Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance via PTEN-mediated crosstalk between the PI3K/Akt and Erk/MAPKs signaling pathways in the skeletal muscles of db/db mice

Chen, Guang; Fan, Xiaoyan; Zheng, Xin; Jin, Yinlong; Liu, Ying; Liu, Shuangchun

doi:10.1186/s13287-020-01865-7

Cited by 24 publications

(5 citation statements)

References 73 publications

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“… 39 , 40 Many studies showed that the PI3K‐AKT‐mTOR and MAPK pathways might crosstalk at various stages of signal transduction. 41 , 42 , 43 , 44 Surprisingly, our study showed that the PI3K‐AKT‐mTOR pathway regulated ACD without influencing apoptosis and that the MAPK pathway was involved in apoptosis without impacting ACD in ATG9b‐overexpressing HSCs. The results indicate that a change in the PI3K‐AKT‐mTOR pathway via activators affects apoptosis to a lesser extent than ATG9b overexpression and that the change in the MAPK pathway via inhibitors affects ACD to a lesser degree than ATG9b overexpression.…”

Section: Discussionmentioning

confidence: 67%

Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

Wang,

Ding,

Xiu

et al. 2023

J Cellular Molecular Medi

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Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy‐related protein 9b (ATG9b) in HSC ACD was detected using co‐immunoprecipitation and co‐localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol‐treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5‐ATG12‐LC3 compartments and increased the co‐localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b‐induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.

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Section: Discussionmentioning

confidence: 67%

Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

Wang,

Ding,

Xiu

et al. 2023

J Cellular Molecular Medi

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“…MSCs with exendin-4 have also shown significant alleviation of diabetic cardiomyopathy relative to the use of MSCs alone (Wassef et al 2018 ). hUCMSCs are believed to be a valuable option for disease therapy (Chen et al 2020 ). However, whether hUCMSCs@Ex-4 can be applied in the treatment of T1DM has not been addressed and was thus explored in this study.…”

Section: Discussionmentioning

confidence: 99%

hUCMSCs carrying exenatide prevent T1DM by improving intestinal microflora composition and islet tissue damage repair

Wang

Chi

et al. 2022

Mol Med

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Background Exenatide is a stable analogue of glucagon-like peptide 1 that can reduce postprandial hyperglycemia and has been utilized as adjunctive therapy for type 1 diabetes mellitus (T1DM). The human umbilical cord is a rich source of MSCs, and human umbilical cord mesenchymal stem cells (hUCMSCs) also show potential to enhance insulin secretion. Here, we aimed to explore the effects of hUCMSCs carrying exenatide in T1DM and further identify the possible mechanisms involved. Methods hUCMSCs were isolated from human umbilical cord tissues, identified, and transduced with recombinant lentivirus carrying exenatide to obtain exenatide-carrying hUCMSCs (hUCMSCs@Ex-4). Results The results showed that hUCMSCs@Ex-4 restored the blood glucose levels and body weight of NOD mice, and repressed immune cell infiltration and islet tissue changes. Additionally, in T1DM mice, treatment with hUCMSCs@Ex-4 reduced the blood glucose levels and promoted repair of islet tissue damage. Moreover, hUCMSCs@Ex-4 attenuated renal tissue lesions in T1DM mice. Applying bioinformatic analysis, the effects of hUCMSCs@Ex-4 were suggested to correlate with decreased abundance of pro-inflammatory intestinal bacteria and increased abundance of anti-inflammatory intestinal bacteria. Conclusion Overall, the study indicated that hUCMSCs carrying exenatide might improve beneficial intestinal microflora abundance and promote islet tissue damage repair, thereby alleviating T1DM.

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“…The db/db mouse is a genetic model of type II diabetes mellitus and it exhibits the typical features of human Type 2 diabetes mellitus [ 33 - 35 ]. Therefore, these mice were used to investigate the development of diabetic complications including cognitive impairment, vascular endothelial dysfunction, and enhanced ischemia-reperfusion-induced myocardial injury.…”

Section: Discussionmentioning

confidence: 99%

Whole body hypoxic preconditioning-mediated multiorgan protection in db/db mice via nitric oxide-BDNF-GSK-3β-Nrf2 signaling pathway

Huang

Cheng

et al. 2021

Korean J Physiol Pharmacol

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The beneficial effects of hypoxic preconditioning are abolished in the diabetes. The present study was designed to investigate the protective effects and mechanisms of repeated episodes of whole body hypoxic preconditioning (WBHP) in db/db mice. The protective effects of preconditioning were explored on diabetesinduced vascular dysfunction, cognitive impairment and ischemia-reperfusion (IR)-induced increase in myocardial injury. Sixteen-week old db/db (diabetic) and C57BL/6 (non-diabetic) mice were employed. There was a significant impairment in cognitive function (Morris Water Maze test), endothelial function (acetylcholineinduced relaxation in aortic rings) and a significant increase in IR-induced heart injury (Langendorff apparatus) in db/db mice. WBHP stimulus was given by exposing mice to four alternate cycles of low (8%) and normal air O 2 for 10 min each. A single episode of WBHP failed to produce protection; however, two and three episodes of WBHP significantly produced beneficial effects on the heart, brain and blood vessels. There was a significant increase in the levels of brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) in response to 3 episodes of WBHP. Moreover, pretreatment with the BDNF receptor, TrkB antagonist (ANA-12) and NO synthase inhibitor (L-NAME) attenuated the protective effects imparted by three episodes of WBHP. These pharmacological agents abolished WBHP-induced restoration of p-GSK-3/GSK-3 ratio and Nrf2 levels in IR-subjected hearts. It is concluded that repeated episodes of WHBP attenuate cognitive impairment, vascular dysfunction and enhancement in IRinduced myocardial injury in diabetic mice be due to increase in NO and BDNF levels that may eventually activate GSK-3 and Nrf2 signaling pathway to confer protection.

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Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance via PTEN-mediated crosstalk between the PI3K/Akt and Erk/MAPKs signaling pathways in the skeletal muscles of db/db mice

Cited by 24 publications

References 73 publications

Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

hUCMSCs carrying exenatide prevent T1DM by improving intestinal microflora composition and islet tissue damage repair

Whole body hypoxic preconditioning-mediated multiorgan protection in db/db mice via nitric oxide-BDNF-GSK-3β-Nrf2 signaling pathway

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