bims-amsmem 2022-04-10 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–04–10
23 papers selected by
Dipsikha Biswas, Københavns Universitet

Disrupting AMPK-Glycogen Binding in Mice Increases Carbohydrate Utilization and Reduces Exercise Capacity.
Effective fraction from Simiao Wan prevents hepatic insulin resistant by inhibition of lipolysis via AMPK activation.
Dietary Phosphorus Reduced Hepatic Lipid Deposition by Activating Ampk Pathway and Beclin1 Phosphorylation Levels to Activate Lipophagy in Tilapia Oreochromis niloticus.
Aged green tea reduces high-fat diet-induced fat accumulation and inflammation via activating the AMP-activated protein kinase signaling pathway.
Combination of Ascorbic Acid and Menadione Induces Cytotoxic Autophagy in Human Glioblastoma Cells.
S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects.
Paeoniflorin Ameliorates Skeletal Muscle Atrophy in Chronic Kidney Disease via AMPK/SIRT1/PGC-1α-Mediated Oxidative Stress and Mitochondrial Dysfunction.
Incretin-induced changes in the transcriptome of skeletal muscles of fa/fa Zucker rat (ZFR) with obesity, without diabetes.
Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway.
Phloretin ameliorates diabetes-induced endothelial injury through AMPK-dependent anti-EndMT pathway.
Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.
Ferulic acid protects renal tubular epithelial cells against anoxia/reoxygenation injury mediated by AMPKα1.
Ming-Mu-Di-Huang-Pill Activates SQSTM1 via AMPK-Mediated Autophagic KEAP1 Degradation and Protects RPE Cells from Oxidative Damage.
Sex Differences in Cardiac Pathology of SARS-CoV2 Infected and Trypanosoma cruzi Co-infected Mice.
Metformin Inhibits NLR Family Pyrin Domain Containing 3 (NLRP)-Relevant Neuroinflammation via an Adenosine-5'-Monophosphate-Activated Protein Kinase (AMPK)-Dependent Pathway to Alleviate Early Brain Injury After Subarachnoid Hemorrhage in Mice.
Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway.
Novel dual glucagon-like peptide-1/ glucose-dependent insulinotropic polypeptide receptor agonist attenuates diabetes and myocardial injury through inhibiting hyperglycemia, inflammation and oxidative stress in rodent animals.
Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice.
Decorin Protects Retinal Pigment Epithelium Cells from Oxidative Stress and Apoptosis via AMPK-mTOR-Regulated Autophagy.
NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells.
Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder.
Trehalose induces B cell autophagy to alleviate myocardial injury via the AMPK/ULK1 signalling pathway in acute viral myocarditis induced by Coxsackie virus B3.
Graphene oxide induces autophagy and apoptosis via ROS-dependent AMPK/mTOR/ULK-1 pathway in colorectal cancer cells.

Front Physiol. 2022 ;13 859246

Disrupting AMPK-Glycogen Binding in Mice Increases Carbohydrate Utilization and Reduces Exercise Capacity.

Natalie R Janzen, Jamie Whitfield, Lisa Murray-Segal, Bruce E Kemp, John A Hawley, Nolan J Hoffman.

  The AMP-activated protein kinase (AMPK) is a central regulator of cellular energy balance and metabolism and binds glycogen, the primary storage form of glucose in liver and skeletal muscle. The effects of disrupting whole-body AMPK-glycogen interactions on exercise capacity and substrate utilization during exercise in vivo remain unknown. We used male whole-body AMPK double knock-in (DKI) mice with chronic disruption of AMPK-glycogen binding to determine the effects of DKI mutation on exercise capacity, patterns of whole-body substrate utilization, and tissue metabolism during exercise. Maximal treadmill running speed and whole-body energy utilization during submaximal running were determined in wild type (WT) and DKI mice. Liver and skeletal muscle glycogen and skeletal muscle AMPK α and β2 subunit content and signaling were assessed in rested and maximally exercised WT and DKI mice. Despite a reduced maximal running speed and exercise time, DKI mice utilized similar absolute amounts of liver and skeletal muscle glycogen compared to WT. DKI skeletal muscle displayed reduced AMPK α and β2 content versus WT, but intact relative AMPK phosphorylation and downstream signaling at rest and following exercise. During submaximal running, DKI mice displayed an increased respiratory exchange ratio, indicative of greater reliance on carbohydrate-based fuels. In summary, whole-body disruption of AMPK-glycogen interactions reduces maximal running capacity and skeletal muscle AMPK α and β2 content and is associated with increased skeletal muscle glycogen utilization. These findings highlight potential unappreciated roles for AMPK in regulating tissue glycogen dynamics and expand AMPK's known roles in exercise and metabolism.

Keywords:  AMP-activated protein kinase; carbohydrate binding module; energy utilization; exercise; glycogen; metabolism; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2022.859246
Chin J Nat Med. 2022 Mar;pii: S1875-5364(21)60115-2. [Epub ahead of print]20(3): 161-176

Effective fraction from Simiao Wan prevents hepatic insulin resistant by inhibition of lipolysis via AMPK activation.

Qi-Xin Jiang, Yi-Meng Chen, Jing-Jie Ma, Yu-Ping Wang, Ping Li, Xiao-Dong Wen, Jie Yang.

  Simiao Wan (SMW) is a traditional Chinese formula, including Atractylodis Rhizoma, Achyranthis Bidentatae Radix, Phellodendri Chinensis Cortex and Coicis Semen at the ratio of 1:1:2:2. It can be used to the treatment of diabetes. However, its bioactive compounds and underlying mechanism are unclear. This study aimed to screen the antilipolytic fraction from SMW and investigate its therapeutic mechanisms on hepatic insulin resistance. Different fractions of SMW were prepared by membrane separation combined with macroporous resin and their antilipolytic activities were screened in fasted mice. The effects of 60% ethanol elution (ESMW) on lipolysis were investigated in 3T3-L1 adipocytes stimulated by palmitic acid (PA) and high fat diet (HFD)-fed mice. In our study, ESMW is the bioactive fraction responsible for the antilipolytic activity of SMW and 13 compounds were characterized from ESMW by UHPLC-QTOF-MS/MS. ESMW suppressed protein kinase A (PKA)-hormone-sensitive lipase (HSL) related lipolysis and increased AMP-activated protein kinase (AMPK) phosphorylation in PA challenged 3T3-L1 adipocytes. AMPKα knockdown abolished the inhibitory effects of ESMW on IL-6 and HSL pSer-660, revealing that the antilipolytic and anti-inflammatory activities of ESMW are AMPK dependent. Furthermore, ESMW ameliorated insulin resistance and suppressed lipolysis in HFD-fed mice. It inhibited diacylglycerol accumulation in the liver and inhibited hepatic gluconeogenesis. Conditional medium collected from ESMW-treated 3T3-L1 cells ameliorated insulin action on hepatic gluconeogenesis in liver cells, demonstrating the antilipolytic activity contributed to ESMW beneficial effects on hepatic glucose production. In conclusion, ESMW, as the antilipolytic fraction of SMW, inhibited PKA-HSL related lipolysis by activating AMPK, thus inhibiting diacylglycerol (DAG) accumulation in the liver and thereby improving insulin resistance and hepatic gluconeogenesis.

Keywords:  AMPK; Insulin resistance; Lipolysis; Simiao Wan

DOI:  https://doi.org/10.1016/S1875-5364(21)60115-2
Front Nutr. 2022 ;9 841187

Dietary Phosphorus Reduced Hepatic Lipid Deposition by Activating Ampk Pathway and Beclin1 Phosphorylation Levels to Activate Lipophagy in Tilapia Oreochromis niloticus.

Xiangyuan Liu, Tao Zhao, Xiaolei Wei, Dianguang Zhang, Wuhong Lv, Zhi Luo.

  High-phosphorus diet (HPD) reduces lipid deposition and significantly influences lipid metabolism. However, the relevant mechanism is unknown. Herein, using widely-cultured teleost tilapia Oreochromis niloticus as the experimental animals, we found that HPD and Pi incubation reduced triglyceride (TG) content (P ≤ 0.05), suppressed lipogenesis, activated AMP-activated protein kinase (AMPK) pathway and autophagy (P ≤ 0.05), and increased fatty acid β-oxidation and lipolysis in tilapia liver and hepatocytes (P ≤ 0.05). Our further investigation indicated that Pi treatments activated the lipophagy and facilitated mitochondrial fatty acid β-oxidation, and according reduced TG deposition (P ≤ 0.05). Mechanistically, phosphorus increased the AMPKα1 phosphorylation level at S496 and Beclin1 phosphorylation at S90, and Beclin1 phosphorylation by AMPKα1 was required for phosphorus-induced lipophagy and lipolysis. Our study revealed a mechanism for Beclin1 regulation and autophagy induction in response to high-phosphorus diet, and provided novel evidences for the link between dietary phosphorus addition and lipolytic metabolism via the AMPK/Beclin1 pathway. Our results also suggested that AMPK should be the potential target for the prevention and control of lipid metabolic disorders. Overall, these results suggested that HPD reduced hepatic lipid deposition by activating AMPK pathway and Beclin1 phosphorylation levels to activate lipophagy, which provided potential targets for the prevention and control of fatty liver in fish.

Keywords:  AMPK/Beclin1 pathway; lipid metabolism; phosphorus; phosphorylation; vertebrates

DOI:  https://doi.org/10.3389/fnut.2022.841187
Food Nutr Res. 2022 ;66

Aged green tea reduces high-fat diet-induced fat accumulation and inflammation via activating the AMP-activated protein kinase signaling pathway.

Ruohong Chen, Xingfei Lai, Limin Xiang, Qiuhua Li, Lingli Sun, Zhaoxiang Lai, Zhigang Li, Wenji Zhang, Shuai Wen, Junxi Cao, Shili Sun.

   Background: Obesity is a global public health concern and increases the risk of metabolic syndrome and other diseases. The anti-obesity effects of various plant-derived bioactive compounds, such as tea extracts, are well-established. The mechanisms underlying the anti-obesity activity of Jinxuan green tea (JXGT) from different storage years are still unclear.
Objective: The aim of this study was to evaluate the effects of JXGTs from three different years on the high fat diet (HFD)-fed mouse model.
Design: The mice were divided into six groups, the control group received normal diet and the obese model group received HFD. We analyzed the effects of JXGTs from 2005, 2008, and 2016 on HFD-fed obese mice over a period of 7 weeks.
Results: The JXGTs reduced the body weight of the obese mice, and also alleviated fat accumulation and hepatic steatosis. Mechanistically, JXGTs increased the phosphorylation of AMP-activated protein kinase (p-AMPK)/AMP-activated protein kinase (AMPK) ratio, up-regulated carnitine acyl transferase 1A (CPT-1A), and down-regulated fatty acid synthase (FAS), Glycogen synthase kinase-3beta (GSK-3β), Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α), Interleukin 6 (IL-6), and Tumour necrosis factor alpha (TNFα). Thus, JXGTs can alleviate HFD-induced obesity by inhibiting lipid biosynthesis and inflammation, thereby promoting fatty acid oxidation via the AMPK pathway.
Discussion: The anti-obesity effect of three aged JXGTs were similar. However, JXGT2016 exhibited a more potent activation of AMPK, and JXGT2005 and JXGT2008 exhibited a more potent inhibiting glycogen synthase and inflammation effect. Furthermore, the polyphenol (-)-epicatechin (EC) showed the strongest positive correlation with the anti-obesity effect of JXGT.
Conclusions: These findings demonstrate that JXGT treatment has a potential protection on HFD-induced obesity mice via activating the AMPK/CPT-1A and down-regulating FAS/GSK-3β/PGC-1α and IL-6/TNFα. Our study results also revealed that different storage time would not affect the anti-obesity and anti-inflammation effect of JXGT.
Graphical abstract:

Keywords:  AMPK; aged green tea; anti-inflammation; anti-obesity; metabolism

DOI:  https://doi.org/10.29219/fnr.v66.7923
Oxid Med Cell Longev. 2022 ;2022 2998132

Combination of Ascorbic Acid and Menadione Induces Cytotoxic Autophagy in Human Glioblastoma Cells.

Ana Despotović, Aleksandar Mirčić, Sonja Misirlić-Denčić, Ljubica Harhaji-Trajković, Vladimir Trajković, Nevena Zogović, Gordana Tovilović-Kovačević.

We investigated the ability of the ascorbic acid (AA) and menadione (MD) combination, the well-known reactive oxidative species- (ROS-) generating system, to induce autophagy in human U251 glioblastoma cells. A combination of AA and MD (AA+MD), in contrast to single treatments, induced necrosis-like cell death mediated by mitochondrial membrane depolarization and extremely high oxidative stress. AA+MD, and to a lesser extent MD alone, prompted the appearance of autophagy markers such as autophagic vacuoles, autophagosome-associated LC3-II protein, degradation of p62, and increased expression of beclin-1. While both MD and AA+MD increased phosphorylation of AMP-activated protein kinase (AMPK), the well-known autophagy promotor, only the combined treatment affected its downstream targets, mechanistic target of rapamycin complex 1 (mTORC1), Unc 51-like kinase 1 (ULK1), and increased the expression of several autophagy-related genes. Antioxidant N-acetyl cysteine reduced both MD- and AA+MD-induced autophagy, as well as changes in AMPK/mTORC1/ULK1 activity and cell death triggered by the drug combination. Pharmacological and genetic autophagy silencing abolished the toxicity of AA+MD, while autophagy upregulation enhanced the toxicity of both AA+MD and MD. Therefore, by upregulating oxidative stress, inhibiting mTORC1, and activating ULK1, AA converts MD-induced AMPK-dependent autophagy from nontoxic to cytotoxic. These results suggest that AA+MD or MD treatment in combination with autophagy inducers could be further investigated as a novel approach for glioblastoma therapy.

DOI: https://doi.org/10.1155/2022/2998132
Aging Cell. 2022 Apr 07. e13604

S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects.

Takafumi Ogawa, Koji Masumura, Yuki Kohara, Muneyoshi Kanai, Tomoyoshi Soga, Yoshikazu Ohya, T Keith Blackwell, Masaki Mizunuma.

  Methionine restriction (MetR) can extend lifespan and delay the onset of aging-associated pathologies in most model organisms. Previously, we showed that supplementation with the metabolite S-adenosyl-L-homocysteine (SAH) extends lifespan and activates the energy sensor AMP-activated protein kinase (AMPK) in the budding yeast Saccharomyces cerevisiae. However, the mechanism involved and whether SAH can extend metazoan lifespan have remained unknown. Here, we show that SAH supplementation reduces Met levels and recapitulates many physiological and molecular effects of MetR. In yeast, SAH supplementation leads to inhibition of the target of rapamycin complex 1 (TORC1) and activation of autophagy. Furthermore, in Caenorhabditis elegans SAH treatment extends lifespan by activating AMPK and providing benefits of MetR. Therefore, we propose that SAH can be used as an intervention to lower intracellular Met and confer benefits of MetR.

Keywords:   Caenorhabditis elegans ; Saccharomyces cerevisiae ; S-adenosyl-L-homocysteine (SAH); S-adenosyl-L-methionine (SAM); methionine restriction (MetR)

DOI:  https://doi.org/10.1111/acel.13604
Front Pharmacol. 2022 ;13 859723

Paeoniflorin Ameliorates Skeletal Muscle Atrophy in Chronic Kidney Disease via AMPK/SIRT1/PGC-1α-Mediated Oxidative Stress and Mitochondrial Dysfunction.

Qiang Li, Jing Wu, Jiawen Huang, Rong Hu, Haiyan You, Lingyu Liu, Dongtao Wang, Lianbo Wei.

  Skeletal muscle atrophy is a common and serious complication of chronic kidney disease (CKD). Oxidative stress and mitochondrial dysfunction are involved in the pathogenesis of muscle atrophy. The aim of this study was to explore the effects and mechanisms of paeoniflorin on CKD skeletal muscle atrophy. We demonstrated that paeoniflorin significantly improved renal function, calcium/phosphorus disorders, nutrition index and skeletal muscle atrophy in the 5/6 nephrectomized model rats. Paeoniflorin ameliorated the expression of proteins associated with muscle atrophy and muscle differentiation, including muscle atrophy F-box (MAFbx/atrogin-1), muscle RING finger 1 (MuRF1), MyoD and myogenin (MyoG). In addition, paeoniflorin modulated redox homeostasis by increasing antioxidant activity and suppressing excessive accumulation of reactive oxygen species (ROS). Paeoniflorin alleviated mitochondrial dysfunction by increasing the activities of electron transport chain complexes and mitochondrial membrane potential. Furthermore, paeoniflorin also regulates mitochondrial dynamics. Importantly, paeoniflorin upregulated the expression of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and phosphorylation of AMP-activated protein kinase (AMPK). Similar results were observed in C2C12 myoblasts treated with TNF-α and paeoniflorin. Notably, these beneficial effects of paeoniflorin on muscle atrophy were abolished by inhibiting AMPK and SIRT1 and knocking down PGC-1α. Taken together, this study showed for the first time that paeoniflorin has great therapeutic potential for CKD skeletal muscle atrophy through AMPK/SIRT1/PGC-1α-mediated oxidative stress and mitochondrial dysfunction.

Keywords:  AMPK/SIRT1/PGC-1α; chronic kidney disease; mitochondrial dysfunction; oxidative stress; paeoniflorin; skeletal muscle atrophy

DOI:  https://doi.org/10.3389/fphar.2022.859723
Int J Obes (Lond). 2022 Apr 05.

Incretin-induced changes in the transcriptome of skeletal muscles of fa/fa Zucker rat (ZFR) with obesity, without diabetes.

Ides M Colin, Bernard Knoops, Anne-Catherine Gérard.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1ra) are increasingly used in treating type 2 diabetes and obesity. Exendin-4 (Ex-4), a long acting GLP-1ra, was previously reported to decrease oxidative stress in hepatocytes, adipocytes and skeletal muscle cells in obese nondiabetic fa/fa Zucker rats (ZFR), thereby improving insulin resistance.
AIM: We aimed first to identify Ex-4-induced changes in the transcriptome of skeletal muscle cells in ZFR.
RESULTS: Ontology analysis of differentially expressed genes (DEGs) in ZFR versus lean animals (LR) showed that the extracellular matrix (ECM) is the first most affected cellular compartment, followed by myofibrils and endoplasmic reticulum (ER). Interestingly, among 15 genes regulated in ZFR versus LR, 14 of them were inversely regulated by Ex-4, as further confirmed by RT-qPCR. Picro-Sirius red histological staining showed that decreased ECM fiber area in ZFR is partially restored by Ex-4. Ontology analysis of the myofibril compartment revealed that decreased muscle contractile function in ZFR is partially restored by Ex-4, as confirmed by Phalloidin histological staining that showed a partial restoration by Ex-4 of altered contractile apparatus in ZFR. Ontology analysis of ER DEGs in ZFR versus LR showed that some of them are related to the AMP-activated protein kinase (AMPK) signaling pathway. Phosphorylated AMPK levels were strongly increased in Ex-4-treated ZFR.
CONCLUSION: Altogether, our results suggest that GLP-1ra strongly restructure ECM and reinforce contractile capabilities in ZFR, while optimizing the cellular metabolism through AMPK.

DOI: https://doi.org/10.1038/s41366-022-01114-2
Front Pharmacol. 2022 ;13 864326

Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway.

Xue Tian, Xu Chen, Qianqian Jiang, Qianbin Sun, Tiantian Liu, Yiqin Hong, Yawen Zhang, Yanyan Jiang, Mingyan Shao, Ran Yang, Chun Li, Qiyan Wang, Yong Wang.

  Aims: Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5'monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway. Methods: In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo, NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro, NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining. Results: NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor. Conclusion: NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway.

Keywords:  AMPK; NGR1; apoptosis; cardiac lipotoxicity; heart failure

DOI:  https://doi.org/10.3389/fphar.2022.864326
Pharmacol Res. 2022 Apr 02. pii: S1043-6618(22)00150-5. [Epub ahead of print] 106205

Phloretin ameliorates diabetes-induced endothelial injury through AMPK-dependent anti-EndMT pathway.

Wenbo Mao, Yujuan Fan, Xu Wang, Guize Feng, Yan You, Haidong Li, Yongyan Chen, Jialin Yang, Hongbo Weng, Xiaoyan Shen.

  Diabetic cardiovascular complications contribute more than half of diabetes mortality. Endothelial damage and subsequent pathological changes play a key role in this process. Phloretin, a plant-derived dihydrochalcone compound, was reported to have the activities in regulating metabolism homeostasis and anti-inflammation. However, its effects and the mechanism on early stage endothelial injury caused by diabetes are not clear yet. In our present study, human umbilical vein endothelial cells (HUVECs) were stimulated by high glucose or advanced glycation end products (AGEs) to induce endothelial damage, and streptozotocin (STZ) -induced diabetes mouse model was used for in vivo study. Our results showed that phloretin effectively reduced endothelial damage marker monocyte chemotactic protein-1 (MCP1) as well as pro-calcification factors bone morphogenetic protein-2 (BMP2) and receptor activator of NF-κB ligand (RANKL) expression, reversed the increased vimentin and decreased CD31 dose-dependently in vitro and in vivo. Phloretin had no effect on blood glucose level. However, it ameliorated endothelial injury and vascular fibrosis in diabetic mice. Further experiments revealed that phloretin could enhance AMP activated protein kinase (AMPK) activation and upregulate peroxidase proliferator activated receptor-gamma coactivator-lα (PGC1α) level, and inhibit the activation of TGFβ-Smad2-Snail signalling pathway which was abrogated by AMPK inhibitor, providing a rational mechanism that AMPK activation was required for the effects of phloretin on endothelial injury and endothelial-mesenchymal transformation (EndMT). Our data reveal a new role of phloretin in protection of diabetic endothelial damage via AMPK-dependent anti-EndMT activation, and also provide a potential therapeutic way for diabetic endothelial damage and its subsequent cardiovascular complications.

Keywords:  AGEs; AMPK; EndMT; Endothelial damage; Phloretin

DOI:  https://doi.org/10.1016/j.phrs.2022.106205
Adv Sci (Weinh). 2022 Apr 09. e2105376

Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.

Long Wu, Wei Xie, Yang Li, Qiankun Ni, Peter Timashev, Meng Lyu, Ligang Xia, Yuan Zhang, Lingrong Liu, Yufeng Yuan, Xing-Jie Liang, Qiqing Zhang.

  Metabolic interventions via targeting intratumoral dysregulated metabolism pathways have shown promise in reinvigorating antitumor immunity. However, approved small molecule immunomodulators often suffer from ineffective response rates and severe off-target toxicity. ATP occupies a crucial role in energy metabolism of components that form the tumor microenvironment (TME) and influences cancer immunosurveillance. Here, a nanocarrier-assisted immunometabolic therapy strategy that targets the ATP-adenosine axis for metabolic reprogramming of TME is reported. An ecto-enzyme (CD39) antagonist POM1 and AMP-activated protein kinase (AMPK) agonist metformin are both encapsulated into cancer cell-derived exosomes and used as nanocarriers for tumor targeting delivery. This method increases the level of pro-inflammatory extracellular ATP (eATP) while preventing the accumulation of immunosuppressive adenosine and alleviating hypoxia. Elevated eATP triggers the activation of P2X7-NLRP3-inflammasome to drive macrophage pyroptosis, potentiates the maturation and antigen capacity of dendritic cells (DCs) to enhance the cytotoxic function of T cells and natural killer (NK) cells. As a result, synergistic antitumor immune responses are initiated to suppress tumor progress, inhibit tumor distant metastases, provide long-term immune memory that offers protection against tumor recurrence and overcome anti-PD1 resistance. Overall, this study provides an innovative strategy to advance eATP-driven antitumor immunity in cancer therapy.

Keywords:  AMPK activation; ATP-adenosine pathway; CD39 inhibition; exosome; immunnometabolic therapy

DOI:  https://doi.org/10.1002/advs.202105376
Free Radic Res. 2022 Apr 05. 1-36

Ferulic acid protects renal tubular epithelial cells against anoxia/reoxygenation injury mediated by AMPKα1.

Tianpeng Chen, Li Niu, Liang Wang, Qing Zhou, Xiaoyu Zhao, Songqing Lai, Xinlan He, Huan He, Ming He.

  Anoxia/reoxygenation (A/R) injury causes dysfunction of rat renal tubular epithelial cells (NRK-52E), which is associated with excess reactive oxygen species (ROS) generation and eventually leads to apoptosis. Ferulic acid (FA), a phenolic acid, which is abundant in fruits and vegetables. FA possesses the properties of scavenging free radicals and cytoprotection against oxygen stress. In the study, the protective effects of FA against NRK-52E cells damage induced by A/R were explored and confirmed the role of AMP-activated protein kinaseα1 (AMPKα1). We found that after NRK-52E cells suffered A/R damage, FA pretreatment increased the cell viability and decreased LDH activity in culture medium in a concentration-dependent manner, the activities of endogenous antioxidant enzymes such as glutathione peroxidase, superoxide dismutase and catalase improved, intracellular ROS generation and malondialdehyde contents mitigated. In addition, pretreatment of 75 μM FA ameliorated mitochondrial dysfunction by A/R-injury and ultimately decreased apoptosis (25.3 ± 0.61 vs 12.1 ± 0.60), which was evidenced by preventing the release of cytochrome c from mitochondria to the cytoplasm. 75 μM FA pretreatment also significantly upregulated AMPKα1 expression (3.16 ± 0.18 folds) and phosphorylation (2.56 ± 0.13 folds). However, compound C, a specific AMPK inhibitor, significantly attenuated FA pretreatment's effects, as mentionedabove. These results firstly clarified that FA pretreatment attenuated NRK-52E cell damage induced by A/R via upregulating AMPKα1 expression and phosphorylation.

Keywords:  AMPKα1; Ferulic acid; NRK-52E cell; anoxia/reoxygenation injury; apoptosis

DOI:  https://doi.org/10.1080/10715762.2022.2062339
Oxid Med Cell Longev. 2022 ;2022 5851315

Ming-Mu-Di-Huang-Pill Activates SQSTM1 via AMPK-Mediated Autophagic KEAP1 Degradation and Protects RPE Cells from Oxidative Damage.

Xi Chen, Yujie Zhu, Xiaoqing Shi, Jing Zuo, Tianming Hu, Hao Wu, Ying Xia, Wei Shi, Wei Wei.

Oxidative stress and diminished autophagy in the retinal pigment epithelium (RPE) play crucial roles in the pathogenesis of age-related macular degeneration (AMD). Enhancing autophagy has recently been identified as an important strategy to protect RPE cells from oxidative damage. Ming-Mu-Di-Huang-Pill (MMDH pill) is a traditional herbal medicine used to treat AMD, and its molecular mechanism is not well understood. The aim of the present study was to investigate whether the MMDH pill relieved acute oxidative damage by activating autophagy in an in vitro and in vivo model of sodium iodate (NaIO3). The results showed that NaIO3 induced cell death and inhibited proliferation. The MMDH pill increased cell viability, restored the activities of antioxidant enzymes, and reduced reactive oxygen species (ROS) fluorescence intensity. The MMDH pill mediated Kelch-like ECH-associated protein 1 (Keap1) degradation and decreased oxidative damage, which was blocked in autophagy inhibitor (chloroquine) or sequestosome-1 (SQSTM1) siRNA-treated RPE cells. Furthermore, we indicated that the MMDH pill could promote adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and autophagy adaptor-SQSTM1 expression, which could stimulate autophagic degradation of Keap1. In addition, the MMDH pill increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation in a SQSTM1-dependent manner and induced the expression of the downstream antioxidant factors heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1). In conclusion, MMDH pill plays a protective role in relieving NaIO3-induced oxidative stress by activating the AMPK/SQSTM1/Keap1 pathway. The MMDH pill may be useful to treat AMD by maintaining redox homeostasis and autophagy.

DOI: https://doi.org/10.1155/2022/5851315
Front Cardiovasc Med. 2022 ;9 783974

Sex Differences in Cardiac Pathology of SARS-CoV2 Infected and Trypanosoma cruzi Co-infected Mice.

Dhanya Dhanyalayam, Hariprasad Thangavel, Kezia Lizardo, Neelam Oswal, Enriko Dolgov, David S Perlin, Jyothi F Nagajyothi.

  Coronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; CoV2) is a deadly contagious infectious disease. For those who survive COVID-19, post-COVID cardiac damage greatly increases the risk of cardiomyopathy and heart failure. Currently, the number of COVID-related cases are increasing in Latin America, where a major COVID comorbidity is Chagas' heart disease, which is caused by the parasite Trypanosoma cruzi. However, the interplay between indeterminate Chagas disease and COVID-19 is unknown. We investigated the effect of CoV2 infection on heart pathology in T. cruzi infected mice (coinfected with CoV2 during the indeterminate stage of T. cruzi infection). We used transgenic human angiotensin-converting enzyme 2 (huACE2/hACE2) mice infected with CoV2, T. cruzi, or coinfected with both in this study. We found that the viral load in the hearts of coinfected mice is lower compared to the hearts of mice infected with CoV2 alone. We demonstrated that CoV2 infection significantly alters cardiac immune and energy signaling via adiponectin (C-ApN) and AMP-activated protein kinase (AMPK) signaling. Our studies also showed that increased β-adrenergic receptor (b-AR) and peroxisome proliferator-activated receptors (PPARs) play a major role in shifting the energy balance in the hearts of coinfected female mice from glycolysis to mitochondrial β-oxidation. Our findings suggest that cardiac metabolic signaling may differently regulate the pathogenesis of Chagas cardiomyopathy (CCM) in coinfected mice. We conclude that the C-ApN/AMPK and b-AR/PPAR downstream signaling may play major roles in determining the progression, severity, and phenotype of CCM and heart failure in the context of COVID.

Keywords:  Chagas' heart disease; CoV2 infection; adiponectin; cardiomyopathy; energy metabolism; glycolysis; inflammation; mitochondrial oxidation

DOI:  https://doi.org/10.3389/fcvm.2022.783974
Front Pharmacol. 2022 ;13 796616

Metformin Inhibits NLR Family Pyrin Domain Containing 3 (NLRP)-Relevant Neuroinflammation via an Adenosine-5'-Monophosphate-Activated Protein Kinase (AMPK)-Dependent Pathway to Alleviate Early Brain Injury After Subarachnoid Hemorrhage in Mice.

Lei Jin, Fa Jin, Shenquan Guo, Wenchao Liu, Boyang Wei, Haiyan Fan, Guangxu Li, Xin Zhang, Shixing Su, Ran Li, Dazhao Fang, Chuanzhi Duan, Xifeng Li.

  Neuroinflammation plays a key role in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have shown that metformin exerts anti-inflammatory effects and promotes functional recovery in various central nervous system diseases. We designed this study to investigate the effects of metformin on EBI after SAH. Our results indicate that the use of metformin alleviates the brain edema, behavioral disorders, cell apoptosis, and neuronal injury caused by SAH. The SAH-induced NLRP3-associated inflammatory response and the activation of microglia are also suppressed by metformin. However, we found that the blockade of AMPK with compound C weakened the neuroprotective effects of metformin on EBI. Collectively, our findings indicate that metformin exerts its neuroprotective effects by inhibiting neuroinflammation in an AMPK-dependent manner, by modulating the production of NLRP3-associated proinflammatory factors and the activation of microglia.

Keywords:  NLRP3 inflammasome; metformin; neuroinflammation; neuron injury; subarachnoid hemorrhage

DOI:  https://doi.org/10.3389/fphar.2022.796616
Anal Cell Pathol (Amst). 2022 ;2022 3634908

Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway.

Yajiang Yuan, Xiangyi Fan, Zhanpeng Guo, Zipeng Zhou, Weiran Gao.

Spinal cord injury (SCI) is an extreme neurological impairment with few effective drug treatments. Pyroptosis is a recently found and proven type of programmed cell death that is characterized by a reliance on inflammatory caspases and the release of a large number of proinflammatory chemicals. Pyroptosis differs from other cell death mechanisms such as apoptosis and necrosis in terms of morphological traits, incidence, and regulatory mechanism. Pyroptosis is widely involved in the occurrence and development of SCI. In-depth research on pyroptosis will help researchers better understand its involvement in the onset, progression, and prognosis of SCI, as well as provide new therapeutic prevention and treatment options. Herein, we investigated the role of AMPK-mediated activation of the NLRP3 inflammasome in the neuroprotection of MET-regulated pyroptosis. We found that MET treatment reduced NLRP3 inflammasome activation by activating phosphorylated AMPK and reduced proinflammatory cytokine (IL-1β, IL-6, and TNF-α) release. At the same time, MET improved motor function recovery in rats after SCI by reducing motor neuron loss in the anterior horn of the spinal cord. Taken together, our study confirmed that MET inhibits neuronal pyroptosis after SCI via the AMPK/NLRP3 signaling pathway, which is mostly dependent on the AMPK pathway increase, hence decreasing NLRP3 inflammasome activation.

DOI: https://doi.org/10.1155/2022/3634908
Bioengineered. 2022 Apr;13(4): 9184-9196

Novel dual glucagon-like peptide-1/ glucose-dependent insulinotropic polypeptide receptor agonist attenuates diabetes and myocardial injury through inhibiting hyperglycemia, inflammation and oxidative stress in rodent animals.

Ying Wang, Fei Cai, Gang Li, Yong Tao.

  This study was aimed to evaluate the therapeutic effects and potent mechanisms of a novel GLP-1/GIP dual agonist on hyperglycemia and myocardial injury in diabetic mice. Novel dual-receptor agonists were designed and then evaluated via in vitro receptor activation assays. Acute hypoglycemic effects were assessed in diabetic mice induced by intraperitoneal injection of streptozotocin. Chronic effects of dual-receptor agonists on diabetes as well as diabetic cardiomyopathy were investigated in DCM model mice. Effects of the in vitro coculture of dual-receptor agonists with or without signaling pathway inhibitors on the cell viability and apoptosis of primary cardiomyocytes under a high-glucose state were assessed via MTT and western blotting methods to investigate the probable mechanism. AP5 exhibited balanced activities of dual-receptor activation in vitro and improved hypoglycemic ability in diabetic mice. Moreover, chronic treatment of AP5 achieved the prominently improved efficacy in reversing the deteriorative diabetic disorders and reducing the myocardial injury markers in DCM mice. Moreover, AP5 also inhibited the apoptosis and improved the survival rate of primary cardiomyocytes under a high-glucose state via increasing the expression levels of antiapoptotic proteins and inhibiting the release of apoptotic proteins, respectively, as well as activating the AMPK/PI3K/Akt signaling pathway. In conclusion, the dual GLP-1/GIP receptor agonist, AP5, can effectively improve diabetic symptoms and exert therapeutic effects on DCM via activating the AMPK/PI3K/Akt pathway, reducing the ROS production, oxidative stress and inflammatory markers in the rodent DCM model.Abbreviation: Diabetes mellitus, DM; diabetic cardiomyopathy, DCM; streptozotocin, STZ; glucagon-like peptide-1, GLP-1; malondialdehyde, MDA; glucose-dependent insulinotropic polypeptide, GIP; creatine kinase, CK; diabetic cardiomyopathy, DCM; serum superoxide dismutase; SOD; total superoxide disumutase, T-SOD; Methyl Thiazolyl Tetrazolium, MTT; lactate dehydrogenase; LDH; Adenosine Monophosphate-Activated Protein Kinase, AMPK; Dulbecco's modified Eagle medium, DMEM; Fetal Bovine Serum, FBS; Reactive Oxygen Species, ROS; Glyceraldehyde-phosphate dehydrogenase, GAPDH; Surface Plasmon Resonance, SPR; Ethylene Diamine Tetraacetic Acid, EDTA; Interleukin-1β, IL-1β; Phosphoinositol 3-kinase, PI3K; Tumor necrosis factor, TNF-α; Renin-angiotensin-aldosterone system, RAAS; Glucose transporter, GLUT; Dipeptidyl peptidase-IV, DPP-IV; oxygen free radicals, OFR.

Keywords:  Dual GLP-1/GIP receptor agonist; apoptosis; diabetic cardiomyopathy; inflammation; mouse model; oxidative stress

DOI:  https://doi.org/10.1080/21655979.2022.2051859
J Neuroinflammation. 2022 Apr 07. 19(1): 82

Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice.

Yao Wang, Mi Tian, Jiaying Tan, Xu Pei, Chaocheng Lu, Yuewen Xin, Shuixiang Deng, Feng Zhao, Yanqin Gao, Ye Gong.

   BACKGROUND: Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin αVβ5/AMPK pathway after ICH.
METHODS: Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin αVβ5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function.
RESULTS: Endogenous irisin and its receptor, integrin αVβ5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin αVβ5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin αVβ5, p-AMPK and Bcl-2, and decreased the expression of IL-1β, TNF-α, MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin αVβ5 inhibitor cilengitide and AMPK inhibitor dorsomorphin.
CONCLUSIONS: This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin αVβ5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising therapeutic approach for the early management of ICH.

Keywords:  AMPK; Integrin αVβ5; Intracerebral hemorrhage; Irisin; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-022-02438-6
Oxid Med Cell Longev. 2022 ;2022 3955748

Decorin Protects Retinal Pigment Epithelium Cells from Oxidative Stress and Apoptosis via AMPK-mTOR-Regulated Autophagy.

Xinyi Xie, Duo Li, Yuqing Cui, Tianhua Xie, Jiping Cai, Yong Yao.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss among the elderly worldwide with unidentified pathogenesis and limited therapeutic options. Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is central in the development and progression of AMD. Decorin (DCN), a small leucine-rich proteoglycan, possesses powerful antifibrotic, anti-inflammatory, and antiangiogenic properties. DCN has also been reported to serve a cytoprotective role in various cell types, but its protective effects against H2O2-induced oxidative stress and apoptosis in ARPE-19 cells remain unclear. In this study, we showed that DCN significantly attenuated the increase in cell viability loss, apoptosis rate, and reactive oxygen species (ROS) levels in ARPE-19 cells induced by H2O2. Furthermore, DCN activated the AMPK/mTOR pathway to promote autophagy while genetic inhibition of autophagy-related gene 5 (ATG5) hindered autophagic process and diminished the protective role of DCN against oxidative stress in ARPE-19 cells. Collectively, these results suggest that DCN could protect RPE cells from H2O2-induced oxidative stress and apoptosis via autophagy promotion, thus providing the therapeutic potential for AMD prevention and treatment.

DOI: https://doi.org/10.1155/2022/3955748
Cell Signal. 2022 Apr 04. pii: S0898-6568(22)00091-2. [Epub ahead of print] 110330

NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells.

Ruijie Zhang, Chunxiao Liu, Liu Yang, Tong Ji, Nana Zhang, Xiaoqing Dong, Xin Chen, Jing Ma, Wei Gao, Shile Huang, Long Chen.

  Oxidative stress is closely related to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. NADPH oxidase 2 (NOX2) is involved in hydrogen peroxide (H2O2) generation. Recently, we have reported that treatment with H2O2 and PD toxins, including 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenylpyridin-1-ium (MPP+) and rotenone, induces neuronal apoptosis by inhibiting the mTOR pathway. Here, we show that treatment with 6-OHDA, MPP+ or rotenone induced H2O2 generation by upregulating the levels of NOX2 and its regulatory proteins (p22phox, p40phox, p47phox, p67phox, and Rac1), leading to apoptotic cell death in PC12 cells and primary neurons. Inhibition of NOX2 with apocynin or diphenyleneiodonium, or knockdown of NOX2 powerfully attenuated PD toxins-evoked NOX2 and H2O2, thereby hindering activation of AMPK, inhibition of Akt/mTOR, and induction of apoptosis in neuronal cells. Pretreatment with catalase, a H2O2-scavenging enzyme, blocked the effects of PD toxins on NOX2-dependent H2O2 production, AMPK/Akt/mTOR signaling and apoptosis in the cells. Similar effects were also seen in the cells pretreated with Mito-TEMPO, a mitochondria-selective superoxide scavenger, implying a mitochondrial H2O2-dependent mechanism involved. Further research revealed that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPK with compound C suppressed PD toxins-induced expression of NOX2 and its regulatory proteins, as well as consequential H2O2 production and apoptosis in the cells. Taken together, these results indicate that certain PD toxins can impede the AMPK/Akt-mTOR signaling pathway leading to neuronal apoptosis by eliciting NOX2-derived H2O2 production. Our findings suggest that neuronal loss in PD may be prevented by regulating the NOX2, AMPK/Akt-mTOR signaling and/or applying antioxidants to ameliorate oxidative stress.

Keywords:  AMPK; Akt; Hydrogen peroxide; NADPH oxidase 2; Neuronal cells; mTOR

DOI:  https://doi.org/10.1016/j.cellsig.2022.110330
Mech Ageing Dev. 2022 Mar 30. pii: S0047-6374(22)00052-5. [Epub ahead of print]204 111670

Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder.

C Trujillo-Del Río, J Tortajada-Pérez, A P Gómez-Escribano, F Casterá, C Peiró, J M Millán, M J Herrero, R P Vázquez-Manrique.

  Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamines (polyQs). These polyQs make the protein prone to aggregate and cause it to acquire a toxic gain of function. Principally affecting the frontal cortex and the striatum, mHtt disrupts many cellular functions. In addition, this protein is expressed ubiquitously, and some reports show that many other cell types are affected by the toxicity of mHtt. Several studies reported that metformin, a widely-used anti-diabetic drug, is neuroprotective in models of HD. Here, we provide a review of the benefits of this substance to treat HD. Metformin is a pleiotropic drug, modulating different targets such as AMPK, insulin signalling and many others. These molecules regulate autophagy, chaperone expression, and more, which in turn reduce mHtt toxicity. Moreover, metformin alters gut microbiome and its metabolic processes. The study of potential targets, interactions between the drug, host and microbiome, or genomic and pharmacogenomic approaches may allow us to design personalised medicine to treat HD.

Keywords:  AMPK; Gut microbiome; Huntington disease; Metformin; Pharmacogenetics; Pleiotropic effects

DOI:  https://doi.org/10.1016/j.mad.2022.111670
Int J Biochem Cell Biol. 2022 Apr 02. pii: S1357-2725(22)00053-X. [Epub ahead of print] 106208

Trehalose induces B cell autophagy to alleviate myocardial injury via the AMPK/ULK1 signalling pathway in acute viral myocarditis induced by Coxsackie virus B3.

Bin Wei, Feiyu Lu, Qing Kong, Yanlan Huang, Kai Huang, Weifeng Wu.

  Viral myocarditis (VMC) is the main cause of sudden acute heart failure and cardiac death in adolescents; however, treatment for VMC is limited. Trehalose is a natural non-reductive disaccharide that protects against cardiovascular diseases by inducing autophagy. The protective effect of trehalose on VMC and the specific mechanism remains unclear. In this study, we established a VMC mouse model, treated with trehalose in vivo, and cultured B cells from VMC mice with trehalose in vitro to elucidate the effect of trehalose on B cells in acute VMC. Trehalose alleviated myocardial injury in VMC mice and increased the number of autophagosomes, LC3II/LC3I ratio, and expression level of LAMP2, whereas it decreased the expression of p62 in VMC-B cells. Bafilomycin A1 suppressed VMC-B cell autophagy induced by trehalose. At the mechanistic level, trehalose treatment significantly upregulated the phosphorylation of AMPK and ULK1 in VMC-B cells. Dorsomorphin and SBI-0206965 abolished the increased phosphorylation level and altered the expression levels of autophagy-related proteins. In conclusion, trehalose alleviates myocardial inflammatory damage of VMC by inducing B cell autophagy, mediated by the AMPK/ULK1 signalling pathway. Thus, trehalose may be a potentially useful molecule for alleviating myocardial injury in VMC.

Keywords:  B cells; acute viral myocarditis; autophagy; cardiac injury; trehalose

DOI:  https://doi.org/10.1016/j.biocel.2022.106208
Nanomedicine (Lond). 2022 Apr 08.

Graphene oxide induces autophagy and apoptosis via ROS-dependent AMPK/mTOR/ULK-1 pathway in colorectal cancer cells.

Jiamen Shen, Jiatian Dong, Feng Shao, Jiaying Zhao, Lifeng Gong, Huipeng Wang, Wenjie Chen, Yafei Zhang, Yuankun Cai.

  Aim: To investigate the anticancer effects and action mechanism of graphene oxide (GO) in colorectal cancer (CRC). Materials & methods: Anticancer effects and mechanisms of GO in CRC were investigated both in vivo and in vitro. Results: GO significantly inhibited tumor growth both in vitro and in vivo. GO was able to enter HCT116 cells through endocytosis. GO treatment resulted in cytotoxicity, reactive oxygen species (ROS) production, apoptosis, autophagy and activation of the AMPK/mTOR/ULK1 signal pathway. However, ROS scavenger N-acetylcysteine (NAC) attenuated the above effects and restored the effects of GO on protein expressions related to apoptosis, autophagy and AMPK/mTOR/ULK1 signal pathways. Conclusion: GO exerts anticancer effects against CRC via ROS-dependent AMPK/mTOR/ULK-1 pathway-related autophagy and apoptosis.

Keywords:  apoptosis; autophagy; colorectal cancer; graphene oxide; reactive oxygen species

DOI:  https://doi.org/10.2217/nnm-2022-0030