bims-amsmem 2022-11-13 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022‒11‒13
twenty-two papers selected by
Dipsikha Biswas, Københavns Universitet

PRL stimulates mitotic errors by suppressing kinetochore-localized activation of AMPK during mitosis.
A bioactive component of Portulaca Oleracea L., HM-chromanone, improves palmitate-induced insulin resistance by inhibiting mTOR/S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells.
The Inhibition of Zinc Excitotoxicity and AMPK Phosphorylation by a Novel Zinc Chelator, 2G11, Ameliorates Neuronal Death Induced by Global Cerebral Ischemia.
Effect of quercetin and Abelmoschus esculentus (L.) Moench on lipids metabolism and blood glucose through AMPK-α in diabetic rats (HFD/STZ).
Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function.
Role of AMPK in Regulation of Oxaliplatin-Resistant Human Colorectal Cancer.
AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
Therapeutic Effects of Omentin-1 on Pulmonary Fibrosis by Attenuating Fibroblast Activation via AMP-Activated Protein Kinase Pathway.
SIRT1 Promotes Host Protective Immunity against Toxoplasma gondii by Controlling the FoxO-Autophagy Axis via the AMPK and PI3K/AKT Signalling Pathways.
Arginine Reduces Glycation in γ2 Subunit of AMPK and Pathologies in Alzheimer's Disease Model Mice.
FNDC3B protects steatosis and ferroptosis via the AMPK pathway in alcoholic fatty liver disease.
Nicorandil protects against coronary microembolization-induced myocardial injury by suppressing cardiomyocyte pyroptosis via the AMPK/TXNIP/NLRP3 signaling pathway.
Metformin: a promising antidiabetic medication for cancer treatment.
Anesthetic sevoflurane simultaneously regulates autophagic flux and pyroptotic cell death-associated cellular inflammation in the hypoxic/re-oxygenated cardiomyocytes: Identification of sevoflurane as putative drug for the treatment of myocardial ischemia-reperfusion injury.
Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism.
Regulation of autophagy of the heart in ischemia and reperfusion.
Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells.
ERK Inhibition Increases RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells by Stimulating AMPK Activation and RANK Expression and Inhibiting Anti-Osteoclastogenic Factor Expression.
Supercritical Extract of Cannabis sativa Inhibits Lung Metastasis in Colorectal Cancer Cells by Increasing AMPK and MAPKs-Mediated Apoptosis and Cell Cycle Arrest.
Muscle glycogen unavailability and fat oxidation rate during exercise: Insights from McArdle disease.
Isosilybin regulates lipogenesis and fatty acid oxidation via the AMPK/SREBP-1c/PPARα pathway.
Metformin antagonizes nickel-refining fumes-induced cell pyroptosis via Nrf2/GOLPH3 pathway in vitro and in vivo.

Cell Struct Funct. 2022 Nov 05.

PRL stimulates mitotic errors by suppressing kinetochore-localized activation of AMPK during mitosis.

Kajung Ryu, Atsushi Yoshida, Yosuke Funato, Daisuke Yamazaki, Hiroaki Miki.

  Phosphatase of regenerating liver (PRL) is frequently overexpressed in various malignant cancers and is known to be a driver of malignancy. Here, we demonstrated that PRL overexpression causes mitotic errors that accompany spindle misorientation and aneuploidy, which are intimately associated with cancer progression. Mechanistic analyses of this phenomenon revealed dysregulation of the energy sensor kinase, AMP-activated protein kinase (AMPK), in PRL-induced mitotic errors. Specifically, immunofluorescence analysis showed that levels of phosphorylated AMPK (P-AMPK), an activated form of AMPK, at the kinetochore were reduced by PRL expression. Moreover, artificial activation of AMPK using chemical activators, such as A769662 and AICAR, in PRL-expressing cells restored P-AMPK signals at the kinetochore and normalized spindle orientation. Collectively, these results indicate the crucial importance of the activation of kinetochore-localized AMPK in the normal progression of mitosis, which is specifically perturbed by PRL overexpression.Key words: cancer, AMPK, PRL, kinetochore, mitotic errors.

Keywords:  AMPK; PRL; cancer; kinetochore; mitotic errors

DOI:  https://doi.org/10.1247/csf.22034
Toxicol Res (Camb). 2022 Oct;11(5): 774-783

A bioactive component of Portulaca Oleracea L., HM-chromanone, improves palmitate-induced insulin resistance by inhibiting mTOR/S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells.

Jae Eun Park, Ji Sook Han.

  Increased free fatty acid levels in the blood are common in obesity and cause insulin resistance associated with type 2 diabetes in the muscles. Previous studies have confirmed the antidiabetic and anti-obesity potential of (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone). However, it is unknown how HM-chromanone alleviates obesity-related insulin resistance in L6 skeletal muscle cells. Palmitate induced insulin resistance and reduced glucose uptake, whereas HM-chromanone significantly increased glucose uptake. In palmitate-treated L6 skeletal muscle cells, HM-chromanone stimulated liver kinase B1 (LKB1) and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. The AMPK inhibitor compound C, and the LKB1 inhibitor radicicol blocked the effects of HM-chromanone. Furthermore, HM-chromanone significantly inhibited mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase 1 (S6K1) activation, but there was no change in protein kinase C θ (PKC θ) expression. When pAMPK was inhibited with compound C, the effect of HM-chromanone on the inhibition of mTOR and S6K1 was significantly diminished. This indicates that HM-chromanone inhibits mTOR and S6K1 activation through pAMPK activation. Inhibition of mTOR and S6K1 by HM-chromanone significantly reduced IRS-1Ser307 and IRS-1Ser632 phosphorylation, leading to insulin resistance. This resulted in an increase in PM-GLUT4 (glucose transporter 4) expression, thereby stimulating glucose uptake in insulin-resistant muscle cells. HM-chromanone can improve palmitate-induced insulin resistance by inhibiting mTOR and S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells. These results show the therapeutic potential of HM-chromanone for improving insulin resistance in type 2 diabetes.

Keywords:  AMPK; HM-chromanone; homoisoflavonoid; insulin resistance; palmitate

DOI:  https://doi.org/10.1093/toxres/tfac055
Antioxidants (Basel). 2022 Nov 05. pii: 2192. [Epub ahead of print]11(11):

The Inhibition of Zinc Excitotoxicity and AMPK Phosphorylation by a Novel Zinc Chelator, 2G11, Ameliorates Neuronal Death Induced by Global Cerebral Ischemia.

Dae Ki Hong, Jae-Won Eom, A Ra Kho, Song Hee Lee, Beom Seok Kang, Si Hyun Lee, Jae-Young Koh, Yang-Hee Kim, Bo Young Choi, Sang Won Suh.

  AMP-activated protein kinase (AMPK) is necessary for maintaining a positive energy balance and essential cellular processes such as glycolysis, gene transcription, glucose uptake, and several other biological functions. However, brain injury-induced energy and metabolic stressors, such as cerebral ischemia, increase AMPK phosphorylation. Phosphorylated AMPK contributes to excitotoxicity, oxidative, and metabolic problems. Furthermore, brain disease-induced release of zinc from synaptic vesicles contributes to neuronal damage via mechanisms including ROS production, apoptotic cell death, and DNA damage. For this reason, we hypothesized that regulating zinc accumulation and AMPK phosphorylation is critical for protection against global cerebral ischemia (GCI). Through virtual screening based on the structure of AMPK subunit alpha 2, we identified a novel compound, 2G11. In this study, we verified that 2G11 administration has neuroprotective effects via the blocking of zinc translocation and AMPK phosphorylation after GCI. As a result, we demonstrated that 2G11 protected hippocampal neurons against GCI and OGD/R-derived cellular damage. In conclusion, we propose that AMPK inhibition and zinc chelation by 2G11 may be a promising tool for preventing GCI-induced hippocampal neuronal death.

Keywords:  2G11; AMP-activated protein kinase; global cerebral ischemia; neuronal death; zinc

DOI:  https://doi.org/10.3390/antiox11112192
J Food Biochem. 2022 Nov 12. e14506

Effect of quercetin and Abelmoschus esculentus (L.) Moench on lipids metabolism and blood glucose through AMPK-α in diabetic rats (HFD/STZ).

Zohreh Nasrollahi, Kahin ShahaniPour, Ramesh Monajemi, Ali Mohammad Ahadi.

  Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in the glyconeogenesis pathway. The AMP-activated protein kinase alpha (AMPK-α) pathway regulates PEPCK, which itself is activated by the AMP/ATP ratio and liver kinase B1 (KB1). The Abelmoschus esculentus (L.) Moench (okra) plant contains a large amount of quercetin that can function as an agonist or an antagonist. The aim of this study was to examine the effects of quercetin flavonoid and A. esculentus extract on the level of AMPK-α expression and associated metabolic pathways. The findings demonstrate that metformin, quercetin, and okra extract may significantly raise AMPK-α levels while significantly lowering PEPCK and hormone-sensitive lipase (HSL) levels, in addition to improving glucose and lipid profiles. By stimulating KB1, these substances increased AMPK-α activation. Additionally, AMPK-α activation improved insulin resistance and Glucose transporter type 4 (GLUT4) gene expression levels. Since AMPK-α maintains energy balance and its activity has not been reported to be inhibited so far, it could be a potent therapeutic target. PRACTICAL APPLICATIONS: The development of effective AMPK-α agonists and antagonists holds promise for the treatment of metabolic disorders like diabetes. Dietary polyphenols are a valuable source for developing new drugs. However, due to the lack of understanding of the underlying mechanisms of their effect on cells, their use in the treatment of diabetes is controversial. In addition to chemicals that have medicinal benefits, chemists are searching for less harmful substances. Using plants containing bioactive chemicals for this purpose can be a good alternative to chemical drugs.

Keywords:   AMPK-α ; Abelmoschus esculentus ; PEPCK ; glyconeogenesis; lipolysis

DOI:  https://doi.org/10.1111/jfbc.14506
Front Pharmacol. 2022 ;13 947387

Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function.

Yan Yan, Ming Li, Jie Lin, Yanan Ji, Kexin Wang, Dajun Yan, Yuntian Shen, Wei Wang, Zhongwei Huang, Haiyan Jiang, Hualin Sun, Lei Qi.

  Skeletal muscle is one of the largest organs in the body and the largest protein repository. Mitochondria are the main energy-producing organelles in cells and play an important role in skeletal muscle health and function. They participate in several biological processes related to skeletal muscle metabolism, growth, and regeneration. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor and regulator of systemic energy balance. AMPK is involved in the control of energy metabolism by regulating many downstream targets. In this review, we propose that AMPK directly controls several facets of mitochondrial function, which in turn controls skeletal muscle metabolism and health. This review is divided into four parts. First, we summarize the properties of AMPK signal transduction and its upstream activators. Second, we discuss the role of mitochondria in myogenesis, muscle atrophy, regeneration post-injury of skeletal muscle cells. Third, we elaborate the effects of AMPK on mitochondrial biogenesis, fusion, fission and mitochondrial autophagy, and discuss how AMPK regulates the metabolism of skeletal muscle by regulating mitochondrial function. Finally, we discuss the effects of AMPK activators on muscle disease status. This review thus represents a foundation for understanding this biological process of mitochondrial dynamics regulated by AMPK in the metabolism of skeletal muscle. A better understanding of the role of AMPK on mitochondrial dynamic is essential to improve mitochondrial function, and hence promote skeletal muscle health and function.

Keywords:  AMPK; mitochondria; muscle atrophy; muscle regeneration; skeletal muscle

DOI:  https://doi.org/10.3389/fphar.2022.947387
Biomedicines. 2022 Oct 25. pii: 2690. [Epub ahead of print]10(11):

Role of AMPK in Regulation of Oxaliplatin-Resistant Human Colorectal Cancer.

Sun Young Park, Ye Seo Chung, So Yeon Park, So Hee Kim.

  Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC50) of oxaliplatin were 4.40-12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs.

Keywords:  AMPK; Akt-mTOR; autophagy; chemoresistance; colorectal cancer; glycolysis; oxaliplatin

DOI:  https://doi.org/10.3390/biomedicines10112690
Sci Adv. 2022 Nov 11. 8(45): eabo7956

AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.

Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.

Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.

DOI: https://doi.org/10.1126/sciadv.abo7956
Biomedicines. 2022 Oct 26. pii: 2715. [Epub ahead of print]10(11):

Therapeutic Effects of Omentin-1 on Pulmonary Fibrosis by Attenuating Fibroblast Activation via AMP-Activated Protein Kinase Pathway.

Yan Zhou, Yunna Zhang, Haipeng Cheng, Xiaohong Li, Dandan Feng, Shaojie Yue, Jianping Xu, Hui Xie, Ziqiang Luo.

  Idiopathic pulmonary fibrosis (IPF) is a fatal age-related chronic lung disease, characterized by progressive scarring of the lungs by activated fibroblasts. The effect of omentin-1 against pulmonary fibrosis and fibroblast activation has not been investigated. The purpose of this experiment is to investigate the role of omentin-1 in bleomycin (BLM)-induced lung fibrosis and its mechanism. Our results showed that the loss of omentin-1 exaggerated lung fibrosis induced by BLM. On the contrary, adenoviral-overexpression of omentin-1 significantly alleviated BLM-induced lung fibrosis both in preventive and therapeutic regimens. Moreover, omentin-1 prevented fibroblast activation determined by a decreased number of S100A4+ (fibroblasts marker) α-SMA+ cells in vivo, and a decreased level of α-SMA expression both in mice primary fibroblasts and human primary fibroblasts induced by TGF-β in vitro. Furthermore, the phosphorylation of AMP-activated protein kinase (p-AMPK) was significantly lower in the fibrotic foci induced by BLM, and the adenoviral-overexpression of omentin-1 significantly increased the p-AMPK level in vivo. Importantly, Compound C, the inhibitor of AMPK, significantly attenuated the protective effect of omentin-1 on BLM-induced lung fibrosis and reversed the effect of omentin-1 on fibroblast activation by TGF-β. Omentin-1 can be a promising therapeutic agent for the prevention and treatment of lung fibrosis.

Keywords:  AMPK pathway; bleomycin; fibroblast activation; lung fibrosis; myofibroblast; omentin-1

DOI:  https://doi.org/10.3390/biomedicines10112715
Int J Mol Sci. 2022 Nov 05. pii: 13578. [Epub ahead of print]23(21):

SIRT1 Promotes Host Protective Immunity against Toxoplasma gondii by Controlling the FoxO-Autophagy Axis via the AMPK and PI3K/AKT Signalling Pathways.

Jina Lee, Jinju Kim, Jae-Hyung Lee, Yong Min Choi, Hyeonil Choi, Hwan-Doo Cho, Guang-Ho Cha, Young-Ha Lee, Eun-Kyeong Jo, Byung-Hyun Park, Jae-Min Yuk.

  Sirtuin 1 (SIRT1) regulates cellular processes by deacetylating non-histone targets, including transcription factors and intracellular signalling mediators; thus, its abnormal activation is closely linked to the pathophysiology of several diseases. However, its function in Toxoplasma gondii infection is unclear. We found that SIRT1 contributes to autophagy activation via the AMP-activated protein kinase (AMPK) and PI3K/AKT signalling pathways, promoting anti-Toxoplasma responses. Myeloid-specific Sirt1-/- mice exhibited an increased cyst burden in brain tissue compared to wild-type mice following infection with the avirulent ME49 strain. Consistently, the intracellular survival of T. gondii was markedly increased in Sirt1-deficient bone-marrow-derived macrophages (BMDMs). In contrast, the activation of SIRT1 by resveratrol resulted in not only the induction of autophagy but also a significantly increased anti-Toxoplasma effect. Notably, SIRT1 regulates the FoxO-autophagy axis in several human diseases. Importantly, the T. gondii-induced phosphorylation, acetylation, and cytosolic translocation of FoxO1 was enhanced in Sirt1-deficient BMDMs and the pharmacological inhibition of PI3K/AKT signalling reduced the cytosolic translocation of FoxO1 in BMDMs infected with T. gondii. Further, the CaMKK2-dependent AMPK signalling pathway is responsible for the effect of SIRT1 on the FoxO3a-autophagy axis and for its anti-Toxoplasma activity. Collectively, our findings reveal a previously unappreciated role for SIRT1 in Toxoplasma infection.

Keywords:  AMP-activated protein kinase; Class O of forkhead box transcription factors; PI3K/AKT signalling pathway; Sirtuin 1; Toxoplasma gondii; autophagy; bone-marrow-derived macrophages

DOI:  https://doi.org/10.3390/ijms232113578
Cells. 2022 Nov 07. pii: 3520. [Epub ahead of print]11(21):

Arginine Reduces Glycation in γ2 Subunit of AMPK and Pathologies in Alzheimer's Disease Model Mice.

Rui Zhu, Ying Lei, Fangxiao Shi, Qing Tian, Xinwen Zhou.

  The metabolism disorders are a common convergence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). The characteristics of AD are senile plaques and neurofibrillary tangles (NFTs) composed by deposits of amyloid-β (Aβ) and phosphorylated tau, respectively. Advanced glycation end-products (AGEs) are a stable modification of proteins by non-enzymatic reactions, which could result in the protein dysfunction. AGEs are associated with some disease developments, such as diabetes mellitus and AD, but the effects of the glycated γ2 subunit of AMPK on its activity and the roles in AD onset are unknown.METHODS: We studied the effect of glycated γ2 subunit of AMPK on its activity in N2a cells. In 3 × Tg mice, we administrated L-arginine once every two days for 45 days and evaluated the glycation level of γ2 subunit and function of AMPK and alternation of pathologies.
RESULTS: The glycation level of γ2 subunit was significantly elevated in 3 × Tg mice as compared with control mice, meanwhile, the level of pT172-AMPK was obviously lower in 3 × Tg mice than that in control mice. Moreover, we found that arginine protects the γ2 subunit of AMPK from glycation, preserves AMPK function, and improves pathologies and cognitive deficits in 3 × Tg mice.
CONCLUSIONS: Arginine treatment decreases glycated γ2 subunit of AMPK and increases p-AMPK levels in 3 × Tg mice, suggesting that reduced glycation of the γ2 subunit could ameliorate AMPK function and become a new target for AD therapy in the future.

Keywords:  AMPK; Alzheimer’s disease; L−arginine; advanced glycation end−products; glycation

DOI:  https://doi.org/10.3390/cells11213520
Free Radic Biol Med. 2022 Nov 03. pii: S0891-5849(22)00953-4. [Epub ahead of print]

FNDC3B protects steatosis and ferroptosis via the AMPK pathway in alcoholic fatty liver disease.

Yajing You, Chenxi Liu, Tiantian Liu, Miaomiao Tian, Nijin Wu, Zhen Yu, Fenglin Zhao, Jianni Qi, Qiang Zhu.

  BACKGROUND: Alcoholic liver disease (ALD) is a leading cause of chronic liver disease worldwide with limited therapeutic options. The role of fibronectin type III domain-containing protein 3B (FNDC3B), an important regulator of metabolism, in ALD, and the underlying mechanism as well as its potential implication in ALD therapeutic strategies remain unknown.METHODS: Hepatocyte-specific FNDC3B knockdown or control C57BL/6 N mice received a Lieber-DeCarli diet for four weeks, followed by oral gavage (chronic-binge). Primary mouse hepatocytes and cell lines were used for in vitro studies. Liver injury, hepatic steatosis, and lipid peroxidation were assessed.
RESULTS: In cultured cells and mouse livers, alcohol exposure increased FNDC3B expression. Hepatocyte-specific FNDC3B deletion aggravated alcohol-induced liver steatosis via AMP-activated protein kinase (AMPK) inhibition. In vitro, FNDC3B expression was negatively regulated by miR-192-5p. Furthermore, FNDC3B deletion significantly exacerbated ethanol-mediated lipid peroxidation. The RNA sequence assay revealed a connection between FNDC3B and ferroptosis, which was verified by the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Additionally, FNDC3B inhibition-mediated AMPK inactivation downregulated transferrin expression, which was associated with marked iron overload and ferroptosis.
CONCLUSIONS: This study elucidated the critical role of FNDC3B in preventing hepatic steatosis and ferroptosis in response to chronic alcohol consumption. Our findings indicate that FNDC3B is a potential therapeutic target for ALD.

Keywords:  Lipid deposition; Metabolism; Peroxidation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.10.322
Eur J Pharmacol. 2022 Nov 03. pii: S0014-2999(22)00626-4. [Epub ahead of print] 175365

Nicorandil protects against coronary microembolization-induced myocardial injury by suppressing cardiomyocyte pyroptosis via the AMPK/TXNIP/NLRP3 signaling pathway.

Yangchun Liu, Jin Shu, Tao Liu, Jian Xie, Tao Li, Haoliang Li, Lang Li.

  BACKGROUND: Coronary microembolization (CME) is a common and intractable complication of coronary revascularization, which leads to perioperative myocardial injury, cardiac dysfunction, and poor prognosis. Nicorandil is widely used for the management of ischemic heart diseases, but the cardioprotective effects of nicorandil beyond anti-angina in CME-induced myocardial injury are worthy of further exploration. Therefore, the present study investigated the effect of nicorandil on CME-induced cardiomyocyte pyroptosis and explored the underlying mechanism.METHODS: A rat model of CME was established via the injection of microspheres into the left ventricle. A cell model of H9c2 cardiomyocytes stimulated by lipopolysaccharide (LPS) and hypoxia mimicked the microenvironment induced by CME. Nicorandil or the adenosine monophosphate-activated protein kinase (AMPK)-specific inhibitor compound C (CC) was administered before CME induction and cell modeling. Cardiac function, histological alterations in the myocardium, myocardial injury biomarkers in serum and cell culture supernatant, cell viability, adenosine triphosphate (ATP) level, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, reactive oxygen species (ROS) activity, mitochondrial membrane potential, and pyroptosis-associated index were assessed after the animal and cell modeling of CME.
RESULTS: Nicorandil pretreatment attenuated cardiac dysfunction and myocardial injury following CME. Nicorandil also alleviated oxidative stress and mitochondrial damage. Moreover, nicorandil promoted AMPK activation, reduced the expression of thioredoxin-interacting protein (TXNIP), inhibited the activation of the NOD-like receptor pyrin containing 3 (NLRP3) inflammasome, and mitigated cardiomyocyte pyroptosis. However, co-treatment with CC reversed the cardioprotective effects of nicorandil.
CONCLUSION: Nicorandil pretreatment inhibits cardiomyocyte pyroptosis and alleviates CME-induced myocardial injury via the AMPK/TXNIP/NLRP3 signaling pathway.

Keywords:  AMPK/TXNIP/NLRP3; Cardiomyocyte; Coronary microembolization; Myocardial injury; Nicorandil; Pyroptosis

DOI:  https://doi.org/10.1016/j.ejphar.2022.175365
Curr Drug Targets. 2022 Nov 04.

Metformin: a promising antidiabetic medication for cancer treatment.

Wei Mu, Yunyun Jiang, Guoqiang Liang, Yue Feng, Falin Qu.

  Metformin is a widely used drug in patients with type 2 diabetes mellitus. Metformin inhibits hepatic gluconeogenesis and increases glucose utilization in peripheral tissues. In recent years, several studies have shown that metformin is a potential therapeutic agent against cancer, alone or combined with other anticancer treatments. Metformin mainly activates the AMPK complex and regulates intracellular energy status, inhibiting the mitochondrial respiratory chain complex I and reducing the production of reactive oxygen species. Other anticancer targets of metformin are specific transcription factors inhibiting cell proliferation, promoting apoptosis and reducing drug resistance. In addition, metformin modulates tumor cells response to anticancer treatments, favoring the activity of T cells. In diabetic patients, metformin reduces the occurrence of cancer and improves the prognosis and efficacy of anticancer treatments. In this review, we provided a comprehensive perspective of metformin as an anticancer drug.

Keywords:  AMPK complex; ICIs.; Metformin; ROS; Sps; anticancer

DOI:  https://doi.org/10.2174/1389450124666221104094918
Eur J Pharmacol. 2022 Nov 04. pii: S0014-2999(22)00624-0. [Epub ahead of print] 175363

Anesthetic sevoflurane simultaneously regulates autophagic flux and pyroptotic cell death-associated cellular inflammation in the hypoxic/re-oxygenated cardiomyocytes: Identification of sevoflurane as putative drug for the treatment of myocardial ischemia-reperfusion injury.

Lin Deng, Lihua Jiang, Na Wei, Jiahang Zhang, Xiaohong Wu.

  PRE: and post-conditioning of sevoflurane attenuate cardiomyocyte death and protects against myocardial ischemia/reperfusion (I/R) injury, and this process is considered to be associated with cell autophagy and pyroptosis, but the detailed molecular mechanisms regarding to this issue have not been fully studied. In this study, we verified that sevoflurane exerted its protective effects in myocardial I/R injury by synergistically regulating the AMPK/ULK1 pathway-mediated autophagy and NLRP3-mediated pyroptotic cell death, and the interplays between cell autophagy and pyroptosis were also preliminarily investigated. Specifically, sevoflurane conditioning suppressed NLRP3 and cleaved caspase-1 expressions to inactivate cell pyroptosis, upregulated LC3B-II/I ratio, facilitated autophagosome formation and accelerated p62 degradation to trigger autophagy, and promoted the expressions of CDK2, CDK6 and Cyclin D1 to recover cell cycle in I/R mouse myocardial tissues in vivo and hypoxic/re-oxygenated (H/R) cardiomyocytes in vitro. Further experiments validated that sevoflurane promoted the phosphorylation of both AMPK (p-AMPK) and ULK1 (p-ULK1) to activate the AMPK/ULK1 pathway, and the promoting effects of sevoflurane on cell autophagy in H/R cardiomyocytes were abrogated by co-treating cells with AMPK inhibitor (compound C) and ULK1 inhibitor (SBI-0206965). Moreover, it was verified that compound C, SBI-0206965 and autophagy blocker chloroquine reversed H/R-induced cell death and pyroptosis in cardiomyocytes. Taken together, we concluded that sevoflurane activated the AMPK/ULK1 pathway to trigger autophagic flux and suppress NLRP3-mediated pyroptotic cell death in I/R or H/R-treated cardiomyocytes, which further ameliorated myocardial I/R injury.

Keywords:  AMPK/ULK1 pathway; Autophagic flux; Ischemia-reperfusion injury; NLRP3 inflammasome; Pyroptotic cell death

DOI:  https://doi.org/10.1016/j.ejphar.2022.175363
Biology (Basel). 2022 Nov 04. pii: 1613. [Epub ahead of print]11(11):

Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism.

Neha Attal, Emilio Marrero, Kyle J Thompson, Iain H McKillop.

  Fatty acid binding protein-4 (FABP4) is not normally expressed in the liver but is induced in alcohol-dependent liver disease (ALD)). This study sought to identify mechanisms whereby ethanol (EtOH) metabolism alters triglyceride accumulation and FABP4 production. Human hepatoma cells which were stably transfected to express alcohol dehydrogenase (ADH) or cytochrome P4502E1 (CYP2E1) were exposed to EtOH in the absence/presence of inhibitors of ADH (4-methylpyrazole) or CYP2E1 (chlormethiazole). Cells were analyzed for free fatty acid (FFA) content and FABP4 mRNA, then culture medium assayed for FABP4 levels. Cell lysates were analyzed for AMP-activated protein kinase-α (AMPKα), Acetyl-CoA carboxylase (ACC), sterol regulatory element binding protein-1c (SREBP-1c), and Lipin-1β activity and localization in the absence/presence of EtOH and pharmacological inhibitors. CYP2E1-EtOH metabolism led to increased FABP4 mRNA/protein expression and FFA accumulation. Analysis of signaling pathway activity revealed decreased AMPKα activation and increased nuclear-SREBP-1c localization following CYP2E1-EtOH metabolism. The role of AMPKα-SREBP-1c in regulating CYP2E1-EtOH-dependent FFA accumulation and increased FABP4 was confirmed using pharmacological inhibitors and over-expression of AMPKα. Inhibition of ACC or Lipin-1β failed to prevent FFA accumulation or changes in FABP4 mRNA expression or protein secretion. These data suggest that CYP2E1-EtOH metabolism inhibits AMPKα phosphorylation to stimulate FFA accumulation and FABP4 protein secretion via an SREBP-1c dependent mechanism.

Keywords:  AMPKα; SREBP-1c; alcohol; cytochrome P4502E1; fatty acid binding protein; liver disease

DOI:  https://doi.org/10.3390/biology11111613
Apoptosis. 2022 Nov 11.

Regulation of autophagy of the heart in ischemia and reperfusion.

Sergey V Popov, Alexander V Mukhomedzyanov, Nikita S Voronkov, Ivan A Derkachev, Alla A Boshchenko, Feng Fu, Galina Z Sufianova, Maria S Khlestkina, Leonid N Maslov.

  Ischemia/reperfusion (I/R) of the heart leads to increased autophagic flux. Preconditioning stimulates autophagic flux by AMPK and PI3-kinase activation and mTOR inhibition. The cardioprotective effect of postconditioning is associated with activation of autophagy and increased activity of NO-synthase and AMPK. Oxidative stress stimulates autophagy in the heart during I/R. Superoxide radicals generated by NADPH-oxidase acts as a trigger for autophagy, possibly due to AMPK activation. There is reason to believe that AMPK, GSK-3β, PINK1, JNK, hexokinase II, MEK, PKCα, and ERK kinases stimulate autophagy, while mTOR, PKCδ, Akt, and PI3-kinase can inhibit autophagy in the heart during I/R. However, there is evidence that PI3-kinase could stimulate autophagy in ischemic preconditioning of the heart. It was found that transcription factors FoxO1, FoxO3, NF-κB, HIF-1α, TFEB, and Nrf-2 enhance autophagy in the heart in I/R. Transcriptional factors STAT1, STAT3, and p53 inhibit autophagy in I/R. MicroRNAs could stimulate and inhibit autophagy in the heart in I/R. Long noncoding RNAs regulate the viability and autophagy of cardiomyocytes in hypoxia/reoxygenation (H/R). Nitric oxide (NO) donors and endogenous NO could activate autophagy of cardiomyocytes. Activation of heme oxygenase-1 promotes cardiomyocyte tolerance to H/R and enhances autophagy. Hydrogen sulfide increases cardiac tolerance to I/R and inhibits apoptosis and autophagy via mTOR and PI3-kinase activation.

Keywords:  Autophagy; Heart; Ischemia/reperfusion; Kinases; Reactive oxygen species; microRNAs

DOI:  https://doi.org/10.1007/s10495-022-01786-1
Curr Issues Mol Biol. 2022 Nov 03. 44(11): 5474-5484

Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells.

Jingya Lyu, Hitomi Imachi, Kensaku Fukunaga, Seisuke Sato, Toshihiro Kobayashi, Takanobu Saheki, Salimah Japar, Hisakazu Iwama, Yuta Matsumura, Miyo Ozaki, Takafumi Yoshimura, Koji Murao.

  Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been clinically proven to protect endothelial function. Previously, we demonstrated that endothelial NO synthase (eNOS) was activated by high-density lipoprotein (HDL) via its scavenger receptor of the B class/human homologue of SR-BI, CD36 and LIMPII analogous-1(hSR-BI/CLA-1). Here, we investigated the effect of GLP-1RA and exendin-4 on the expression of hSR-BI/CLA-1 in HUVECs. Our results confirmed that GLP-1R was expressed in HUVECs by PCR and exendin-4 significantly enhanced HDL-induced eNOS activation. Next, exendin-4 increased the expression of hSR-BI/CLA-1 and a blockade of GLP-1R cancelled this effect. Further, the hSR-BI/CLA-1 transcriptional activity was enhanced by exendin-4, which was diminished by the inhibition of AMPK or dominant-negative AMPK-α-subunit. Moreover, AMPK was phosphorylated by the activation of GLP-1R. Next, ChIP assay demonstrated that exendin-4 increased the FoxO1-binding in the hSR-BI/CLA-1 promoter by upregulation of FoxO1. Mutation of FoxO1-binding or silencing of FoxO1 cancelled the effect of exendin-4 on hSR-BI/CLA-1 expression. Exendin-4 reduced FoxO1 phosphorylation and induced its nuclear accumulation, while this effect was altered by the blocking of GLP-1R or inhibition of AMPK pathway. In summary, our results proved that exendin-4 increased hSR-BI/CLA-1 expression via the AMPK/FoxO1 pathway to activate eNOS, providing a basic mechanism underlining the protective effect of GLP-1RA on endothelial function.

Keywords:  AMPK; GLP-1; HDL; activation of eNOS; human SR-BI/CLA-1

DOI:  https://doi.org/10.3390/cimb44110370
Int J Mol Sci. 2022 Nov 04. pii: 13512. [Epub ahead of print]23(21):

ERK Inhibition Increases RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells by Stimulating AMPK Activation and RANK Expression and Inhibiting Anti-Osteoclastogenic Factor Expression.

Eun-Bi Choi, Taiwo Samuel Agidigbi, In-Soon Kang, Chaekyun Kim.

  Bone absorption is necessary for the maintenance of bone homeostasis. An osteoclast (OC) is a monocyte-macrophage lineage cell that absorbs bone tissue. Extracellular signal-regulated kinases (ERKs) are known to play important roles in regulating OC growth and differentiation. In this study, we examined specific downstream signal pathways affected by ERK inhibition during OC differentiation. Our results showed that the ERK inhibitors PD98059 and U0126 increased receptor activator of NF-κB ligand (RANKL)-induced OC differentiation in RAW 264.7 cells, implying a negative role in OC differentiation. This is supported by the effect of ERK2-specific small interfering RNA on increasing OC differentiation. In contrast to our findings regarding the RAW 264.7 cells, the ERK inhibitors attenuated the differentiation of bone marrow-derived cells into OCs. The ERK inhibitors significantly increased the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) but not the activation of p38 MAPK, Lyn, and mTOR. In addition, while the ERK inhibition increased the expression of the RANKL receptor RANK, it decreased the expression of negative mediators of OC differentiation, such as interferon regulatory factor-8, B-cell lymphoma 6, and interferon-γ. These dichotomous effects of ERK inhibition suggest that while ERKs may play positive roles in bone marrow-derived cells, ERKs may also play negative regulatory roles in RAW 264.7 cells. These data provide important information for drug development utilizing ERK inhibitors in OC-related disease treatment.

Keywords:  AMPK; ERK; RANKL; anti-osteoclastogenic mediators; macrophage; osteoclast

DOI:  https://doi.org/10.3390/ijms232113512
Nutrients. 2022 Oct 28. pii: 4548. [Epub ahead of print]14(21):

Supercritical Extract of Cannabis sativa Inhibits Lung Metastasis in Colorectal Cancer Cells by Increasing AMPK and MAPKs-Mediated Apoptosis and Cell Cycle Arrest.

Jeong-Geon Mun, Hee Dong Jeon, Dae Hwan Yoon, Yoon Seung Lee, Shin Young Park, Jong-Sik Jin, Noh-Joon Park, Ji-Ye Kee.

  Colorectal cancer (CRC) is one of the diseases with the highest rates of prevalence and mortality despite therapeutic methods in the world. In particular, there are not enough methods to treat metastasis of CRC cells to distant organs. Cannabis sativa Linne (C. sativa) is a popular medicinal plant used by humans to treat many diseases. Recently, extracts of C. sativa have shown diverse pharmacological effects as a result of choosing different extraction methods. In this study, we performed experiments to confirm the inhibitory effect and related mechanisms of supercritical extract of C. sativa on metastatic CRC cells. The effect of SEC on the viability of CRC cell lines, CT26 and HCT116, was determined using CCK reagent. Flow cytometry was performed to confirm whether SEC can promote cell cycle arrest and apoptosis. Additionally, SEC reduced proliferation of CT26 and HCT116 cells without causing toxicity to normal colon cell line CCD-18Co cells. SEC treatment reduced colony formation in both CRC cell lines, promoted G0/G1 phase arrest and apoptosis in CT26 and HCT116 cells through AMPK activation and MAPKs such as ERK, JNK, and p38 inactivation. Moreover, oral administration of SEC decreased pulmonary metastasis of CT26 cells. Our research demonstrates the inhibitory effect of SEC on CRC cell proliferation and metastasis. Thus, SEC might have therapeutic potential for CRC treatment.

Keywords:  AMPK; Cannabis sativa; MAPKs; apoptosis; cell cycle arrest; colorectal cancer; metastasis

DOI:  https://doi.org/10.3390/nu14214548
J Physiol. 2022 Nov 12.

Muscle glycogen unavailability and fat oxidation rate during exercise: Insights from McArdle disease.

Carlos Rodriguez-Lopez, Alfredo Santalla, Pedro L Valenzuela, Alberto Real-Martínez, Mónica Villarreal-Salazar, Irene Rodriguez-Gomez, Tomàs Pinós, Ignacio Ara, Alejandro Lucia.

  KEY POINTS: Physically active McArdle patients shown an exceptional fat oxidation capacity. Maximal fat oxidation rate occurs near-maximal exercise capacity in these patients. McArdle patients' exercise tolerance might rely on maximal fat oxidation rate capacity. Hyperpnoea patients might, however, cloud substrate oxidation measurements in some patients. An animal model revealed overall no higher molecular markers of lipid transport/metabolism.ABSTRACT: Carbohydrate availability affects fat metabolism during exercise; however, the effects of complete muscle glycogen unavailability on maximal fat oxidation (MFO) rate remain unknown. Our purpose was to examine MFO rate in patients with McArdle disease-an inherited condition caused by complete blockade of muscle glycogen metabolism-compared to healthy controls. Nine patients (3 women, 36 ± 12yrs) and 12 healthy controls (4 women, 40 ± 13yrs) were studied. Several molecular markers of lipid transport/metabolism were also determined in skeletal muscle (gastrocnemius) and white adipose tissue of McArdle (Pygm p.50R*/p.50R*) and wild-type mice. Peak oxygen uptake (VO2 peak), MFO rate, the exercise intensity eliciting MFO rate (FATmax), and the MFO rate-associated workload were determined by indirect calorimetry during an incremental cycle-ergometer test. Despite having a much lower V̇O2 peak (24.7 ± 4 vs. 42.5  ±  11.4 ml·kg-1 ·min-1 , respectively; P < 0.0001), patients showed considerably higher values of MFO rate (0.53 ± 0.12 vs. 0.33 ± 0.10 g·min-1 , P = 0.001), FATmax (94.4 ± 7.2 vs. 41.3 ± 9.1 % of V̇O2 peak, P < 0.0001) and MFO rate-associated workload (1.33 ± 0.35 vs. 0.81 ± 0.54 watts·kg-1 , P = 0.020) than controls. No between-group differences were found overall in molecular markers of lipid transport/metabolism in mice. In summary, patients with McArdle disease show an exceptionally high MFO rate, which they attained at near-maximal exercise capacity. Pending more mechanistic explanations, these findings support the influence of glycogen availability on MFO rate and suggest that these patients develop a unique fat oxidation capacity, possibly as an adaptation to compensate for the inherited blockade in glycogen metabolism, and point to MFO rate as a potential limiting factor of exercise tolerance in this disease. Abstract figure legend McArdle disease is caused by inherited blockade of glycogen breakdown in skeletal muscle fibers, with subsequent intolerance to most exercise tasks as well as a substantial impairment of peak aerobic capacity. This study supports that the exercise capacity of these patients is mainly sustained by fat oxidation, with active patients showing an exceptional maximal fat oxidation rate (similar in fact to athletes) during endurance exercise, possibly as an adaptation to muscle glycogen unavailability. On the other hand, data in the (untrained) mouse model of the disease revealed overall no major differences at baseline in molecular markers of lipid transport/metabolism, compared with wild-type mice.
ABBREVIATIONS: AMPK, AMP-activated protein kinase; CD36, transmembrane glycoprotein cluster of differentiation 36; HADH, 3-hydroxyacyl-CoA dehydrogenase; HSL, hormone-sensitive lipase (total or phosphorylated); MFO, maximum fat oxidation; NS, 'no significant' (for between-group comparisons). pAMPK, phosphorylated AMPK; pATGL, phosphorylated adipose triglyceride lipase; Plin5, perilipin 5; VO2 peak, peak oxygen uptake. Data presented as mean (SD). This article is protected by copyright. All rights reserved.

Keywords:  anaplerotic; fatty acids; glycogen depletion; glycogen store disease; lactate; muscle fatigue; substrate oxidation; tricarboxylic acid cycle

DOI:  https://doi.org/10.1113/JP283743
Chem Biol Interact. 2022 Nov 05. pii: S0009-2797(22)00455-0. [Epub ahead of print] 110250

Isosilybin regulates lipogenesis and fatty acid oxidation via the AMPK/SREBP-1c/PPARα pathway.

Xueyun Liu, Man Hu, Chen Ye, Lihong Liao, Chang Ding, Lijuan Sun, Jichao Liang, Yong Chen.

  It is well known that the excessive accumulation of lipid in hepatocytes is one of the important causes of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to explore the effects of isosilybin on lipid metabolism in free fatty acids (FFAs) or TO901317-induced HepG2 cells. Cells were treated with FFAs (oleic acid: palmitic acid, 2:1) or TO901317 to induce steatosis in vitro. Intracellular triglyceride (TG) content was quantified using commercial assay kits. The mRNA and protein expression of genes involved in fatty acid uptake, synthesis and oxidation were analyzed by RT-qPCR and western blotting. Selected biological pathways regulated by isosilybin treatment were determined by GO and KEGG analysis. The results showed that isosilybin significantly reduced TG levels in FFAs- and TO901317-induced HepG2 cells. Further studies showed that isosilybin treatment decreased the mRNA and protein expression of lipid synthesis genes Srebp-1c, Pnpla3, Acc and Fas, as well as the mRNA expression of fatty acid uptake gene CD36, whereas increased the mRNA levels of lipid oxidation genes Pparα, Acox1 and Cpt1α, as well as the mRNA expression of lipid export gene Mttp, in FFAs-induced HepG2 cells. Moreover, TO901317 was employed to induce endogenous lipid synthesis and steatosis, and the expression of Srebp-1c and its target genes in TO901317-induced hepatocytes was basically similar to that in FFAs-induced hepatocytes following isosilybin treatment. We also observed the increased level of phosphorylated AMP kinase (AMPK) after isosilybin treatment, while this effect was reversed after further treatment with AMPK inhibitor, compound C. The results of GO and KEGG analysis indicated that the pathways of fatty acid and TG metabolism were regulated by isosilybin. Interestingly, we found that treatment with the diastereoisomer A of isosilybin increased TG level, while exposure to the diastereoisomer B of isosilybin decreased TG level in FFAs-induced HepG2 cells. The above results suggest that isosilybin can inhibit lipid synthesis and activate lipid oxidation through AMPK signaling pathway, thereby improving steatosis of hepatocytes, and isosilybin B is the basis of its active substance.

Keywords:  AMPK; Isosilybin; Lipid accumulation; Lipid oxidation; Lipid synthesis

DOI:  https://doi.org/10.1016/j.cbi.2022.110250
Ecotoxicol Environ Saf. 2022 Nov 02. pii: S0147-6513(22)01073-9. [Epub ahead of print]247 114233

Metformin antagonizes nickel-refining fumes-induced cell pyroptosis via Nrf2/GOLPH3 pathway in vitro and in vivo.

Tong Zhang, Yue Wang, Wenxue Yao, Yangyang Chen, Dan Zhang, Ying Gao, Shuo Jin, Lina Li, Shikuan Yang, Yonghui Wu.

  Nickel compounds, an international carcinogen in the industrial environment, increased the risk of lung inflammation even lung cancer in Ni refinery workers. Metformin has displayed the intense anti-inflammation and anti-cancer properties through regulating pyroptosis. This study was designed to explore whether Nickel-refining fumes (NiRF) can induce cell pyroptosis and how AMPK/CREB/Nrf2 mediated the protection afforded by metformin against Ni particles-induced lung impairment. Our results represented that Ni fumes exposure evoked pyroptosis via GOLPH3 and induced oxidative stress, while, metformin treatment alleviated Ni particles-mediated above changes. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) involved in the protection of metformin, and the deficiency of Nrf2 attenuated the beneficial protection. We also determined that Nrf2 was a downstream molecule of AMPK/CREB pathway. Furthermore, male C57BL/6 mice were administered with Ni at a dose of 2 mg/kg by non-exposed endotracheal instillation and metformin (100, 200 and 300 mg/kg) via oral gavage for 4 weeks. The results indicated that NiRF promoted GOLPH3 and pyroptosis by stimulating NLRP3, caspase-1, N-GSDMD, IL-18 and IL-1β expression. However, various doses of metformin reduced GOLPH3 and the above protein levels of pyroptosis, also improved AMPK/CREB/Nrf2 expression. In summary, we found that metformin suppressed NiRF-connected GOLPH3-prompted pyroptosis via AMPK/CREB/Nrf2 signaling pathway to confer pulmonary protection.

Keywords:  AMPK/CREB/Nrf2; GOLPH3; Metformin; Nickel-refining fumes; Oxidative stress; Pyroptosis

DOI:  https://doi.org/10.1016/j.ecoenv.2022.114233