yet to be proven whether GB inhibits neuronal apoptosis in ischemic stroke. Methods: In the present research, the inhibition function of GB on neuronal apoptosis and its underpinning process(s) after cerebral ischemia were studied through transient middle cerebral artery occlusion (t-MCAO) in an in vivo rat model as well as in cultured SH-SY5Y cells subjected to oxygen and glucose deprivation (OGD)/reoxygenation in vitro. The neurological score was calculated and Nissl and TUNEL staining were performed to evaluate the stroke outcome, neuronal loss, and neuronal apoptosis. Subsequently, the western blot was utilized to detect Bcl2 and p-AMPK/AMPK expression. Results: Compared to t-MCAO rats, rats receiving GB treatment showed a significant reduction of neuronal loss and apoptosis and improved neurological behavior at 72 h after MCAO. GB treatment also upregulated the expression of Bcl2 and p-AMPK. In vitro, GB suppressed the apoptosis in OGD/reoxygenation-challenged neuronal SH-SY5Y cells through AMPK activation. Conclusions: Our observations suggest that GB enhanced AMPK activation in neural cells, reducing neuronal apoptosis, thus eventually preventing ischemic stroke.

Keywords:  AMPK; OGD; PINK1; apoptosis; ginkgolide B; stroke; t-MCAO

DOI:  https://doi.org/10.3389/fphar.2022.941094
Ecotoxicol Environ Saf. 2022 Jul 12. pii: S0147-6513(22)00713-8. [Epub ahead of print]242 113873

AMPK regulates behavior and physiological plasticity of Haliotis discus hannai under different spectral compositions.

Mo Zhang, Xiaolong Gao, Mingxin Lyu, Shihui Lin, Xuan Luo, Weiwei You, Caihuan Ke.

  In natural environments, the spectral composition of incident light is often subject to drastic changes due to the abundance of suspended particles, floating animals, and plants in coastal waters. In this study, after four months of culturing under blue light (NB), orange light (NY), dark environment (ND), and natural light (NN), the shell length and weight-specific growth rate in Pacific abalone, Haliotis discus hannai, were ranked in the following order: NY > NN > ND > NB. To understand the growth differences in abalone under these different light environments, we first performed 24-h video monitoring and found that the cumulative movement distance and duration were lowest in group NB, whereas the cumulative movement distance and duration were significantly higher in group ND than in any other group (P < 0.05). In group NB, the time spent hidden underneath the attachment substrate accounted for 81% of the resting time, but this ratio was lowest in group ND, at only 37% (P < 0.05). Next, LC-MS metabolomics identified 201 and 105 metabolites in NB vs. NN, ND vs. NN, and NY vs. NN under the positive and negative ion modes, respectively. According to the fold changes and annotations for differential metabolites in the KEGG enrichment pathways, adenosine, NAD+, cGMP, and arachidonic acid were used as differential metabolism markers, and the AMPK signaling pathway was enriched in every comparison group, and thus investigated further. The gene sequences of three subtypes of AMPK were obtained by cloning and we found that the expression levels of AMPKα and AMPKγ, and the AMP content were significantly higher in group NB than in any other group (P < 0.05). In addition, the ATP contents and adenylate energy charge values were ranked in the following order: NY > NN > ND > NB. According to in situ hybridization analysis, the three subtype genes were widely expressed in the hepatopancreas. Finally, the contents of many lipid metabolites differed significantly among groups and the expression levels of the triglyceride hydrolysis-related gene hormone sensitive lipase and fatty acid oxidation-related gene carnitine palmitoyltransferase 1 were higher in groups ND and NB than in groups NN and NY according to fluorescence quantification PCR (P < 0.05). The expression levels of fatty acid synthase and acetyl-CoA carboxylase were significantly lower in groups ND and NB than in groups NN and NY (P < 0.05). These findings indicated that differences in the spectral composition of incident light could reshape the behavior and physiological metabolism in abalone by influencing the "energy switch" AMPK, thereby providing some insights into the mechanisms that allow nocturnal marine organisms to adapt to different lighting environments.

Keywords:  AMPK; Adenylate energy charge; Haliotis discus hannai; Movement behavior; Spectral composition

DOI:  https://doi.org/10.1016/j.ecoenv.2022.113873
Cell Transplant. 2022 Jan-Dec;31:31 9636897221106998

Hypoxic Tumor-Derived Exosomes Induce M2 Macrophage Polarization via PKM2/AMPK to Promote Lung Cancer Progression.

Shiyu Zhou, Yu Lan, Yuqun Li, Zhenxing Li, Jinding Pu, Liping Wei.

  Hypoxia is a major regulator of tumor aggressiveness and metastasis in cancer progression. Exosomes (exos) play an important role in the communication between lung cancer and hypoxic microenvironment. However, the underlying mechanisms are largely undefined. Exos were isolated from A549 cells under hypoxia conditions. Transmission electron microscopy and nanoparticle tracking analysis were carried out to characterize exos. CCK-8 assay, flow cytometry, Western blot, wound healing, and transwell assays were performed to assess the proliferation, apoptosis, migration, and invasion of A549 cells, respectively. The M2 polarization of macrophages was evaluated by RT-qPCR and Western blot analysis. In vivo nude mice model was established to determine the regulatory effect of hypoxia/exos on the progression of lung cancer. Hypoxic A549 cell-derived exos (hypoxia/exos) promoted the proliferation and migration, and inhibited the apoptosis in A549 cells. The expression of PKM2 was significantly upregulated in hypoxia/exos. Hypoxic exosomal PKM2 induced M2 polarization of macrophages by activating AMPK pathway. Co-culture with hypoxia/exos-treated macrophages enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) in A549 cells. Moreover, treatment with hypoxia/exos facilitated the tumor growth and lung metastasis of A549 cells. Our findings reveal that hypoxic exosomal PKM2 induces M2 macrophage polarization via AMPK pathway, and thus exerts a simulative effect on the growth and metastasis of lung carcinoma.

Keywords:  PKM2/AMPK; exosomes; hypoxia; lung cancer; macrophage; metastasis

DOI:  https://doi.org/10.1177/09636897221106998
Exp Gerontol. 2022 Jul 07. pii: S0531-5565(22)00197-8. [Epub ahead of print]166 111889

Systems modelling predicts chronic inflammation and genomic instability prevent effective mitochondrial regulation during biological ageing.

Alvaro Martinez Guimera, Peter Clark, James Wordsworth, Sharath Anugula, Lene Juel Rasmussen, Daryl P Shanley.

  The regulation of mitochondrial turnover under conditions of stress occurs partly through the AMPK-NAD+-PGC1α-SIRT1 signalling pathway. This pathway can be affected by both genomic instability and chronic inflammation since these will result in an increased rate of NAD+ degradation through PARP1 and CD38 respectively. In this work we develop a computational model of this signalling pathway, calibrating and validating it against experimental data. The computational model is used to study mitochondrial turnover under conditions of stress and how it is affected by genomic instability, chronic inflammation and biological ageing in general. We report that the AMPK-NAD+-PGC1α-SIRT1 signalling pathway becomes less responsive with age and that this can prime for the accumulation of dysfunctional mitochondria.

Keywords:  Cell Signalling; DNA damage; Mito-nuclear communication; Mitochondria; NAD; Systems modelling

DOI:  https://doi.org/10.1016/j.exger.2022.111889
J Ginseng Res. 2022 Jul;46(4): 561-571

Upregulation of adiponectin by Ginsenoside Rb1 contributes to amelioration of hepatic steatosis induced by high fat diet.

Yaru Li, Shuchen Zhang, Ziwei Zhu, Ruonan Zhou, Pingyuan Xu, Lingyan Zhou, Yue Kan, Jiao Li, Juan Zhao, Penghua Fang, Xizhong Yu, Wenbin Shang.

  Background: Ginsenoside Rb1 (GRb1) is capable of regulating lipid and glucose metabolism through its action on adipocytes. However, the beneficial role of GRb1-induced up-regulation of adiponectin in liver steatosis remains unelucidated. Thus, we tested whether GRb1 ameliorates liver steatosis and insulin resistance by promoting the expression of adiponectin.Methods: 3T3-L1 adipocytes and hepatocytes were used to investigate GRb1's action on adiponectin expression and triglyceride (TG) accumulation. Wild type (WT) mice and adiponectin knockout (KO) mice fed high fat diet were treated with GRb1 for 2 weeks. Hepatic fat accumulation and function as well as insulin sensitivity was measured. The activation of AMPK was also detected in the liver and hepatocytes.
Results: GRb1 reversed the reduction of adiponectin secretion in adipocytes. The conditioned medium (CM) from adipocytes treated with GRb1 reduced TG accumulation in hepatocytes, which was partly attenuated by the adiponectin antibody. In the KO mice, the GRb1-induced significant decrease of TG content, ALT and AST was blocked by the deletion of adiponectin. The elevations of GRb1-induced insulin sensitivity indicated by OGTT, ITT and HOMA-IR were also weakened in the KO mice. The CM treatment significantly enhanced the phosphorylation of AMPK in hepatocytes, but not GRb1 treatment. Likewise, the phosphorylation of AMPK in liver of the WT mice was increased by GRb1, but not in the KO mice.
Conclusions: The up-regulation of adiponectin by GRb1 contributes to the amelioration of liver steatosis and insulin resistance, which further elucidates a new mechanism underlying the beneficial effects of GRb1 on obesity.

Keywords:  AMPK; Adipocyte; Adiponectin; Ginsenoside Rb1; Hepatic steatosis

DOI:  https://doi.org/10.1016/j.jgr.2021.10.005
Contrast Media Mol Imaging. 2022 ;2022 8464082

Exogenous H2S Protects against Septic Cardiomyopathy by Inhibiting Autophagy through the AMPK/mTOR Pathway.

YuHan Zhao, QingHong Cheng.

Background: Given the cardioprotective role of autophagy, this study aimed to investigate the protective effect of exogenous H2S (NaHS) on infectious cardiomyopathy through the inhibition of the AMPK/mTOR pathway.Methods: In this study, sepsis models were established by cecal ligation and puncture (CLP) induction in vivo and intraperitoneal injection of NaHS was performed. Autophagy- and apoptosis-related proteins were observed by western blot, isolated myocardial tissue morphology was observed by hematoxylin-eosin (H&E) staining, and myocardial apoptosis was evaluated by the tunnel method. The ultrastructure of autophagy was observed by using an electron transmission electron microscope.
Results: In an SD rat model of cecum ligation puncture-induced sepsis, the level of autophagy-related proteins was significantly increased, and hematoxylin and eosin staining showed irregular myocardial bands and swollen cardiomyocytes. Following NaHS treatment, the level of autophagy-related proteins decreased, and electron transmission microscopy revealed decreased autophagosomes. Echocardiography suggested an increase in ejection fraction and significant relief of myocardial inhibition.
Conclusions: Our results suggest that NaHS treatment can attenuate the cellular damage caused by excessive autophagy through the AMPK/mTOR pathway.

DOI: https://doi.org/10.1155/2022/8464082
Biochem Biophys Res Commun. 2022 Jun 30. pii: S0006-291X(22)00897-X. [Epub ahead of print]621 80-87

Isosteviol sodium attenuates high fat/high cholesterol-induced myocardial dysfunction by regulating the Sirt1/AMPK pathway.

Ying Mei, Hui Hu, Liangjun Deng, Xiaoou Sun, Wen Tan.

  A fat-rich diet triggers obesity, and promotes cardiomyocyte injury. Till now, no prior investigations suggested a beneficial role of Isosteviol Sodium (STVNa) in cardiac activity in high fat diet (HFD)-exposed obese rats. However, there is evidence that STVNa accelerates healing of multiple tissue injuries. Herein, we explored the underlying mechanism behind the STVNa-based protection against HFD-induced myocardial dysfunction (MCD) in a rat model of myocardial injury. We employed dosages of 1, 10, and 20 mg/kg STVNa to treat MCD in rats fed with a HFD. Based on our results, STVNa repressed MCD (as indicated by ecocardiographic analysis), myocardium function, pathological structure, and myocardial enzymes. Mechanistically, the STVNa-mediated protection against HFD-induced MCD involved inhibition of inflammation and oxidative stress. Furthermore, using Western blot analysis, we revealed that the critical members of the Sirt1/AMPK network were markedly activated in the STVNa-treated group, relative to HFD-fed controls. Collectively, these evidences suggested that the STVNa offered strong protection against HFD-induced MCD. Moreover, this effect was mediated by the activation of the Sirt1/AMPK network, which, in turn, promoted lipid metabolism.

Keywords:  AMPK; High-fat diet; Isosteviol sodium; Myocardium; Sirt1

DOI:  https://doi.org/10.1016/j.bbrc.2022.06.044
Adv Med Sci. 2022 Jul 12. pii: S1896-1126(22)00025-6. [Epub ahead of print]67(2): 262-268

Inverse correlation between the expression of AMPK/SIRT1 and NAMPT in psoriatic skin: A pilot study.

Fabio D'Amico, Giuseppe Costantino, Lucia Salvatorelli, Alice Ramondetta, Rocco De Pasquale, Maria Angela Sortino, Sara Merlo.

  PURPOSE: Epidermal hyperplasia and the involvement of immune cells characterize the clinical picture of psoriasis. Among the several factors involved, attention has been focused on sirtuin 1 (SIRT1) - a deacetylase endowed with a variety of functions including the control of metabolic and inflammatory processes-, and on nicotinamide phosphoribosyltransferase (NAMPT), important for SIRT1 activation and involved in inflammatory events. The aim of the study was to analyze changes of SIRT1 and NAMPT expression in psoriatic skin.PATIENTS AND METHODS: Samples from healthy controls and psoriatic patients were subjected to immunohistochemical analysis.
RESULTS: A strong downregulation of SIRT1 expression was observed in skin samples from psoriatic patients compared to healthy controls. This was accompanied by a parallel reduction of adenosine monophosphate-activated kinase (AMPK) expression and, more strikingly, by the disappearance of cells immunolabeled for its active, phosphorylated form (pAMPK). In both cases, analysis of the distribution of immunopositive cells revealed a shift towards reduced intensity of staining. In contrast, NAMPT expression was upregulated in psoriatic samples in line with its pro-inflammatory role. This was again more visible with an intensity-based distribution analysis that evidenced a shift towards more intensely immunostained cell populations.
CONCLUSIONS: The present data correlate in the same samples the expression of SIRT1, pAMPK/AMPK and NAMPT in psoriasis and open the way for novel pharmacological targets in the treatment of the disease.

Keywords:  Adenosine monophosphate-activated protein kinase; Inflammation; Nicotinamide phosphoribosyltransferase; Psoriasis; Silent information regulator 1

DOI:  https://doi.org/10.1016/j.advms.2022.07.001
Behav Brain Res. 2022 Jul 07. pii: S0166-4328(22)00269-8. [Epub ahead of print]433 114001

Adipose-derived mesenchymal stem cells reduced transient cerebral ischemia injury by modulation of inflammatory factors and AMPK signaling.

Mina Ranjbaran, Reyhaneh Vali, Zahra Yaghoobi, Fardin Sehati, Vida Jashn, Sevda Mahdipour Kolur, Fariba Akhondzadeh, Ghorbangol Ashabi.

  Stem cell-based treatments have been recommended as a feasible therapy for stroke victims due to their potential for angiogenesis, neurogenesis, and synaptic plasticity. The intracellular mechanisms of stem cells against cerebral hypoperfusion are not well recognized. In this study, by releasing the clips, the reperfusion period was extended to 96 h, and two hours after cerebral ischemia, animals received adipose-derived MSCs. MSCs were isolated from the inguinal fat pads of rats and injected into two-vessel occlusion (2VO) rats 1 h after ischemia induction. Ninety-six hours after 2VO induction, behavioral and molecular tests were assessed. Adipose-derived MSCs treatment improves neurological scores, passive avoidance memory, and novel object recognition tests in the 2VO model compared to 2VO rats (P < 0.001). MSCs treatment decreased TNF-α (P < 0.01) and IL-6 (P < 0.01) and apoptotic factors (Bax/Bcl-2 ratio and caspase-3 level (P < 0.01)) compared with ischemic rats. MSCs treatment of ischemic rats could enhance Klotho-α and AMPK-α compared with ischemic rats (P < 0.001). The study disclosed that adipose-derived MSCs could improve neurological damage and memory deficits by reducing neuronal death in cerebral ischemia. Data proposed that adipose-derived MSCs inhibit pro-inflammatory factors such as IL-6 and TNF-α, consequently decreasing apoptosis in the hippocampus of CCAO rats. Besides, the Klotho-α and AMPK-α measurements found that MSCs might induce intracellular neuroprotective pathways via activation of Klotho-α/AMPK-α signaling.

Keywords:  AMPK; Apoptosis; Cerebral ischemia; Inflammation; Memory; Mesenchymal stem cells

DOI:  https://doi.org/10.1016/j.bbr.2022.114001
Front Endocrinol (Lausanne). 2022 ;13 895360

LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy.

Panai Song, Yinyin Chen, Zhiwen Liu, Hong Liu, Li Xiao, Lin Sun, Jiali Wei, Liyu He.

  Background: Diabetic nephropathy (DN) is a serious complication among patients with diabetes. Elucidating its pathogenesis is crucial for identifying novel biomarkers and therapeutic targets for DN.Methods: DN tissues were harvested for examining MALAT1, LIN28A and Nox4. Human kidney-2 (HK-2) cells were treated with high glucose (HG) for establishing a cell model of DN. Cell viability was examined by MTT assay. HG-induced cell apoptosis and secretion of TNF-α and IL-6 were analyzed by TUNEL and ELISA assays, respectively. RIP and RNA pull-down assays were applied to analyze the interaction between MALAT1, LIN28A and Nox4 in HK-2 and human embryonic kidney 293T (HEK-293T) cells. A rat model of DN was established to determine the role of MALAT1 in DN in vivo.
Results: MALAT1, LIN28A and Nox4 were upregulated in DN tissues and HG-treated HK-2 cells. Overexpression of MALAT1, LIN28A or Nox4 reduced cell viability and enhanced cell apoptosis, ROS generation and secretion of inflammatory cytokines in HG-treated HK-2 cells, whereas knockdown of MALAT1, LIN28A or Nox4 exerted opposite effects. Furthermore, MALAT1 directly interacted with LIN28A. Moreover, MALAT1 facilitated the interaction between LIN28A and Nox4 to increase Nox4 stability. Knockdown of Nox4 relieved HG-induced injury by suppressing the AMPK/mTOR signaling in HK-2 cells. Knockdown of MALAT1 alleviated renal tubular epithelial injury by suppressing LIN28A and the Nox4/AMPK/TOR signaling in DN.
Conclusion: MALAT1 activates the AMPK/mTOR signaling via interacting with LIN28A to stabilize Nox4 mRNA, thereby aggravating high glucose-induced renal tubular epithelial injury. Our findings provide potential therapeutic targets for DN.

Keywords:  AMPK/mTOR signaling; LIN28A; MALAT1; diabetic nephropathy; renal tubular injury

DOI:  https://doi.org/10.3389/fendo.2022.895360