218
Views
2
CrossRef citations to date
0
Altmetric
ORIGINAL RESEARCH

Aerobic Exercise Ameliorates Liver Injury in Db/Db Mice by Attenuating Oxidative Stress, Apoptosis and Inflammation Through the Nrf2 and JAK2/STAT3 Signalling Pathways

ORCID Icon, ORCID Icon, , , , , , , , & show all
Pages 4805-4819 | Received 06 Jul 2023, Accepted 12 Oct 2023, Published online: 24 Oct 2023

References

  • Donath MY, Ehses JA, Maedler K, et al. Mechanisms of beta-cell death in type 2 diabetes. Diabetes. 2005;54(Suppl 2):S108–S113. doi:10.2337/diabetes.54.suppl_2.S108
  • Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42(5):987–1000. doi:10.1002/hep.20920
  • Manna P, Das J, Ghosh J, Sil PC. Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid. Free Radic Biol Med. 2010;48(11):1465–1484. doi:10.1016/j.freeradbiomed.2010.02.025
  • Bae CS, Lee Y, Ahn T. Therapeutic treatments for diabetes mellitus-induced liver injury by regulating oxidative stress and inflammation. Appl Microsc. 2023;53(1):4. doi:10.1186/s42649-023-00089-2
  • Tiercelin C, Lemoine AY, Ratheau L, Larger E. High frequency of transaminase elevation following diabetic ketoacidosis. Diabetes Metab. 2021;47(1):101123. doi:10.1016/j.diabet.2019.09.001
  • Torbenson M, Chen YY, Brunt E, et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol. 2006;30(4):508–513. doi:10.1097/00000478-200604000-00012
  • Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22(3):377–388. doi:10.1038/cdd.2014.150
  • Peng ML, Fu Y, Wu CW, Zhang Y, Ren H, Zhou SS. Signaling pathways related to oxidative stress in diabetic cardiomyopathy. Front Endocrinol. 2022;13:907757. doi:10.3389/fendo.2022.907757
  • Malaguarnera L, Madeddu R, Palio E, Arena N, Malaguarnera M. Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. J Hepatol. 2005;42(4):585–591. doi:10.1016/j.jhep.2004.11.040
  • Zhang L, Li HX, Pan WS, et al. Administration of methyl palmitate prevents non-alcoholic steatohepatitis (NASH) by induction of PPAR-α. Biomed Pharmacother. 2019;111:99–108. doi:10.1016/j.biopha.2018.12.059
  • Stancic A, Velickovic K, Markelic M, et al. Involvement of ferroptosis in diabetes-induced liver pathology. Int J Mol Sci. 2022;23(16):2–3. doi:10.3390/ijms23169309
  • Zhang Q, Zhao Y, Talukder M, et al. Di(2-ethylhexyl) phthalate induced hepatotoxicity in quail (Coturnix japonica) via modulating the mitochondrial unfolded protein response and NRF2 mediated antioxidant defense. Sci Total Environ. 2019;651:885–894. doi:10.1016/j.scitotenv.2018.09.211
  • Tian S, Zhao H, Song H. Shared signaling pathways and targeted therapy by natural bioactive compounds for obesity and type 2 diabetes. Crit Rev Food Sci Nutr. 2022;3:1–18.
  • Sireesh D, Ganesh M-R, Dhamodharan U, et al. Role of pterostilbene in attenuating immune mediated devastation of pancreatic beta cells via Nrf2 signaling cascade. J Nutr Biochem. 2017;44:11–21. doi:10.1016/j.jnutbio.2017.02.015
  • Feng Y, Cui R, Li Z, et al. Methane alleviates acetaminophen-induced liver injury by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and apoptosis through the Nrf2/HO-1/NQO1 signaling pathway. Oxid Med Cell Longev. 2019;2019:7067619. doi:10.1155/2019/7067619
  • Shaw P, Mondal P, Bandyopadhyay A, Chattopadhyay A. Environmentally relevant concentration of chromium activates Nrf2 and alters transcription of related XME genes in liver of zebrafish. Chemosphere. 2019;214:35–46. doi:10.1016/j.chemosphere.2018.09.104
  • Lima TI, Monteiro IC, Valença S, et al. Effect of exercise training on liver antioxidant enzymes in STZ-diabetic rats. Life Sci. 2015;128:64–71. doi:10.1016/j.lfs.2015.01.031
  • Liu SX, Zheng F, Xie KL, Xie MR, Jiang LJ, Cai Y. Exercise reduces insulin resistance in type 2 diabetes mellitus via mediating the lncRNA MALAT1/MicroRNA-382-3p/Resistin Axis. Mol Ther Nucleic Acids. 2019;18:34–44. doi:10.1016/j.omtn.2019.08.002
  • Fealy CE, Haus JM, Solomon TP, et al. Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease. J Appl Physiol. 2012;113(1):1–6. doi:10.1152/japplphysiol.00127.2012
  • Gregory JM, Muldowney JA, Engelhardt BG, et al. Aerobic exercise training improves hepatic and muscle insulin sensitivity, but reduces splanchnic glucose uptake in obese humans with type 2 diabetes. Nutr Diabetes. 2019;9(1):25. doi:10.1038/s41387-019-0090-0
  • Fathi R, Nasiri K, Akbari A, Ahmadi-KaniGolzar F, Farajtabar Z. Exercise protects against ethanol-induced damage in rat heart and liver through the inhibition of apoptosis and activation of Nrf2/Keap-1/HO-1 pathway. Life Sci. 2020;256:117958. doi:10.1016/j.lfs.2020.117958
  • O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66(1):311–328. doi:10.1146/annurev-med-051113-024537
  • Zhao J, Liu X, Chen Y, et al. STAT3 promotes schistosome-induced liver injury by inflammation, oxidative stress, proliferation, and apoptosis signal pathway. Infect Immun. 2021;2021:89.
  • Zhang H, Li H, Ge A, Guo E, Liu S, Zhang L. RETRACTED: long non-coding RNA TUG1 inhibits apoptosis and inflammatory response in LPS-treated H9c2 cells by down-regulation of miR-29b. Biomed Pharmacother. 2018;101:663–669. doi:10.1016/j.biopha.2018.02.129
  • Wang Y, Li H, Huang H, et al. Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling. Clin Sci. 2016;130(10):801–812. doi:10.1042/CS20150617
  • Zhong T, Li M, Wu H, et al. Novel Flavan-3,4-diol vernicidin B from Toxicodendron Vernicifluum (Anacardiaceae) as potent antioxidant via IL-6/Nrf2 cross-talks pathways. Phytomedicine. 2022;100:154041. doi:10.1016/j.phymed.2022.154041
  • Wang J, Polaki V, Chen S, Bihl JC, Pagliaro P. Exercise improves endothelial function associated with alleviated inflammation and oxidative stress of perivascular adipose tissue in type 2 diabetic mice. Oxid Med Cell Longev. 2020;2020:8830537. doi:10.1155/2020/8830537
  • Ma Y, Wang L, Yang S, et al. The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice. Stem Cell Res Ther. 2021;12(1):385. doi:10.1186/s13287-021-02463-x
  • Xu L, Yu Y, Sang R, Li J, Ge B, Zhang X. Protective effects of taraxasterol against ethanol-induced liver injury by regulating CYP2E1/Nrf2/HO-1 and NF-kappaB signaling pathways in mice. Oxid Med Cell Longev. 2018;2018:8284107. doi:10.1155/2018/8284107
  • Xiong Y, Wang Y, Xiong Y, Teng L. Protective effect of Salidroside on hypoxia-related liver oxidative stress and inflammation via Nrf2 and JAK2/STAT3 signaling pathways. Food Sci Nutr. 2021;9(9):5060–5069. doi:10.1002/fsn3.2459
  • Qaed E, Wang J, Almoiliqy M, et al. Phosphocreatine improves cardiac dysfunction by normalizing mitochondrial respiratory function through JAK2/STAT3 signaling pathway in vivo and in vitro. Oxid Med Cell Longev. 2019;2019:6521218. doi:10.1155/2019/6521218
  • Pereira RM, Rodrigues K, Anaruma CP, et al. Short-term strength training reduces gluconeogenesis and NAFLD in obese mice. J Endocrinol. 2019;241(1):59–70. doi:10.1530/JOE-18-0567
  • Yang Z, Huang G, Zhou P, Zhang Y, Ding J, Sun Q. Hua T: exercise ameliorates high-fat diet-induced insulin resistance accompanied by changes in protein levels of hepatic ATF3-related signaling in rats. Physiol Behav. 2022;249:113766. doi:10.1016/j.physbeh.2022.113766
  • Botezelli JD, Coope A, Ghezzi AC, et al. Strength training prevents hyperinsulinemia, insulin resistance, and inflammation independent of weight loss in fructose-fed animals. Sci Rep. 2016;6(1):31106. doi:10.1038/srep31106
  • Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. Cmaj. 2005;172(3):367–379. doi:10.1503/cmaj.1040752
  • Sabag A, Way KL, Sultana RN, et al. The effect of a novel low-volume aerobic exercise intervention on liver fat in type 2 diabetes: a randomized controlled trial. Diabetes Care. 2020;43(10):2371–2378. doi:10.2337/dc19-2523
  • Rector RS, Thyfault JP, Morris RT, et al. Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in otsuka long-Evans Tokushima fatty rats. Am J Physiol Gastrointest Liver Physiol. 2008;294(3):G619–G626. doi:10.1152/ajpgi.00428.2007
  • Zhang Y, Gu M, Wang R, Li M, Li D, Xie Z. Dietary supplement of Yunkang 10 green tea and treadmill exercise ameliorate high fat diet induced metabolic syndrome of C57BL/6 J mice. Nutr Metab. 2020;17(1):14. doi:10.1186/s12986-020-0433-9
  • Amanat S, Ghahri S, Dianatinasab A, Fararouei M, Dianatinasab M. Exercise and type 2 diabetes. Adv Exp Med Biol. 2020;1228:91–105.
  • Lin L, Wang Y, Xu W, et al. Aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice. Dis Markers. 2022;2022:6010504. doi:10.1155/2022/6010504
  • Motiani KK, Collado MC, Eskelinen JJ, et al. Exercise training modulates gut microbiota profile and improves endotoxemia. Med Sci Sports Exerc. 2020;52(1):94–104. doi:10.1249/MSS.0000000000002112
  • Chandirasegaran G, Elanchezhiyan C, Ghosh K. Effects of Berberine chloride on the liver of streptozotocin-induced diabetes in albino Wistar rats. Biomed Pharmacother. 2018;99:227–236. doi:10.1016/j.biopha.2018.01.007
  • Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30(3):734–743. doi:10.2337/dc06-1539
  • Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A. 2006;103(8):2653–2658. doi:10.1073/pnas.0511154103
  • Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47(9):1304–1309. doi:10.1016/j.freeradbiomed.2009.07.035
  • Qi X, Lu XT, Sun XH, Lin CQ, Cui CB. The regulatory effect of total flavonoids of Sedum aizoon L. on oxidative stress in type 1 diabetic mice. Curr Res Food Sci. 2022;5:1140–1147. doi:10.1016/j.crfs.2022.06.010
  • Liu J, Wu KC, Lu YF, Ekuase E, Klaassen CD. Nrf2 protection against liver injury produced by various hepatotoxicants. Oxid Med Cell Longev. 2013;2013:305861. doi:10.1155/2013/305861
  • Axelsson AS, Tubbs E, Mecham B, et al. Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci Transl Med. 2017;9(394):eaah4477.
  • Ariza J, González-Reyes JA, Jódar L, Díaz-Ruiz A, de Cabo R, Villalba JM. Mitochondrial permeabilization without caspase activation mediates the increase of basal apoptosis in cells lacking Nrf2. Free Radic Biol Med. 2016;95:82–95. doi:10.1016/j.freeradbiomed.2016.03.015
  • Jia R, Cao LP, Du JL, et al. Effects of high-fat diet on antioxidative status, apoptosis and inflammation in liver of tilapia (Oreochromis niloticus) via Nrf2, TLRs and JNK pathways. Fish Shellfish Immunol. 2020;104:391–401. doi:10.1016/j.fsi.2020.06.025
  • Gokila Vani M, Kumar KJ, Liao JW, et al. Antcin C from antrodia cinnamomea protects liver cells against free radical-induced oxidative stress and apoptosis in vitro and in vivo through Nrf2-dependent mechanism. Evid Based Complement Alternat Med. 2013;2013:296082.
  • Song JX, An JR, Chen Q, et al. Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice. Bioengineered. 2022;13(4):8334–8348. doi:10.1080/21655979.2022.2051858
  • Chen X, Li H, Wang K, et al. Aerobic exercise ameliorates myocardial inflammation, fibrosis and apoptosis in high-fat-diet rats by inhibiting P2X7 purinergic receptors. Front Physiol. 2019;10:1286. doi:10.3389/fphys.2019.01286
  • Yang Y, Zhao J, Song X, et al. Amygdalin reduces lipopolysaccharide-induced chronic liver injury in rats by down-regulating PI3K/AKT, JAK2/STAT3 and NF-κB signalling pathways. Artif Cells Nanomed Biotechnol. 2019;47(1):2688–2697. doi:10.1080/21691401.2019.1634084
  • Zhou GY, Yi YX, Jin LX, et al. The protective effect of juglanin on fructose-induced hepatitis by inhibiting inflammation and apoptosis through TLR4 and JAK2/STAT3 signaling pathways in fructose-fed rats. Biomed Pharmacother. 2016;81:318–328. doi:10.1016/j.biopha.2016.04.013
  • El-Nasr NME A, Saleh DO, Mahmoud SS, et al. Olmesartan attenuates type 2 diabetes-associated liver injury: cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways. Eur J Pharmacol. 2020;874:173010. doi:10.1016/j.ejphar.2020.173010
  • Lu C, Xu W, Shao J, Zhang F, Chen A, Zheng S. Nrf2 induces lipocyte phenotype via a SOCS3-dependent negative feedback loop on JAK2/STAT3 signaling in hepatic stellate cells. Int Immunopharmacol. 2017;49:203–211. doi:10.1016/j.intimp.2017.06.001
  • Li J, Sapper TN, Mah E, et al. Green tea extract provides extensive Nrf2-independent protection against lipid accumulation and NFκB pro- inflammatory responses during nonalcoholic steatohepatitis in mice fed a high-fat diet. Mol Nutr Food Res. 2016;60(4):858–870. doi:10.1002/mnfr.201500814
  • Shan Y, Wang L, Sun J, Chang S, Di W, Lv H. Exercise preconditioning attenuates cerebral ischemia-induced neuronal apoptosis, Th17/Treg imbalance, and inflammation in rats by inhibiting the JAK2/STAT3 pathway. Brain Behav. 2023;13(6):e3030. doi:10.1002/brb3.3030
  • Wang Y, Guo Y, Xu Y, et al. HIIT ameliorates inflammation and lipid metabolism by regulating macrophage polarization and mitochondrial dynamics in the liver of type 2 diabetes mellitus mice. Metabolites. 2022;13(1):13. doi:10.3390/metabo13010013
  • Liu HW, Chang SJ. Moderate exercise suppresses NF-kappaB signaling and activates the SIRT1-AMPK-PGC1alpha axis to attenuate muscle loss in diabetic db/db mice. Front Physiol. 2018;9:636. doi:10.3389/fphys.2018.00636