scholarly journals miRNA‑214 suppresses oxidative stress in diabetic nephropathy via the ROS/Akt/mTOR signaling pathway and uncoupling protein 2

2019 ◽  
Author(s):  
Shufang Yang ◽  
Xiaoqiang Fei ◽  
Yu Lu ◽  
Bangkui Xu ◽  
Yongmei Ma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Uncoupling Protein ◽  
Mtor Signaling ◽  
Uncoupling Protein 2 ◽  
Mtor Signaling Pathway

scholarly journals Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy

2019 ◽  
Author(s):  
Liming Guo ◽  
Kuibi Tan ◽  
Qun Luo ◽  
Xu Bai
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Rat Model ◽  
Interstitial Fibrosis ◽  
Mtor Signaling ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Mtor Signaling Pathway ◽  
Renal Interstitial Fibrosis ◽  
Gene Assay

Diabetic nephropathy (DN) is the most common complication of diabetes and is prone to kidney failure. Dihydromyricetin (DHM) has been reported to have a variety of pharmacological activities. This study aims to explore the effect of DHM on DN and the underlying molecular mechanism. An in vivo DN rat model was established. The degree of renal interstitial fibrosis (RIF) was detected by hematoxylin-eosin (HE) staining, Masson's trichrome staining, and immunohistochemistry (IHC). In vitro, NRK-52E cells were divided into four groups: normal glucose (NG), high glucose (HG), HG+DHM, and HG+rapamycin (autophagy inhibitor). The levels of autophagy- and fibrosis-related proteins were analyzed by western blotting. The expression of miR-155-5p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and their relationship were assessed by quantitative reverse transcription (qRT)-PCR and dual luciferase reporter gene assay. Our results showed that RIF was increased in DN rat model and in HG-induced NRK-52E cells. DHM treatment attenuated the increased RIF and also increased autophagy. MiR-155-5p expression was increased, while PTEN expression was decreased in DN rat and cell model, and DHM reversed both effects. Dual luciferase assay showed that PTEN was the target gene of miR-155-5p. DHM inhibited HG-induced fibrosis and promoted autophagy by inhibiting miR-155-5p expression in NRK-52E cells. In addition, DHM promoted autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, DHM promotes autophagy and attenuates RIF by regulating the miR-155-5p/PTEN signaling and PI3K/AKT/mTOR signaling pathway in DN.

scholarly journals NOX2-Derived Hydrogen Peroxide Impedes the AMPK/Akt-mTOR Signaling Pathway in Parkinson's Disease in Vitro Models

2021 ◽  
Author(s):  
Ruijie Zhang ◽  
Nana Zhang ◽  
Xiaoqing Dong ◽  
Xin Chen ◽  
Jing Ma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Hydrogen Peroxide ◽  
Parkinson's Disease ◽  
Signaling Pathway ◽  
Neuronal Apoptosis ◽  
Mtor Signaling ◽  
Regulatory Proteins ◽  
Mtor Signaling Pathway ◽  
Compound C

Abstract Oxidative stress is closely related to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. NADPH oxidase 2 (NOX2) is involved in hydrogen peroxide (H2O2) generation. Recently, we have reported that H2O2 and PD toxins, including 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenylpyridin-1-ium (MPP+) and rotenone, induce neuronal apoptosis by inhibiting mTOR pathway. Here, we show that 6-OHDA, MPP+ or rotenone induced H2O2 generation by upregulation of NOX2 and its regulatory proteins (p22phox, p40phox, p47phox, p67phox, and Rac1), leading to apoptotic cell death in PC12 cells and primary neurons. Pretreatment with catalase, a H2O2-scavenging enzyme, significantly blocked PD toxins-evoked NOX2-derived H2O2, thereby hindering activation of AMPK, inhibition of Akt/mTOR, induction of apoptosis in neuronal cells. Similar events were also seen in the cells pretreated with Mito-TEMPO, a mitochondria-specific superoxide scavenger, implying a mitochondrial H2O2-dependent mechanism involved. Further research revealed that inhibiting NOX2 with apocynin or silencing NOX2 attenuated the effects of PD toxins on AMPK/Akt/mTOR and apoptosis in the cells. Of importance, ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPK with compound C suppressed PD toxins-induced expression of NOX2 and its regulatory proteins, as well as consequential H2O2 and apoptosis in the cells. Taken together, these results indicate that certain PD toxins can impede the AMPK/Akt-mTOR signaling pathway leading to neuronal apoptosis by eliciting NOX2-derived H2O2. Our findings suggest that neuronal loss in PD may be prevented by regulating of NOX2, AMPK/Akt-mTOR signaling and/or administering antioxidants to ameliorate oxidative stress.

scholarly journals Catalpol protects rat ovarian granulosa cells against oxidative stress and apoptosis through modulating the PI3K/Akt/mTOR signaling pathway

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Jin Yan ◽  
Disi Deng ◽  
Yeke Wu ◽  
Keming Wu ◽  
Jie Qu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Follicular Development ◽  
Oxidative Injury ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Inhibitory Effects ◽  
Caspase 9 ◽  
Antioxidative Stress

Abstract Disrupted follicular development may result in increased follicular atresia, which is a crucial mechanism of various ovarian pathologies. It has been demonstrated that oxidative stress is associated with disrupted follicular development. Catalpol is a natural compound that has been found to possess antioxidative stress. However, the effects of catalpol on oxidative stress-induced disrupted follicular development remain unclear. In the present study, we evaluated the protective effect of catalpol on hydrogen peroxide (H2O2)-induced oxidative damage in granulosa cells (GCs), which play crucial roles in the follicular development. Our results showed that catalpol significantly improved cell viability, reduced reactive oxygen species (ROS) and malondialdehyde (MDA) production, and elevated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in H2O2-induced GCs. Catalpol treatment caused significant increase in bcl-2 expression, and decreases in bax and caspase-9 expressions. Compared with the H2O2-induced GCs, caspase-3 activity in catalpol-treated cells was markedly decreased. Furthermore, catalpol caused significant activation of PI3K/Akt/mTOR pathway in GCs in response to H2O2 stimulation. Additionally, inhibition of this pathway reversed the inhibitory effects of catalpol on H2O2-induced oxidative injury and apoptosis in GCs. In conclusion, these findings suggested that catalpol protected GCs from H2O2-induced oxidative injury and apoptosis via activating PI3K/Akt/mTOR signaling pathway. Thus, catalpol might serve as a therapeutic approach for regulating disrupted follicular development.

IL‐8 protects prostate cancer cells from GSK‐3β‐induced oxidative stress by activating the mTOR signaling pathway

The Prostate ◽  
2019 ◽  
Vol 79 (10) ◽  
pp. 1180-1190 ◽  
Author(s):  
Yi Sun ◽  
Jian‐Zhong Ai ◽  
Xi Jin ◽  
Liang‐Ren Liu ◽  
Tian‐Hai Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Prostate Cancer Cells ◽  
Gsk 3Β

scholarly journals LncRNA Hoxb3os protects podocytes from high glucose-induced cell injury through autophagy dependent on the Akt-mTOR signaling pathway

2021 ◽  
Author(s):  
Juan Jin ◽  
Jianguang Gong ◽  
Li Zhao ◽  
Yiwen Li ◽  
Qiang He
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
High Glucose ◽  
Cell Injury ◽  
Damage Model ◽  
Mtor Signaling ◽  
Cell Counting ◽  
Tunel Staining ◽  
Mtor Signaling Pathway ◽  
Potential Biomarker

Background: Diabetic nephropathy (DN) is in the first place of the causes that lead to end-stage renal disease in the world. Thus, it is urgent to develop a novel diagnostic or therapeutic strategy that could stop the progression of diabetic nephropathy. Methods: RNA-sequencing was conducted in high glucose (HG)-treated MPC5 cells (podocytes). Cell morphology was examined under a light microscope. Upon high-glucose challenge, the effects of lncRNA Hoxb3os overexpression on MPC5 cells apoptosis, viability, autophagy and Akt-mTOR signaling were evaluated using flow cytometry, Cell Counting Kit-8, qRT-PCR, and Western blotting. TUNEL staining and ELISA were performed to confirm the establishment of DN model in db/db mice. Results: High-glucose exposure dramatically altered lncRNA expression profile in MPC5 cells (fold change>2), including 305 upregulated lncRNAs and 451 downregulated lncRNAs. LncRNA Hoxb3os expression was significantly reduced in the HG-induced podocyte damage model, as well as in the renal tissues from db/db mice with spontaneous DN. Overexpression of Hoxb3os significantly reduced the apoptosis rate and increased the viability of MPC5 cells under HG conditions. Further study revealed that exogenous Hoxb3os increased autophagy level in HG-exposed MPC5 cells via abrogating Akt-mTOR signaling pathway and that the process was possibly implicated in the upregulation of SIRT1. Conclusion: LncRNA Hoxb3os protected podocytes from HG-induced damage by regulating Akt-mTOR pathway and cell autophagy. Thus, lncRNA Hoxb3os appears as a potential biomarker in the diagnosis and treatment of DN in the future.

Regulation of Erythroid Cell Maturation Is Mediated by a Foxo3-mTOR Cross Talk: Outcome for Beta-Thalassemic Erythropoiesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 176-176
Author(s):  
Xin Zhang ◽  
Valentina D'Escamard ◽  
Pauline Rimmele ◽  
Saghi Ghaffari
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Cell Maturation ◽  
Erythroid Cell ◽  
Beta Thalassemia ◽  
Erythroid Cells ◽  
Mtor Signaling Pathway ◽  
Erythroid Precursors

Abstract Abstract 176 Differentiation of erythroid progenitors to mature red blood cells requires erythropoietin receptor (EpoR) signaling. Stimulation of EpoR results in Jak2-mediated activation of mainly AKT, ERK/MAPK and STAT5 signaling pathways. Although alteration of these pathways is involved with the pathophysiology of major erythroid disorders such as beta-thalassemia mechanisms by which these signals impact transcriptional programs of erythroid cell maturation are largely unknown. We have shown previously that AKT signaling is required for Epo-mediated erythroid cell maturation and identified Foxo3 transcription factor, that is negatively regulated by AKT, as a critical regulator of erythroid cell cycle, maturation and lifespan mostly through the control of oxidative stress (Marinkovic et al., JCI, 2007). In addition to Foxo3, AKT regulates several proteins including the mammalian target of rapamycin (mTOR). Here we asked how Foxo3 regulation of oxidative stress impacts erythroid cell maturation. We found that AKT/mTOR signaling pathway is constitutively activated, possibly as part of a feedback loop, in primary Foxo3−/− erythroid precursors. In addition, Epo stimulation of primary Foxo3−/− erythroid precursors led to hyperphosphorylation of Jak2, AKT, mTOR and its target p70S6 Kinase (S6K) as compared to control cells. Since Foxo3 controls levels of reactive oxygen species (ROS) in erythroid cells, and ROS are known to modify signaling proteins, we asked whether ROS are involved in the hyperactivation of AKT/mTOR signaling pathway in Foxo3−/− erythroid precursors. Combined in vivo and in vitro treatment of Foxo3−/− erythroid precursors with ROS scavenger N-Acetyl-Cysteine (NAC) reduced significantly the hyper-phosphorylation of AKT, mTOR and S6K in response to Epo. These results strongly suggest that ROS mediate the hyperactivation of AKT/mTOR signaling pathway in Foxo3−/− erythroid precursors. Next we addressed whether the imbalanced production versus maturation of Foxo3−/− erythroid precursors (Marinkovic et al., JCI, 2007) is due to the constitutive activation of AKT/mTOR signaling. This was indeed the case since in vivo treatment of Foxo3−/− mice for three weeks with the mTOR inhibitor rapamycin shifted the balance from immature towards mature erythroid cells. Interestingly while rapamycin treatment decreased cycling of Foxo3−/− erythroid progenitors as anticipated, it resulted in highly increased proliferation of Foxo3−/− mature erythroblasts as analyzed by in vivo BrdU assay. Importantly, the described Foxo3−/− erythroid phenotype was maintained on two distinct genetic backgrounds (C57BL/6 and BALB/c) in mice. These results strongly suggest that the oxidative stress-induced activation of mTOR signaling pathway mediates the imbalanced production of mature erythroid cells in Foxo3−/− mice. Given that both oxidative stress and delayed erythroid cell differentiation as seen in Foxo3−/−erythroid precursors, contribute significantly to beta-thalassemia, we asked whether the mTOR signaling is involved in the pathogenesis of this disease. Rapamycin treatment improved erythroid cell maturation in the bone marrow as analyzed by cell size, CD44, TER 119 and CD71 surface markers, and resulted in significant increase in total peripheral blood red cells and hemoglobin (1 to 1.5 g/dl increase), significant reduction in reticulocyte production as well as decrease in the spleen size of beta-thalassemic intermedia (th3/+) mice similar to what was seen in Foxo3−/− mice. Collectively these results indicate an important function for the Foxo3-mTOR cross talk in the regulation of erythroid cell maturation and suggest that rapamycin may be considered for treatment of beta-thalassemia. Disclosures: No relevant conflicts of interest to declare.

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