Bone marrow mesenchymal stem cells conditioned medium protects VSC4.1 cells against 2,5-hexanedione-induced autophagy via NGF-PI3K/Akt/mTOR signaling pathway

Zhang, Xin; Kong, Ying; Sun, Yijie; Qian, Zhiqiang; Gao, Chenxue; Shi, Xiaoxia; Li, Shuangyue; Piao, Yongjun; Piao, Fengyuan

doi:10.1016/j.brainres.2018.04.028

Cited by 12 publications

(10 citation statements)

References 23 publications

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“…This fact could be related to that these patients have less activity of PI3K/Akt/mTOR, because they have lost the ability to react to the aggression and they have damage that makes them enter apoptosis. In contrast, young patients with venous reflux have greater expression, which could be related according to some authors [ 12 , 48 , 49 ] with possible cellular senescence and autophagy process. Young patients with venous reflux have a greater ability to react to the cell damage that occurs.…”

Section: Discussionmentioning

confidence: 96%

Implication of the PI3K/Akt/mTOR Pathway in the Process of Incompetent Valves in Patients with Chronic Venous Insufficiency and the Relationship with Aging

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Asúnsolo

Leal

et al. 2018

Oxidative Medicine and Cellular Longevity

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Chronic venous insufficiency (CVI) is a multifactorial disease, commonly caused by valvular incompetence (clinically diagnosed by venous reflux) and venous hypertension. The incidence of these factors clearly increases with patient age, and aging is one of the risk factors involved. The activity of the PI3K/Akt/mTOR pathway is considered fundamental in vascular pathologies, and understanding its involvement would help in the development of possible therapeutic targets. This is an observational, analytical, and prospective cohort study that reviewed 110 patients with CVI scheduled to undergo stratified saphenectomy. They were distributed according to the presence (R = 81) or absence (NR = 29) of valvular incompetence (venous reflux) diagnosed clinically. Each of the groups was further divided according to age, with a cutoff point of 50 years (NR < 50 = 13, NR ≥ 50 = 16, R < 50 = 32, and R ≥ 50 = 49). The involvement of the PI3K/Akt/mTOR pathway, as well as that of HIF-1α and HIF-2α and of CD4+, CD8+, and CD19+ cells and mastocytes, was assessed. Saphenous vein tissue samples obtained during surgery were processed for RT-qPCR and immunohistochemistry. Patients with venous reflux showed a significant increase in mRNA and protein expression levels for PI3K/mTOR and HIF-1α/HIF-2α. The number of mast cells was significantly elevated in the R group. In distribution by age, PI3K/Akt/mTOR and HIF-1α were significantly higher in R < 50 patients. Furthermore, these patients had a significant increase in the number of CD4+, CD8+, and CD19+ cells and mastocytes in the saphenous vein wall. These findings provide a basis for the possible existence of changes in PI3K/Akt/mTOR pathway expression in young patients, with potential accelerated asynchronous aging that is enhanced by CVI.

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Section: Discussionmentioning

confidence: 96%

Implication of the PI3K/Akt/mTOR Pathway in the Process of Incompetent Valves in Patients with Chronic Venous Insufficiency and the Relationship with Aging

Ortega

Asúnsolo

Leal

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…Nerve growth factor (NGF), as a secretory neutrophin functioning in a paracrine manner, could be a crucial factor involved in BMSCs' protective effect against HD-induced damage. Several studies by us [21,24,34] and others [35,36] have shown that the remyelination-promoting effect of BMSCs appeared to be closely related with NGF. Therefore, we further tested whether there be any potential linkage between NGF secretion and TNFα production.…”

Section: Inhibition Of Tnfα Production Is Related With Ngf Secretion From Bmscsmentioning

confidence: 96%

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

Guan

Zhang³

et al. 2021

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Background: N-hexane, with its metabolite 2,5-hexanedine (HD), is a hazardous material widely used in industry and chronic exposure causes nerve demyelination. Demyelinating conditions are difficult to treat and frequently cause disabilities. Stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted significant recovery of motor dysfunction in rats modelling N-hexane neurotoxicity. The present study aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods: Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). BMSCs (5×107cells/kg) were administrated by tail vein injection. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD +/- BMSCs-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and quantitative imaging analysis. The expressional changes of Hes1, a key transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied and some key signaling molecules in these pathways were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA test and performed using SPSS 13.0. Results: The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent on Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression and BMSCs was found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions: Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.

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“… 7 It is one of two complexes regulating autophagy and is the major inhibitory signal of autophagy. 8 Its mechanism is to phosphorylate autophagy-related protein 13 (ATG13), preventing its binding with ATG1 to form the autophagosome. 6 It can also promote adhesion of the ribosome to the endoplasmic reticulum to suppress endoplasmic reticulum detachment and form the autophagosome membrane.…”

Section: Introductionmentioning

confidence: 99%

“… 6 It can also promote adhesion of the ribosome to the endoplasmic reticulum to suppress endoplasmic reticulum detachment and form the autophagosome membrane. 8 The PI3K/AKT cell survival signaling pathway is one of two upstream pathways regulating mTOR. Suppression of PI3K can greatly block the downstream signaling pathways AKT and mTOR.…”

Section: Introductionmentioning

confidence: 99%

The PI3K/AKT/mTOR pathway regulates autophagy to induce apoptosis of alveolar epithelial cells in chronic obstructive pulmonary disease caused by PM2.5 particulate matter

Zhang

Wang

et al. 2020

J Int Med Res

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Objective Many lung diseases are associated with changes in autophagic activity. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a key regulatory role in autophagy. Our aim was to explore the function of PI3K/AKT/mTOR pathway on autophagy in chronic obstructive pulmonary disease (COPD) caused by particulate matter with a diameter <2.5 µm (PM2.5). Methods Male C57BL/6 mice were randomly divided into sham, model, and PI3K inhibitor groups. Mice were exposed to PM2.5 for 4 weeks to establish an in vivo COPD model. Alveolar epithelial cells were stimulated with PM2.5 to establish an in vitro COPD model. Results In mice with COPD induced by PM2.5, the PI3K inhibitor PF-04979064 suppressed protein expression of PI3K, p-AKT, and p-mTOR to increase apoptosis of alveolar epithelial cells and reduce autophagy. Short interfering PI3K suppressed the PI3K/AKT/mTOR pathway to induce apoptosis and reduce autophagy of alveolar epithelial cells in an in vitro model of COPD. Activation of PI3K induced the PI3K/AKT/mTOR pathway to reduce apoptosis of alveolar epithelial cells in the in vitro model of COPD by promoting autophagy. Conclusions These data demonstrate that PI3K/AKT/mTOR pathway regulates autophagy to induce apoptosis of alveolar epithelial cells in COPD.

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Bone marrow mesenchymal stem cells conditioned medium protects VSC4.1 cells against 2,5-hexanedione-induced autophagy via NGF-PI3K/Akt/mTOR signaling pathway

Cited by 12 publications

References 23 publications

Implication of the PI3K/Akt/mTOR Pathway in the Process of Incompetent Valves in Patients with Chronic Venous Insufficiency and the Relationship with Aging

Implication of the PI3K/Akt/mTOR Pathway in the Process of Incompetent Valves in Patients with Chronic Venous Insufficiency and the Relationship with Aging

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

The PI3K/AKT/mTOR pathway regulates autophagy to induce apoptosis of alveolar epithelial cells in chronic obstructive pulmonary disease caused by PM2.5 particulate matter

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