The Role and Mechanism of Metformin in Inflammatory Diseases

References

• Marciano O, Mehazri L, Shpungin S, Varvak A, Zacksenhaus E, Nir U. Fer and FerT Govern mitochondrial susceptibility to metformin and hypoxic stress in colon and lung carcinoma cells. Cells. 2021;10(1):97. doi:10.3390/cells10010097
   PubMed Web of Science ®Google Scholar
• Bosi E. Metformin--The gold standard in type 2 diabetes: what does the evidence tell us? Diabetes Obes Metab. 2009;11 Suppl 2:3–8. doi:10.1111/j.1463-1326.2008.01031.x
   PubMed Web of Science ®Google Scholar
• Bharath LP, Nikolajczyk BS. The intersection of metformin and inflammation. Am J Physiol Cell Physiol. 2021;320(5):C873–c879. doi:10.1152/ajpcell.00604.2020
   PubMed Web of Science ®Google Scholar
• Chen S, Gan D, Lin S, et al. Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms. Theranostics. 2022;12(6):2722–2740. doi:10.7150/thno.71360
   PubMed Web of Science ®Google Scholar
• Kamarudin MNA, Sarker MMR, Zhou JR, Parhar I. Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects. J Exp Clin Cancer Res. 2019;38(1):491. doi:10.1186/s13046-019-1495-2
   PubMed Web of Science ®Google Scholar
• Luo F, Das A, Chen J, Wu P, Li X, Fang Z. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol. 2019;18(1):54. doi:10.1186/s12933-019-0860-y
   PubMedGoogle Scholar
• Glaría E, Letelier NA, Valledor AF. Integrating the roles of liver X receptors in inflammation and infection: mechanisms and outcomes. Curr Opin Pharmacol. 2020;53:55–65. doi:10.1016/j.coph.2020.05.001
   PubMed Web of Science ®Google Scholar
• Zindel J, Kubes P. DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation. Annu Rev Pathol. 2020;15:493–518. doi:10.1146/annurev-pathmechdis-012419-032847
   PubMed Web of Science ®Google Scholar
• Zhu X, Chen Z, Shen W, et al. Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention. Signal Transduct Target Ther. 2021;6(1):245. doi:10.1038/s41392-021-00646-9
   PubMed Web of Science ®Google Scholar
• Makino Y, Fujikawa K, Matsuki-Fukushima M, Inoue S, Nakamura M. Role of innate inflammation in the regulation of tissue remodeling during tooth eruption. Dent J (Basel). 2021;9(1). doi:10.3390/dj9010007
   PubMedGoogle Scholar
• Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med. 2017;45(2):253–262. doi:10.1097/CCM.0000000000002074
   PubMed Web of Science ®Google Scholar
• Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Ann Afr Med. 2019;18(3):121–126. doi:10.4103/aam.aam_56_18
   PubMed Web of Science ®Google Scholar
• Kim JW, Kim SM, Park JS, et al. Metformin improves salivary gland inflammation and hypofunction in murine Sjögren’s syndrome. Arthritis Res Thera. 2019;21(1):136. doi:10.1186/s13075-019-1904-0
   PubMedGoogle Scholar
• van den Bosch MHJ. Osteoarthritis year in review 2020: biology. Osteoarthritis Cartilage. 2021;29(2):143–150. doi:10.1016/j.joca.2020.10.006
   PubMed Web of Science ®Google Scholar
• Li X, Wang L, Zhou XE, et al. Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res. 2015;25(1):50–66. doi:10.1038/cr.2014.150
   PubMed Web of Science ®Google Scholar
• Kim DH, Kim SJ, Yu KY, Jeong SI, Kim SY. Anti-hyperglycemic effects and signaling mechanism of Perilla frutescens sprout extract. Nutr Res Pract. 2018;12(1):20–28. doi:10.4162/nrp.2018.12.1.20
   PubMed Web of Science ®Google Scholar
• Zhou F, Wang M, Ju J, et al. Schizandrin A protects against cerebral ischemia-reperfusion injury by suppressing inflammation and oxidative stress and regulating the AMPK/Nrf2 pathway regulation. Am J Transl Res. 2019;11(1):199–209.
   PubMed Web of Science ®Google Scholar
• González A, Hall MN, Lin SC, Hardie DG. AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth control. Cell Metab. 2020;31(3):472–492. doi:10.1016/j.cmet.2020.01.015
   PubMed Web of Science ®Google Scholar
• El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–228. doi:10.1074/jbc.275.1.223
   PubMed Web of Science ®Google Scholar
• Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348 Pt 3(Pt 3):607–614. doi:10.1042/bj3480607
   PubMedGoogle Scholar
• Yan Z, Tian X, Zhu J, et al. Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype. Mol Med. 2018;24(1):20. doi:10.1186/s10020-018-0013-x
   PubMedGoogle Scholar
• Colombo SL, Moncada S. AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. Biochem J. 2009;421(2):163–169. doi:10.1042/BJ20090613
   PubMedGoogle Scholar
• Lv H, Liu Q, Wen Z, Feng H, Deng X, Ci X. Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis. Redox Biol. 2017;12:311–324. doi:10.1016/j.redox.2017.03.001
   PubMed Web of Science ®Google Scholar
• Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012;2(4):e001076. doi:10.1136/bmjopen-2012-001076
   PubMed Web of Science ®Google Scholar
• Marcum ZA, Forsberg CW, Moore KP, et al. Mortality associated with metformin versus sulfonylurea initiation: a cohort study of veterans with diabetes and chronic kidney disease. J Gen Intern Med. 2018;33(2):155–165. doi:10.1007/s11606-017-4219-3
   PubMed Web of Science ®Google Scholar
• Kawanami D, Takashi Y, Tanabe M. Significance of Metformin Use in Diabetic Kidney Disease. Int J Mol Sci. 2020;21(12):4239. doi:10.3390/ijms21124239
   PubMed Web of Science ®Google Scholar
• Zhou Y, Ma XY, Han JY, et al. Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop. World J Diabetes. 2021;12(1):19–46. doi:10.4239/wjd.v12.i1.19
   PubMed Web of Science ®Google Scholar
• Sun T, Liu J, Xie C, Yang J, Zhao L, Yang J. Metformin attenuates diabetic renal injury via the AMPK-autophagy axis. Exp Ther Med. 2021;21(6):578. doi:10.3892/etm.2021.10010
   PubMed Web of Science ®Google Scholar
• Chen XC, Wu D, Wu HL, et al. Metformin improves renal injury of MRL/lpr lupus-prone mice via the AMPK/STAT3 pathway. Lupus Sci Med. 2022;9(1):e000611. doi:10.1136/lupus-2021-000611
   PubMed Web of Science ®Google Scholar
• Zhang J, Huang L, Shi X, et al. Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway. Aging (Albany NY). 2020;12(23):24270–24287. doi:10.18632/aging.202143
   PubMedGoogle Scholar
• Santana PT, Luna-Gomes T, Rangel-Ferreira MV, et al. P2Y(12) receptor antagonist clopidogrel attenuates lung inflammation triggered by Silica particles. Front Pharmacol. 2020;11:301. doi:10.3389/fphar.2020.00301
   PubMed Web of Science ®Google Scholar
• Cheng D, Xu Q, Wang Y, et al. Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling. J Transl Med. 2021;19(1):349. doi:10.1186/s12967-021-03036-5
   PubMed Web of Science ®Google Scholar
• Saber S, El-Kader EMA. Novel complementary coloprotective effects of metformin and MCC950 by modulating HSP90/NLRP3 interaction and inducing autophagy in rats. Inflammopharmacology. 2021;29(1):237–251. doi:10.1007/s10787-020-00730-6
   PubMed Web of Science ®Google Scholar
• Fei Q, Ma H, Zou J, et al. Metformin protects against ischaemic myocardial injury by alleviating autophagy-ROS-NLRP3-mediated inflammatory response in macrophages. J Mol Cell Cardiol. 2020;145:1–13. doi:10.1016/j.yjmcc.2020.05.016
   PubMed Web of Science ®Google Scholar
• Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015;64(6):2028–2041. doi:10.2337/db14-1225
   PubMed Web of Science ®Google Scholar
• Chen YC, Lee SD, Kuo CH, Ho LT. The effects of altitude training on the AMPK-related glucose transport pathway in the red skeletal muscle of both lean and obese Zucker rats. High Alt Med Biol. 2011;12(4):371–378. doi:10.1089/ham.2010.1088
   PubMed Web of Science ®Google Scholar
• Kim MJ, Nagy LE, Park PH. Globular adiponectin inhibits ethanol-induced reactive oxygen species production through modulation of NADPH oxidase in macrophages: involvement of liver kinase B1/AMP-activated protein kinase pathway. Mol Pharmacol. 2014;86(3):284–296. doi:10.1124/mol.114.093039
   PubMed Web of Science ®Google Scholar
• Jiang WP, Deng JS, Huang SS, et al. Sanghuangporus sanghuang mycelium prevents paracetamol-induced hepatotoxicity through regulating the MAPK/NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt, and CaMKKβ/LKB1/AMPK pathways and suppressing oxidative stress and inflammation. Antioxidants (Basel). 2021;10(6):897.
   PubMedGoogle Scholar
• Wen J, Xu B, Sun Y, et al. Paeoniflorin protects against intestinal ischemia/reperfusion by activating LKB1/AMPK and promoting autophagy. Pharmacol Res. 2019;146:104308. doi:10.1016/j.phrs.2019.104308
   PubMed Web of Science ®Google Scholar
• Liu Z, Zhang W, Zhang M, Zhu H, Moriasi C, Zou MH. Liver kinase B1 suppresses lipopolysaccharide-induced nuclear factor κB (NF-κB) activation in macrophages. J Biol Chem. 2015;290(4):2312–2320. doi:10.1074/jbc.M114.616441
   PubMed Web of Science ®Google Scholar
• MacIver NJ, Blagih J, Saucillo DC, et al. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol. 2011;187(8):4187–4198. doi:10.4049/jimmunol.1100367
   PubMed Web of Science ®Google Scholar
• Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–1646. doi:10.1126/science.1120781
   PubMed Web of Science ®Google Scholar
• Yang Y, Dong R, Hu D, et al. Liver kinase B1/AMP-activated protein kinase pathway activation attenuated the progression of endotoxemia in the diabetic mice. Cell Physiol Biochem. 2017;42(2):761–779. doi:10.1159/000478068
   PubMedGoogle Scholar
• Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2009;50 Suppl(Suppl):S138–143. doi:10.1194/jlr.R800079-JLR200
   PubMedGoogle Scholar
• Liu J, Zhao H, Yang L, et al. The role of CD36-Fabp4-PPARγ in skeletal muscle involves insulin resistance in intrauterine growth retardation mice with catch-up growth. BMC Endocr Disord. 2022;22(1):10. doi:10.1186/s12902-021-00921-4
   PubMed Web of Science ®Google Scholar
• Lingesh A, Paul D, Naidu V, Satheeshkumar N. AMPK activating and anti adipogenic potential of Hibiscus rosa sinensis flower in 3T3-L1 cells. J Ethnopharmacol. 2019;233:123–130. doi:10.1016/j.jep.2018.12.039
   PubMed Web of Science ®Google Scholar
• Lv Q, Zhen Q, Liu L, et al. AMP-kinase pathway is involved in tumor necrosis factor alpha-induced lipid accumulation in human hepatoma cells. Life Sci. 2015;131:23–29. doi:10.1016/j.lfs.2015.03.003
   PubMed Web of Science ®Google Scholar
• Calixto MC, Lintomen L, André DM, et al. Metformin attenuates the exacerbation of the allergic eosinophilic inflammation in high fat-diet-induced obesity in mice. PLoS One. 2013;8(10):e76786. doi:10.1371/journal.pone.0076786
   PubMed Web of Science ®Google Scholar
• Kim D, Lee JE, Jung YJ, et al. Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice. Int J Mol Med. 2013;32(6):1293–1302.
   PubMed Web of Science ®Google Scholar
• Chung MM, Nicol CJ, Cheng YC, et al. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Exp Cell Res. 2017;352(1):75–83. doi:10.1016/j.yexcr.2017.01.017
   PubMed Web of Science ®Google Scholar
• Zhou M, Xu W, Wang J, et al. Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine. 2018;35:345–360. doi:10.1016/j.ebiom.2018.08.035
   PubMed Web of Science ®Google Scholar
• Li F, Li J, Wang PH, et al. SARS-CoV-2 spike promotes inflammation and apoptosis through autophagy by ROS-suppressed PI3K/AKT/mTOR signaling. Biochim Biophys Acta Mol Basis Dis. 2021;1867(12):166260. doi:10.1016/j.bbadis.2021.166260
   PubMed Web of Science ®Google Scholar
• Yi W, Gupta S, Ricker E, et al. The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity. Nat Commun. 2017;8(1):254. doi:10.1038/s41467-017-00348-3
   PubMedGoogle Scholar
• Qu Z, Ji S, Zheng S. BRAF controls the effects of metformin on neuroblast cell divisions in C. elegans. Int J Mol Sci. 2020;22(1):178. doi:10.3390/ijms22010178
   PubMed Web of Science ®Google Scholar
• Yue W, Zheng X, Lin Y, et al. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget. 2015;6(25):21208–21224. doi:10.18632/oncotarget.4126
   PubMedGoogle Scholar
• Van Nostrand JL, Hellberg K, Luo EC, et al. AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation. Genes Dev. 2020;34(19–20):1330–1344. doi:10.1101/gad.339895.120
   PubMed Web of Science ®Google Scholar
• Xiao N, Wang J, Wang T, et al. Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome. Elife. 2022;11:e74713.
   PubMed Web of Science ®Google Scholar
• Mohamed MAE, Abdel-Rahman RF, Mahmoud SS, Khattab MM, Safar MM. Metformin and trimetazidine ameliorate diabetes-induced cognitive impediment in status epileptic rats. Epilepsy Behav. 2020;104(Pt A):106893. doi:10.1016/j.yebeh.2019.106893
   PubMedGoogle Scholar
• Planas D, Pagliuzza A, Ponte R, et al. LILAC pilot study: effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy. EBioMedicine. 2021;65:103270. doi:10.1016/j.ebiom.2021.103270
   PubMed Web of Science ®Google Scholar
• Moon J, Lee SY, Choi JW, et al. Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts. J Transl Med. 2021;19(1):192. doi:10.1186/s12967-021-02860-z
   PubMed Web of Science ®Google Scholar
• Li SX, Li C, Pang XR, et al. Metformin attenuates silica-induced pulmonary fibrosis by activating autophagy via the AMPK-mTOR signaling pathway. Front Pharmacol. 2021;12:719589. doi:10.3389/fphar.2021.719589
   PubMed Web of Science ®Google Scholar
• Xu Z, Ye H, Xiao W, et al. Metformin attenuates inflammation and fibrosis in thyroid-associated ophthalmopathy. Int J Mol Sci. 2022;23(24):15508. doi:10.3390/ijms232415508
   PubMed Web of Science ®Google Scholar
• Vazirpanah N, Ottria A, van der Linden M, et al. mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy? Ann Rheum Dis. 2019;78(5):663–671. doi:10.1136/annrheumdis-2018-214656
   PubMed Web of Science ®Google Scholar
• Liu Y, Yang F, Ma W, Sun Q. Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytes in vitro via mTOR-signaling pathway. Pharm Biol. 2016;54(7):1173–1178. doi:10.3109/13880209.2015.1057652
   PubMed Web of Science ®Google Scholar
• Al-Hashem F, Al-Humayed S, Amin SN, et al. Metformin inhibits mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers in thioacetamide-induced hepatic tissue alterations. J Cell Physiol. 2019;234(6):9328–9337. doi:10.1002/jcp.27616
   PubMed Web of Science ®Google Scholar
• Wu YQ, Xiong J, He ZL, et al. Metformin promotes microglial cells to facilitate myelin debris clearance and accelerate nerve repairment after spinal cord injury. Acta Pharmacol Sin. 2022;43(6):1360–1371. doi:10.1038/s41401-021-00759-5
   PubMed Web of Science ®Google Scholar
• Xia J, Chen J, Vashisth MK, et al. Metformin ameliorates 5-fluorouracil-induced intestinal injury by inhibiting cellular senescence, inflammation, and oxidative stress. Int Immunopharmacol. 2022;113(Pt A):109342. doi:10.1016/j.intimp.2022.109342
   PubMedGoogle Scholar
• Gao Y, Liu J, Li K, et al. Metformin alleviates sepsis-associated myocardial injury by enhancing AMP-activated protein kinase/mammalian target of rapamycin signaling pathway-mediated autophagy. J Cardiovasc Pharmacol. 2023;82(4):308–317. doi:10.1097/FJC.0000000000001463
   PubMed Web of Science ®Google Scholar
• O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346–355. doi:10.1038/nature11862
   PubMed Web of Science ®Google Scholar
• de Mingo Á, de Gregorio E, Moles A, et al. Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation. Cell Death Dis. 2016;7(11):e2464. doi:10.1038/cddis.2016.368
   PubMedGoogle Scholar
• Brand K, Page S, Rogler G, et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest. 1996;97(7):1715–1722. doi:10.1172/JCI118598
   PubMed Web of Science ®Google Scholar
• Ziadlou R, Barbero A, Martin I, et al. Anti-inflammatory and chondroprotective effects of vanillic acid and epimedin C in human osteoarthritic chondrocytes. Biomolecules. 2020;10(6):932. doi:10.3390/biom10060932
   PubMed Web of Science ®Google Scholar
• Jung CH, Lee MJ, Kang YM, et al. Vaspin inhibits cytokine-induced nuclear factor-kappa B activation and adhesion molecule expression via AMP-activated protein kinase activation in vascular endothelial cells. Cardiovasc Diabetol. 2014;13:41. doi:10.1186/1475-2840-13-41
   PubMed Web of Science ®Google Scholar
• Zhou C, Peng B, Qin Z, Zhu W, Guo C. Metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway. BMC Neurosci. 2021;22(1):73. doi:10.1186/s12868-021-00678-5
   PubMed Web of Science ®Google Scholar
• Guo Y, Zhang H, Zhao Z, et al. Hyperglycemia induces meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2022;63(1):30. doi:10.1167/iovs.63.1.30
   PubMed Web of Science ®Google Scholar
• Williamson L, Ayalon I, Shen H, Kaplan J. Hepatic STAT3 inhibition amplifies the inflammatory response in obese mice during sepsis. Am J Physiol Endocrinol Metab. 2019;316(2):E286–e292. doi:10.1152/ajpendo.00341.2018
   PubMed Web of Science ®Google Scholar
• El-Mahdy NA, El-Sayad ME, El-Kadem AH, Abu-Risha SE. Metformin alleviates inflammation in oxazolone induced ulcerative colitis in rats: plausible role of sphingosine kinase 1/sphingosine 1 phosphate signaling pathway. Immunopharmacol Immunotoxicol. 2021;43(2):192–202.
   PubMed Web of Science ®Google Scholar
• Geraghty P, Wyman AE, Garcia-Arcos I, Dabo AJ, Gadhvi S, Foronjy R. STAT3 modulates cigarette smoke-induced inflammation and protease expression. Front Physiol. 2013;4:267. doi:10.3389/fphys.2013.00267
   PubMed Web of Science ®Google Scholar
• Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY. Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol. 2019;9:48. doi:10.3389/fonc.2019.00048
   PubMed Web of Science ®Google Scholar
• Son HJ, Lee J, Lee SY, et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm. 2014;2014:973986. doi:10.1155/2014/973986
   PubMed Web of Science ®Google Scholar
• Lee SY, Lee SH, Yang EJ, et al. Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS One. 2015;10(9):e0135858. doi:10.1371/journal.pone.0135858
   PubMed Web of Science ®Google Scholar
• Yang XP, Ghoreschi K, Steward-Tharp SM, et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol. 2011;12(3):247–254. doi:10.1038/ni.1995
   PubMed Web of Science ®Google Scholar
• Wu HC, Cheng MJ, Yen CH, et al. Chemical constituents with GNMT-promoter-enhancing and NRF2-reduction activities from Taiwan Agarwood excoecaria formosana. Molecules. 2020;25(7):1746.
   PubMed Web of Science ®Google Scholar
• Saha S, Buttari B, Panieri E, Profumo E, Saso L. An overview of Nrf2 Signaling pathway and its role in inflammation. Molecules. 2020;25(22):5474.
   PubMed Web of Science ®Google Scholar
• Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98(3):1169–1203. doi:10.1152/physrev.00023.2017
   PubMed Web of Science ®Google Scholar
• Braun S, Hanselmann C, Gassmann MG, et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol Cell Biol. 2002;22(15):5492–5505. doi:10.1128/MCB.22.15.5492-5505.2002
   PubMed Web of Science ®Google Scholar
• Ishii Y, Itoh K, Morishima Y, et al. Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. J Immunol. 2005;175(10):6968–6975. doi:10.4049/jimmunol.175.10.6968
   PubMedGoogle Scholar
• Zhou J, Ma X, Cui Y, et al. Methyleugenol protects against t-BHP-triggered oxidative injury by induction of Nrf2 dependent on AMPK/GSK3β and ERK activation. J Pharmacol Sci. 2017;135(2):55–63. doi:10.1016/j.jphs.2017.09.003
   PubMed Web of Science ®Google Scholar
• Arbab AAI, Lu X, Abdalla IM, et al. Metformin inhibits lipoteichoic acid-induced oxidative stress and inflammation through AMPK/NRF2/NF-κB signaling pathway in bovine mammary epithelial cells. Front Vet Sci. 2021;8:661380. doi:10.3389/fvets.2021.661380
   PubMed Web of Science ®Google Scholar
• Tao F, Zhou Y, Wang M, et al. Metformin alleviates chronic obstructive pulmonary disease and cigarette smoke extract-induced glucocorticoid resistance by activating the nuclear factor E2-related factor 2/heme oxygenase-1 signaling pathway. Korean J Physiol Pharmacol. 2022;26(2):95–111. doi:10.4196/kjpp.2022.26.2.95
   PubMed Web of Science ®Google Scholar
• L A, Zou T, He J, et al. Rescue of retinal degeneration in rd1 mice by intravitreally injected metformin. Front Mol Neurosci. 2019;12:102. doi:10.3389/fnmol.2019.00102
   PubMed Web of Science ®Google Scholar
• Xian H, Liu Y, Rundberg Nilsson A, et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity. 2021;54(7):1463–1477.e1411. doi:10.1016/j.immuni.2021.05.004
   PubMed Web of Science ®Google Scholar
• Lin CC, Yeh HH, Huang WL, et al. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2013;49(2):241–250. doi:10.1165/rcmb.2012-0244OC
   PubMed Web of Science ®Google Scholar
• Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11(5):390–401. doi:10.1016/j.cmet.2010.03.014
   PubMed Web of Science ®Google Scholar
• Zhou X, Chen J, Yi G, et al. Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget. 2016;7(1):873–884. doi:10.18632/oncotarget.6418
   PubMedGoogle Scholar
• Song YM, Lee YH, Kim JW, et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy. 2015;11(1):46–59. doi:10.4161/15548627.2014.984271
   PubMed Web of Science ®Google Scholar
• Qi T, Chen Y, Li H, et al. A role for PFKFB3/iPFK2 in metformin suppression of adipocyte inflammatory responses. J Mol Endocrinol. 2017;59(1):49–59. doi:10.1530/JME-17-0066
   PubMed Web of Science ®Google Scholar
• Woo SL, Xu H, Li H, et al. Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLoS One. 2014;9(3):e91111. doi:10.1371/journal.pone.0091111
   PubMed Web of Science ®Google Scholar
• Nelson LE, Valentine RJ, Cacicedo JM, Gauthier MS, Ido Y, Ruderman NB. A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells. Am J Physiol Cell Physiol. 2012;303(1):C4–c13. doi:10.1152/ajpcell.00296.2011
   PubMed Web of Science ®Google Scholar
• Kelly B, Tannahill GM, Murphy MP, O’Neill LA. Metformin inhibits the production of reactive oxygen species from NADH: ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated macrophages. J Biol Chem. 2015;290(33):20348–20359. doi:10.1074/jbc.M115.662114
   PubMed Web of Science ®Google Scholar
• Gao J, Yuan J, Wang Q, et al. Metformin protects against PM(2.5)-induced lung injury and cardiac dysfunction independent of AMP-activated protein kinase α2. Redox Biol. 2020;28:101345. doi:10.1016/j.redox.2019.101345
   PubMed Web of Science ®Google Scholar
• Tan S, Lu Q, Shu Y, Sun Y, Chen F, Tang L. Iridoid glycosides fraction isolated from Veronica ciliata Fisch. Protects against Acetaminophen-induced liver injury in mice. Evid Based Complement Alternat Med. 2017;2017:6106572. doi:10.1155/2017/6106572
   PubMed Web of Science ®Google Scholar
• Algire C, Moiseeva O, Deschênes-Simard X, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila). 2012;5(4):536–543. doi:10.1158/1940-6207.CAPR-11-0536
   PubMed Web of Science ®Google Scholar
• Rymut SM, Lu B, Perez A, et al. Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2019;316(6):L1081–l1093. doi:10.1152/ajplung.00369.2018
   PubMed Web of Science ®Google Scholar
• Yin M, Chen WP, Yin XP, Tu JL, Hu N, Li ZY. LncRNA TUG1 demethylated by TET2 promotes NLRP3 expression, contributes to cerebral ischemia/reperfusion inflammatory injury. ASN Neuro. 2021;13:17590914211003247. doi:10.1177/17590914211003247
   Web of Science ®Google Scholar
• Yang CS, Shin DM, Jo EK. The role of NLR-related protein 3 inflammasome in host defense and inflammatory diseases. Int Neurourol J. 2012;16(1):2–12. doi:10.5213/inj.2012.16.1.2
   PubMed Web of Science ®Google Scholar
• Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–225. doi:10.1038/nature09663
   PubMed Web of Science ®Google Scholar
• Chen K, Dai H, Yuan J, et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy. Cell Death Dis. 2018;9(2):105. doi:10.1038/s41419-017-0127-z
   PubMedGoogle Scholar
• Yang F, Qin Y, Wang Y, et al. Metformin inhibits the NLRP3 inflammasome via AMPK/mTOR-dependent effects in diabetic cardiomyopathy. Int J Biol Sci. 2019;15(5):1010–1019. doi:10.7150/ijbs.29680
   PubMed Web of Science ®Google Scholar
• Du RH, Tan J, Sun XY, Lu M, Ding JH, Hu G. Fluoxetine Inhibits NLRP3 Inflammasome Activation: implication in Depression. Int J Neuropsychopharmacol. 2016;19(9):pyw037. doi:10.1093/ijnp/pyw037
   PubMed Web of Science ®Google Scholar
• Ka SM, Kuoping Chao L, Lin JC, et al. A low toxicity synthetic cinnamaldehyde derivative ameliorates renal inflammation in mice by inhibiting NLRP3 inflammasome and its related signaling pathways. Free Radic Biol Med. 2016;91:10–24. doi:10.1016/j.freeradbiomed.2015.12.003
   PubMed Web of Science ®Google Scholar
• Du RW, Bu WG. Metformin improves depressive-like symptoms in mice via inhibition of peripheral and central NF-κB-NLRP3 inflammation activation. Exp Brain Res. 2020;238(11):2549–2556. doi:10.1007/s00221-020-05911-x
   PubMed Web of Science ®Google Scholar
• Cenni V, Squarzoni S, Loi M, Mattioli E, Lattanzi G, Capanni C. Emerin phosphorylation during the early phase of the oxidative stress response influences emerin-BAF interaction and BAF nuclear localization. Cells. 2020;9(6):1415. doi:10.3390/cells9061415
   PubMed Web of Science ®Google Scholar
• Gandellini P, Giannoni E, Casamichele A, et al. miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts. Antioxid Redox Signal. 2014;20(7):1045–1059. doi:10.1089/ars.2013.5292
   PubMed Web of Science ®Google Scholar
• Xu Y, Liu H, Song L. Novel drug delivery systems targeting oxidative stress in chronic obstructive pulmonary disease: a review. J Nanobiotechnology. 2020;18(1):145. doi:10.1186/s12951-020-00703-5
   PubMed Web of Science ®Google Scholar
• Choi HJ, Alam MB, Baek ME, Kwon YG, Lim JY, Lee SH. Protection against UVB-induced photoaging by Nypa fruticans via inhibition of MAPK/AP-1/MMP-1 signaling. Oxid Med Cell Longev. 2020;2020:2905362. doi:10.1155/2020/2905362
   PubMed Web of Science ®Google Scholar
• Sima AV, Stancu CS, Simionescu M. Vascular endothelium in atherosclerosis. Cell Tissue Res. 2009;335(1):191–203. doi:10.1007/s00441-008-0678-5
   PubMed Web of Science ®Google Scholar
• Alhaider AA, Korashy HM, Sayed-Ahmed MM, Mobark M, Kfoury H, Mansour MA. Metformin attenuates streptozotocin-induced diabetic nephropathy in rats through modulation of oxidative stress genes expression. Chem Biol Interact. 2011;192(3):233–242. doi:10.1016/j.cbi.2011.03.014
   PubMed Web of Science ®Google Scholar
• Yang X, Xu Z, Zhang C, Cai Z, Zhang J. Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells. Biochim Biophys Acta Mol Basis Dis. 2017;1863(8):1984–1990. doi:10.1016/j.bbadis.2016.09.019
   PubMed Web of Science ®Google Scholar
• Araújo AA, Pereira A, Medeiros C, et al. Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS One. 2017;12(8):e0183506. doi:10.1371/journal.pone.0183506
   PubMed Web of Science ®Google Scholar
• Mummidi S, Das NA, Carpenter AJ, et al. Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo. J Mol Cell Cardiol. 2016;98:95–102. doi:10.1016/j.yjmcc.2016.07.006
   PubMed Web of Science ®Google Scholar
• Schexnayder C, Broussard K, Onuaguluchi D, et al. Metformin Inhibits migration and invasion by suppressing ROS production and COX2 expression in MDA-MB-231 Breast cancer cells. Int J Mol Sci. 2018;19(11). doi:10.3390/ijms19113692
   PubMed Web of Science ®Google Scholar
• Esteghamati A, Eskandari D, Mirmiranpour H, et al. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin Nutr. 2013;32(2):179–185. doi:10.1016/j.clnu.2012.08.006
   PubMed Web of Science ®Google Scholar
• Müller S, Versini A, Sindikubwabo F, et al. Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells. PLoS One. 2018;13(11):e0206764. doi:10.1371/journal.pone.0206764
   PubMed Web of Science ®Google Scholar
• Picone P, Nuzzo D, Caruana L, et al. Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: use of insulin to attenuate metformin’s effect. Biochim Biophys Acta. 2015;1853(5):1046–1059. doi:10.1016/j.bbamcr.2015.01.017
   PubMed Web of Science ®Google Scholar
• Wong C, Li Y, Lee C, Huang CH. Ensemble learning algorithms for classification of mtDNA into haplogroups. Brief Bioinform. 2011;12(1):1–9. doi:10.1093/bib/bbq008
   PubMed Web of Science ®Google Scholar
• Xu Y, Lindh CH, Jönsson BAG, Broberg K, Albin M. Occupational exposure to asphalt mixture during road paving is related to increased mitochondria DNA copy number: a cross-sectional study. Environ Health. 2018;17(1):29. doi:10.1186/s12940-018-0375-0
   PubMedGoogle Scholar
• Fu MH, Chen IC, Lee CH, et al. Anti-neuroinflammation ameliorates systemic inflammation-induced mitochondrial DNA impairment in the nucleus of the solitary tract and cardiovascular reflex dysfunction. J Neuroinflammation. 2019;16(1):224. doi:10.1186/s12974-019-1623-0
   PubMed Web of Science ®Google Scholar
• Zhou X, Backman LJ, Danielson P. Activation of NF-κB signaling via cytosolic mitochondrial RNA sensing in kerotocytes with mitochondrial DNA common deletion. Sci Rep. 2021;11(1):7360. doi:10.1038/s41598-021-86522-6
   PubMed Web of Science ®Google Scholar
• Paunel-Görgülü A, Wacker M, El Aita M, et al. cfDNA correlates with endothelial damage after cardiac surgery with prolonged cardiopulmonary bypass and amplifies NETosis in an intracellular TLR9-independent manner. Sci Rep. 2017;7(1):17421. doi:10.1038/s41598-017-17561-1
   PubMed Web of Science ®Google Scholar
• Mangold A, Alias S, Scherz T, et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res. 2015;116(7):1182–1192. doi:10.1161/CIRCRESAHA.116.304944
   PubMed Web of Science ®Google Scholar
• Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401–414. doi:10.1016/j.immuni.2012.01.009
   PubMed Web of Science ®Google Scholar
• Xu L, Zhou J, Che J, et al. Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2021;320(6):G1034–g1044. doi:10.1152/ajpgi.00431.2020
   PubMed Web of Science ®Google Scholar
• Nishimoto S, Fukuda D, Sata M. Emerging roles of Toll-like receptor 9 in cardiometabolic disorders. Inflamm Regen. 2020;40:18. doi:10.1186/s41232-020-00118-7
   PubMed Web of Science ®Google Scholar
• Cai J, Li J, Zhou Y, et al. Staphylococcus aureus facilitates its survival in bovine macrophages by blocking autophagic flux. J Cell Mol Med. 2020;24(6):3460–3468. doi:10.1111/jcmm.15027
   PubMed Web of Science ®Google Scholar
• Jiang M, Xue Y, Li J, et al. PKCδ/MAPKs and NF-κB pathways are involved in the regulation of ingenane-type diterpenoids from euphorbia neriifolia on macrophage function. J Inflamm Res. 2021;14:2681–2696. doi:10.2147/JIR.S306846
   PubMed Web of Science ®Google Scholar
• Ding L, Liang G, Yao Z, et al. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget. 2015;6(34):36441–36455. doi:10.18632/oncotarget.5541
   PubMedGoogle Scholar
• Xue Y, Zhang H, Sun X, Zhu MJ. Metformin improves ileal epithelial barrier function in interleukin-10 deficient mice. PLoS One. 2016;11(12):e0168670. doi:10.1371/journal.pone.0168670
   PubMed Web of Science ®Google Scholar
• Jing Y, Wu F, Li D, Yang L, Li Q, Li R. Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol Cell Endocrinol. 2018;461:256–264. doi:10.1016/j.mce.2017.09.025
   PubMed Web of Science ®Google Scholar
• Karnevi E, Andersson R, Rosendahl AH. Tumour-educated macrophages display a mixed polarisation and enhance pancreatic cancer cell invasion. Immunol Cell Biol. 2014;92(6):543–552. doi:10.1038/icb.2014.22
   PubMed Web of Science ®Google Scholar
• Nassif RM, Chalhoub E, Chedid P, et al. Metformin Inhibits ROS Production by Human M2 Macrophages via the Activation of AMPK. Biomedicines. 2022;10(2):319. doi:10.3390/biomedicines10020319
   PubMed Web of Science ®Google Scholar
• Lin CF, Young KC, Bai CH, et al. Blockade of reactive oxygen species and Akt activation is critical for anti-inflammation and growth inhibition of metformin in phosphatase and tensin homolog-deficient RAW264.7 cells. Immunopharmacol Immunotoxicol. 2013;35(6):669–677. doi:10.3109/08923973.2013.837059
   PubMed Web of Science ®Google Scholar
• Xiong W, Sun KY, Zhu Y, Zhang X, Zhou YH, Zou X. Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt. Cell Death Dis. 2021;12(10):934. doi:10.1038/s41419-021-04235-0
   PubMed Web of Science ®Google Scholar
• Filtjens J, Roger A, Quatrini L, et al. Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection. Nat Commun. 2021;12(1):2936. doi:10.1038/s41467-021-22841-6
   PubMed Web of Science ®Google Scholar
• Gavillet M, Martinod K, Renella R, et al. Flow cytometric assay for direct quantification of neutrophil extracellular traps in blood samples. Am J Hematol. 2015;90(12):1155–1158. doi:10.1002/ajh.24185
   PubMed Web of Science ®Google Scholar
• Navrátilová A, Bečvář V, Baloun J, et al. S100A11 (calgizzarin) is released via NETosis in rheumatoid arthritis (RA) and stimulates IL-6 and TNF secretion by neutrophils. Sci Rep. 2021;11(1):6063. doi:10.1038/s41598-021-85561-3
   PubMed Web of Science ®Google Scholar
• Chen K, Geng S, Yuan R, Diao N, Upchurch Z, Li L. Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality. EBioMedicine. 2015;2(4):324–333. doi:10.1016/j.ebiom.2015.03.001
   PubMed Web of Science ®Google Scholar
• Sofoluwe A, Bacchetta M, Badaoui M, Kwak BR, Chanson M. ATP amplifies NADPH-dependent and -independent neutrophil extracellular trap formation. Sci Rep. 2019;9(1):16556. doi:10.1038/s41598-019-53058-9
   PubMedGoogle Scholar
• Pan B, Alam HB, Chong W, et al. CitH3: a reliable blood biomarker for diagnosis and treatment of endotoxic shock. Sci Rep. 2017;7(1):8972. doi:10.1038/s41598-017-09337-4
   PubMedGoogle Scholar
• Menegazzo L, Scattolini V, Cappellari R, et al. The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo. Acta Diabetol. 2018;55(6):593–601. doi:10.1007/s00592-018-1129-8
   PubMed Web of Science ®Google Scholar
• Shaban L, Nguyen GT, Mecsas-Faxon BD, Swanson KD, Tan S, Mecsas J. Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection. PLoS Pathog. 2020;16(5):e1008576. doi:10.1371/journal.ppat.1008576
   PubMed Web of Science ®Google Scholar
• Mogavero A, Maiorana MV, Zanutto S, et al. Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep. 2017;7(1):15992. doi:10.1038/s41598-017-16149-z
   PubMedGoogle Scholar
• Soni C, Reizis B. Self-DNA at the epicenter of SLE: immunogenic forms, regulation, and effects. Front Immunol. 2019;10:1601. doi:10.3389/fimmu.2019.01601
   PubMed Web of Science ®Google Scholar
• Parackova Z, Zentsova I, Vrabcova P, et al. Neutrophil extracellular trap induced dendritic cell activation leads to Th1 polarization in type 1 diabetes. Front Immunol. 2020;11:661.
   PubMed Web of Science ®Google Scholar
• Yang LY, Shen XT, Sun HT, Zhu WW, Zhang JB, Lu L. Neutrophil extracellular traps in hepatocellular carcinoma are enriched in oxidized mitochondrial DNA which is highly pro-inflammatory and pro-metastatic. J Cancer. 2022;13(4):1261–1271. doi:10.7150/jca.64170
   PubMed Web of Science ®Google Scholar
• Wang H, Li T, Chen S, Gu Y, Ye S. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 2015;67(12):3190–3200. doi:10.1002/art.39296
   PubMed Web of Science ®Google Scholar
• Cai Q, Huo GW, Zhu FY, Yue P, Yuan DQ, Chen P. Safety and efficacy of immune checkpoint inhibitors in advanced cancer patients with autoimmune disease: a meta-analysis. Hum Vaccin Immunother. 2022;18(7):2145102. doi:10.1080/21645515.2022.2145102
   PubMedGoogle Scholar
• Ledderose C, Liu K, Kondo Y, et al. Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J Clin Invest. 2018;128(8):3583–3594. doi:10.1172/JCI120972
   PubMed Web of Science ®Google Scholar
• Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int Immunol. 2016;28(4):163–171. doi:10.1093/intimm/dxw006
   PubMed Web of Science ®Google Scholar
• Loza MJ, Foster S, Bleecker ER, Peters SP, Penn RB. Asthma and gender impact accumulation of T cell subtypes. Respir Res. 2010;11(1):103. doi:10.1186/1465-9921-11-103
   PubMedGoogle Scholar
• de Oliveira S, Houseright RA, Graves AL, et al. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol. 2019;70(4):710–721. doi:10.1016/j.jhep.2018.11.034
   PubMed Web of Science ®Google Scholar
• Noguchi M, Nomura A, Doi S, et al. Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction. Sci Rep. 2018;8(1):17374. doi:10.1038/s41598-018-35783-9
   PubMedGoogle Scholar
• Park MJ, Lee SY, Moon SJ, et al. Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs. Transl Res. 2016;173:115–130. doi:10.1016/j.trsl.2016.03.006
   PubMed Web of Science ®Google Scholar
• Li S, Liu S, Chen F, et al. Link-polymorphism of 5-HTT promoter region is associated with autoantibodies in patients with systemic lupus erythematosus. J Immunol Res. 2016;2016:3042726. doi:10.1155/2016/3042726
   PubMed Web of Science ®Google Scholar
• Luo Q, Li X, Fu B, et al. Decreased expression of TIGIT in NK cells correlates negatively with disease activity in systemic lupus erythematosus. Int J Clin Exp Pathol. 2018;11(5):2408–2418.
   PubMed Web of Science ®Google Scholar
• Lee SY, Moon SJ, Kim EK, et al. Metformin suppresses systemic autoimmunity in Roquin(san/san) mice through inhibiting B cell differentiation into plasma cells via regulation of AMPK/mTOR/STAT3. J Immunol. 2017;198(7):2661–2670. doi:10.4049/jimmunol.1403088
   PubMed Web of Science ®Google Scholar
• Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811. doi:10.1146/annurev.immunol.18.1.767
   PubMed Web of Science ®Google Scholar
• Shin S, Hyun B, Lee A, et al. Metformin suppresses MHC-restricted antigen presentation by inhibiting co-stimulatory factors and MHC molecules in APCs. Biomol Ther (Seoul). 2013;21(1):35–41. doi:10.4062/biomolther.2012.094
   PubMed Web of Science ®Google Scholar
• Moschen AR, Wieser V, Tilg H. Dietary factors: major regulators of the gut’s microbiota. Gut Liver. 2012;6(4):411–416. doi:10.5009/gnl.2012.6.4.411
   PubMed Web of Science ®Google Scholar
• Liso M, De Santis S, Scarano A, et al. A bronze-tomato enriched diet affects the intestinal microbiome under homeostatic and inflammatory conditions. Nutrients. 2018;10(12):1862. doi:10.3390/nu10121862
   PubMed Web of Science ®Google Scholar
• Wang X, Yi W, He L, et al. Abnormalities in Gut microbiota and metabolism in patients with chronic spontaneous urticaria. Front Immunol. 2021;12:691304. doi:10.3389/fimmu.2021.691304
   PubMed Web of Science ®Google Scholar
• Davis CD. The gut microbiome and its role in obesity. Nutr Today. 2016;51(4):167–174. doi:10.1097/NT.0000000000000167
   PubMedGoogle Scholar
• Castaner O, Goday A, Park YM, et al. The Gut microbiome profile in obesity: a systematic review. Int J Endocrinol. 2018;2018:4095789. doi:10.1155/2018/4095789
   PubMed Web of Science ®Google Scholar
• Chen ML, Yi L, Zhang Y, et al. Resveratrol attenuates trimethylamine-N-Oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. mBio. 2016;7(2):e02210–02215. doi:10.1128/mBio.02210-15
   PubMed Web of Science ®Google Scholar
• Liu SK, Ma LB, Yuan Y, et al. Alanylglutamine relieved asthma symptoms by regulating gut microbiota and the derived metabolites in mice. Oxid Med Cell Longev. 2020;2020:7101407. doi:10.1155/2020/7101407
   PubMed Web of Science ®Google Scholar
• Poroyko VA, Carreras A, Khalyfa A, et al. Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice. Sci Rep. 2016;6:35405. doi:10.1038/srep35405
   PubMed Web of Science ®Google Scholar
• Yan N, Wang L, Li Y, et al. Metformin intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation. PLoS One. 2021;16(7):e0254321. doi:10.1371/journal.pone.0254321
   PubMed Web of Science ®Google Scholar
• Wu QJ, Wang YQ, Qi YX. The protective effect of procyanidin against LPS-induced acute gut injury by the regulations of oxidative state. Springerplus. 2016;5(1):1645. doi:10.1186/s40064-016-3306-y
   PubMedGoogle Scholar
• Adar T, Ben Ya’acov A, Lalazar G, et al. Oral administration of immunoglobulin G-enhanced colostrum alleviates insulin resistance and liver injury and is associated with alterations in natural killer T cells. Clin Exp Immunol. 2012;167(2):252–260. doi:10.1111/j.1365-2249.2011.04511.x
   PubMed Web of Science ®Google Scholar
• Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol. 2012;18(21):2609–2618. doi:10.3748/wjg.v18.i21.2609
   PubMed Web of Science ®Google Scholar
• Dornas W, Lagente V. Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis. Pharmacol Res. 2019;141:418–428. doi:10.1016/j.phrs.2019.01.026
   PubMed Web of Science ®Google Scholar
• Brandt A, Hernández-Arriaga A, Kehm R, et al. Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine. Sci Rep. 2019;9(1):6668. doi:10.1038/s41598-019-43228-0
   PubMedGoogle Scholar
• Liu Z, Liao W, Zhang Z, et al. Metformin affects gut microbiota composition and diversity associated with amelioration of dextran sulfate sodium-induced colitis in mice. Front Pharmacol. 2021;12:640347. doi:10.3389/fphar.2021.640347
   PubMed Web of Science ®Google Scholar
• Napolitano A, Miller S, Nicholls AW, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014;9(7):e100778. doi:10.1371/journal.pone.0100778
   PubMed Web of Science ®Google Scholar
• Deng J, Zeng L, Lai X, et al. Metformin protects against intestinal barrier dysfunction via AMPKα1-dependent inhibition of JNK signalling activation. J Cell Mol Med. 2018;22(1):546–557. doi:10.1111/jcmm.13342
   PubMed Web of Science ®Google Scholar
• Cao Y, Chen J, Ren G, Zhang Y, Tan X, Yang L. Punicalagin prevents inflammation in LPS-induced RAW264.7 macrophages by inhibiting FoxO3a/Autophagy signaling pathway. Nutrients. 2019;11(11):2794. doi:10.3390/nu11112794
   PubMed Web of Science ®Google Scholar
• Janssen AFJ, Katrukha EA, van Straaten W, Verlhac P, Reggiori F, Kapitein LC. Probing aggrephagy using chemically-induced protein aggregates. Nat Commun. 2018;9(1):4245. doi:10.1038/s41467-018-06674-4
   PubMedGoogle Scholar
• Chen RJ, Lee YH, Yeh YL, Wang YJ, Wang BJ. The roles of autophagy and the inflammasome during environmental stress-triggered skin inflammation. Int J Mol Sci. 2016;17(12):2063. doi:10.3390/ijms17122063
   PubMed Web of Science ®Google Scholar
• Guo W, Liu J, Li W, et al. Niacin alleviates dairy cow mastitis by regulating the GPR109A/AMPK/NRF2 signaling pathway. Int J Mol Sci. 2020;21(9):3321. doi:10.3390/ijms21093321
   PubMed Web of Science ®Google Scholar
• Maulucci G, Chiarpotto M, Papi M, Samengo D, Pani G, De Spirito M. Quantitative analysis of autophagic flux by confocal pH-imaging of autophagic intermediates. Autophagy. 2015;11(10):1905–1916. doi:10.1080/15548627.2015.1084455
   PubMed Web of Science ®Google Scholar
• Rodgers MA, Bowman JW, Liang Q, Jung JU. Regulation where autophagy intersects the inflammasome. Antioxid Redox Signal. 2014;20(3):495–506. doi:10.1089/ars.2013.5347
   PubMed Web of Science ®Google Scholar
• Into T, Horie T, Inomata M, et al. Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88. Sci Rep. 2017;7(1):1009. doi:10.1038/s41598-017-01246-w
   PubMedGoogle Scholar
• Camuzard O, Santucci-Darmanin S, Carle GF, Pierrefite-Carle V. Role of autophagy in osteosarcoma. J Bone Oncol. 2019;16:100235. doi:10.1016/j.jbo.2019.100235
   PubMed Web of Science ®Google Scholar
• Lv S, Liu H, Wang H. Exogenous hydrogen sulfide plays an important role by regulating autophagy in diabetic-related diseases. Int J Mol Sci. 2021;22(13):6715. doi:10.3390/ijms22136715
   PubMed Web of Science ®Google Scholar
• Nakahira K, Haspel JA, Rathinam VA, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–230. doi:10.18632/aging.102512
   PubMed Web of Science ®Google Scholar
• Vinaik R, Barayan D, Jeschke MG. NLRP3 inflammasome in inflammation and metabolism: identifying novel roles in postburn adipose dysfunction. Endocrinology. 2020;161(9). doi:10.1210/endocr/bqaa116
   PubMed Web of Science ®Google Scholar
• He C, Liu G, Zhuang S, et al. Yu Nu compound regulates autophagy and apoptosis through mTOR in vivo and vitro. Diabetes Metab Syndr Obes. 2020;13:2081–2092. doi:10.2147/DMSO.S253494
   PubMed Web of Science ®Google Scholar
• Saitoh T, Fujita N, Jang MH, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456(7219):264–268. doi:10.1038/nature07383
   PubMed Web of Science ®Google Scholar
• Kabat AM, Harrison OJ, Riffelmacher T, et al. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. Elife. 2016;5:e12444. doi:10.7554/eLife.12444
   PubMed Web of Science ®Google Scholar
• Marek-Iannucci S, Ozdemir AB, Moreira D, et al. Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis. JCI Insight. 2021;6(18). doi:10.1172/jci.insight.151981
   PubMed Web of Science ®Google Scholar
• Wang W, Chen L, Shang C, et al. miR-145 inhibits the proliferation and migration of vascular smooth muscle cells by regulating autophagy. J Cell Mol Med. 2020;24(12):6658–6669. doi:10.1111/jcmm.15316
   PubMed Web of Science ®Google Scholar
• Iskandar R, Liu S, Xiang F, et al. Expression of pericardial fluid T-cells and related inflammatory cytokines in patients with chronic heart failure. Exp Ther Med. 2017;13(5):1850–1858. doi:10.3892/etm.2017.4202
   PubMed Web of Science ®Google Scholar
• Bilchick K, Kothari H, Narayan A, et al. Cardiac resynchronization therapy reduces expression of inflammation-promoting genes related to interleukin-1β in heart failure. Cardiovasc Res. 2020;116(7):1311–1322. doi:10.1093/cvr/cvz232
   PubMed Web of Science ®Google Scholar
• Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120(11):1812–1824. doi:10.1161/CIRCRESAHA.117.311082
   PubMed Web of Science ®Google Scholar
• Lu G, Wu Z, Shang J, Xie Z, Chen C, Zhang C. The effects of metformin on autophagy. Biomed Pharmacother. 2021;137:111286. doi:10.1016/j.biopha.2021.111286
   PubMed Web of Science ®Google Scholar
• Niu C, Chen Z, Kim KT, et al. Metformin alleviates hyperglycemia-induced endothelial impairment by downregulating autophagy via the Hedgehog pathway. Autophagy. 2019;15(5):843–870. doi:10.1080/15548627.2019.1569913
   PubMed Web of Science ®Google Scholar
• Sun B, Ou H, Ren F, et al. Propofol inhibited autophagy through Ca(2+)/CaMKKβ/AMPK/mTOR pathway in OGD/R-induced neuron injury. Mol Med. 2018;24(1):58. doi:10.1186/s10020-018-0054-1
   PubMedGoogle Scholar
• Huang KY, Que JQ, Hu ZS, et al. Metformin suppresses inflammation and apoptosis of myocardiocytes by inhibiting autophagy in a model of ischemia-reperfusion injury. Int J Biol Sci. 2020;16(14):2559–2579. doi:10.7150/ijbs.40823
   PubMed Web of Science ®Google Scholar
• Peng C, Rao W, Zhang L, et al. Mitofusin 2 exerts a protective role in ischemia reperfusion injury through increasing autophagy. Cell Physiol Biochem. 2018;46(6):2311–2324. doi:10.1159/000489621
   PubMedGoogle Scholar
• Yin Y, Sun G, Li E, Kiselyov K, Sun D. ER stress and impaired autophagy flux in neuronal degeneration and brain injury. Ageing Res Rev. 2017;34:3–14. doi:10.1016/j.arr.2016.08.008
   PubMed Web of Science ®Google Scholar
• Liu Y, Xue X, Zhang H, et al. Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia. Autophagy. 2019;15(3):493–509. doi:10.1080/15548627.2018.1531196
   PubMed Web of Science ®Google Scholar
• Jiang N, He D, Ma Y, et al. Force-induced autophagy in periodontal ligament stem cells modulates M1 macrophage polarization via AKT signaling. Front Cell Dev Biol. 2021;9:666631. doi:10.3389/fcell.2021.666631
   PubMed Web of Science ®Google Scholar
• Zhang YS, Wang F, Cui SX, Qu XJ. Natural dietary compound naringin prevents azoxymethane/dextran sodium sulfate-induced chronic colorectal inflammation and carcinogenesis in mice. Cancer Biol Ther. 2018;19(8):735–744. doi:10.1080/15384047.2018.1453971
   PubMed Web of Science ®Google Scholar
• Maneechotesuwan K, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ. Role of autophagy in regulating interleukin-10 and the responses to corticosteroids and statins in asthma. Clin Exp Allergy. 2021;51(12):1553–1565. doi:10.1111/cea.13825
   PubMed Web of Science ®Google Scholar
• Chen Y, Liang Y, Luo X, Hu Q. Oxidative resistance of leukemic stem cells and oxidative damage to hematopoietic stem cells under pro-oxidative therapy. Cell Death Dis. 2020;11(4):291. doi:10.1038/s41419-020-2488-y
   PubMed Web of Science ®Google Scholar
• Saladini S, Aventaggiato M, Barreca F, et al. Metformin impairs glutamine metabolism and autophagy in tumour cells. Cells. 2019;8(1):49. doi:10.3390/cells8010049
   PubMed Web of Science ®Google Scholar
• Frasca D, Diaz A, Romero M, Blomberg BB. Ageing and obesity similarly impair antibody responses. Clin Exp Immunol. 2017; 187(1):64-70. doi:10.1111/cei.12824
   Google Scholar
• Tyrrell DJ, Goldstein DR. Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6. Nat Rev Cardiol. 2021;18(1):58–68. doi:10.1038/s41569-020-0431-7
   PubMed Web of Science ®Google Scholar
• Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. 2018;9:586. doi:10.3389/fimmu.2018.00586
   PubMed Web of Science ®Google Scholar
• Andrews NP, Fujii H, Goronzy JJ, Weyand CM. Telomeres and immunological diseases of aging. Gerontology. 2010;56(4):390–403. doi:10.1159/000268620
   PubMed Web of Science ®Google Scholar
• Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21(3):383–421. doi:10.1016/S0197-4580(00)00124-X
   PubMed Web of Science ®Google Scholar
• Li D, Liu Q, Lu X, et al. α-Mangostin remodels visceral adipose tissue inflammation to ameliorate age-related metabolic disorders in mice. Aging (Albany NY). 2019;11(23):11084–11110.
   PubMedGoogle Scholar
• Lau L, Porciuncula A, Yu A, Iwakura Y, David G. Uncoupling the senescence-associated secretory phenotype from cell cycle exit via Interleukin-1 inactivation unveils its protumorigenic role. Mol Cell Biol. 2019;39(12). doi:10.1128/MCB.00586-18
   PubMed Web of Science ®Google Scholar
• Sung JY, Kim SG, Kim JR, Choi HC. Prednisolone suppresses Adriamycin-induced vascular smooth muscle cell senescence and inflammatory response via the SIRT1-AMPK signaling pathway. PLoS One. 2020;15(9):e0239976. doi:10.1371/journal.pone.0239976
   PubMed Web of Science ®Google Scholar
• van Beek AA, Hugenholtz F, Meijer B, et al. Frontline science: tryptophan restriction arrests B cell development and enhances microbial diversity in WT and prematurely aging Ercc1(-/Δ7) mice. J Leukoc Biol. 2017;101(4):811–821. doi:10.1189/jlb.1HI0216-062RR
   PubMed Web of Science ®Google Scholar
• Aguayo-Mazzucato C, Andle J, Lee TB, et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 2019;30(1):129–142.e124. doi:10.1016/j.cmet.2019.05.006
   PubMed Web of Science ®Google Scholar
• Alfaras I, Mitchell SJ, Mora H, et al. Health benefits of late-onset metformin treatment every other week in mice. NPJ Aging Mech Dis. 2017;3:16. doi:10.1038/s41514-017-0018-7
   PubMedGoogle Scholar
• Noren Hooten N, Martin-Montalvo A, Dluzen DF, et al. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell. 2016;15(3):572–581. doi:10.1111/acel.12469
   PubMed Web of Science ®Google Scholar
• Sun X, Tavenier A, Deng W, Leishman E, Bradshaw HB, Dey SK. Metformin attenuates susceptibility to inflammation-induced preterm birth in mice with higher endocannabinoid levels. Biol Reprod. 2018;98(2):208–217.
   PubMed Web of Science ®Google Scholar
• Long DE, Peck BD, Martz JL, et al. Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial. Trials. 2017;18(1):192. doi:10.1186/s13063-017-1932-5
   PubMedGoogle Scholar
• Giaccari A, Solini A, Frontoni S, Del Prato S. Metformin benefits: another example for alternative energy substrate mechanism? Diabetes Care. 2021;44(3):647–654. doi:10.2337/dc20-1964
   PubMed Web of Science ®Google Scholar
• Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32(1):15–30. doi:10.1016/j.cmet.2020.04.001
   PubMed Web of Science ®Google Scholar