scholarly journals mTOR Signaling Pathway Regulates Sperm Quality in Older Men

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 629 ◽  
Author(s):  
Silva ◽  
Cabral ◽  
Correia ◽  
Carvalho ◽  
Sousa ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Sperm Quality ◽  
Older Men ◽  
Mtor Signaling ◽  
Paternal Age ◽  
Signaling Proteins ◽  
Mtor Signaling Pathway ◽  
Mtorc1 Signaling ◽  
The Impact

: Understanding how age affects fertility becomes increasingly relevant as couples delay childbearing toward later stages of their lives. While the influence of maternal age on fertility is well established, the impact of paternal age is poorly characterized. Thus, this study aimed to understand the molecular mechanisms responsible for age-dependent decline in spermatozoa quality. To attain it, we evaluated the impact of male age on the activity of signaling proteins in two distinct spermatozoa populations: total spermatozoa fraction and highly motile/viable fraction. In older men, we observed an inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) in the highly viable spermatozoa population. On the contrary, when considering the entire spermatozoa population (including defective/immotile/apoptotic cells) our findings support an active mTORC1 signaling pathway in older men. Additionally, total spermatozoa fractions of older men presented increased levels of apoptotic/stress markers (e.g., cellular tumor antigen p53-TP53) and mitogen-activated protein kinases (MAPKs) activity. Moreover, we established that the levels of most signaling proteins analyzed were consistently and significantly altered in men more than 27 years of age. This study was the first to associate the mTOR signaling pathway with the age impact on spermatozoa quality. Additionally, we constructed a network of the sperm proteins associated with male aging, identifying TP53 as a central player in spermatozoa aging.

scholarly journals Hyperin Alleviates Triptolide-Induced Ovarian Granulosa Cell Injury by Regulating AKT/TSC1/mTORC1 Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Fang You ◽  
Junyan Cao ◽  
Li Cheng ◽  
Xiaogu Liu ◽  
Li Zeng
Keyword(s):  
Signaling Pathway ◽  
Granulosa Cell ◽  
High Performance ◽  
Cell Injury ◽  
Ovarian Function ◽  
Interaction Network ◽  
Mtor Signaling ◽  
Network Pharmacology ◽  
Mtor Signaling Pathway ◽  
Mtorc1 Signaling

Premature ovarian insufficiency (POI) is characterized by the loss of ovarian function before 40 years of age and affects approximately 1% of women worldwide. Caragana sinica is a traditional Miao (a Chinese ethnic minority) medicine that improves ovarian function and follicular development. In the present study, we aimed to investigate the effect of active ingredients of C. sinica on POI and determine underlying mechanisms. Herein, the chemical composition of the C. sinica compound was analyzed using ultra-high-performance liquid chromatography, which identified hyperin (HR) as one of the main ingredients in C. sinica. Then, interaction targets of HR and POI were predicted and analyzed using network pharmacology and bioinformatics. The effect of HR on triptolide (TP)-induced granulosa cell injury was evaluated, and the underlying mechanism was explored based on bioinformatic results. A total of 100 interaction targets for POI and HR were obtained. The protein-protein interaction network of identified interaction targets emphasized the topological importance of AKT1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that HR might regulate POI by modulating the mechanistic target of rapamycin (mTOR) signaling pathway. In addition, the KEGG graph of the mTOR signaling pathway revealed that AKT phosphorylation inhibits the TSC1/2, while TSC1/2 activation inhibits the expression of mTORC1. The fundamental experiment revealed that HR increased proliferation, progesterone receptor levels, and estradiol levels decreased by TP in KGN cells. Additionally, HR alleviated TP-induced apoptosis and G1/G1 phase arrest in KGN cells. Western blotting demonstrated that HR increased the phosphorylation of AKT and mTORC1 and decreased TSC1 expression in TP-induced KGN cells. Collectively, our findings revealed that HR alleviates TP-induced granulosa cell injury by regulating AKT/TSC1/mTORC1 signaling, providing insight into the treatment of POI.

scholarly journals PRDX2 Performs the Oncogenic Functions in Ewing’s Sarcoma

2020 ◽  
Author(s):  
Ruifeng Xue ◽  
Zhengfu Fan ◽  
Yunhe An
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Es Cells ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Strong Basis ◽  
Apoptotic Protein

Abstract Background: Ewing's sarcoma (ES) is the second most common malignant primary bone tumor in children and adolescents, characterized by malignant proliferation of small round cells. The survival rate of this disease continues to be low. Peroxiredoxin2 (PRDX2) is a multifunctional peroxidase family member with anti-oxidation, involvement in intracellular signaling, chaperones, and tumor. But the function and underlying mechanism of PRDX2 in ES is still unknown. Herein we investigated the role and mechanism of PRDX2 in the development of ES, and tested its potential for the treatment of ES.Methods: We explored the function of PRDX2 on ES through knocking down the expression of NKAP in A673 and RDES cells by siRNA interference (siPRDX2). We examined the effects of siPRDX2 on cell motility and apoptosis using CCK8, colony formation, transwell, gelatin zymography, flow cytometry, PI/Hoechst33342 double dye and western blot assays. In addition, western blot was used to analyze the activation of the AKT/mTOR signaling pathway.Results: Here we showed that downregulation of PRDX2 strongly inhibited the motility of A673 and RDES cells. Interestingly, siPRDX2 induced cell apoptosis. Furthermore, the expression of anti-apoptotic protein Bcl2 in siPRDX2 group was significantly decreased, while the expression of pro-apoptotic protein Bax and cleaved Caspase-9 was strongly increased. Finally to identify the molecular mechanisms involved, we examined related proteins of the AKT/mTOR signaling pathway and found that siPRDX2 significantly inhibited the phosphorylation of AKT and the expression of Cyclin D1.Conclusion: These observations suggest that siPRDX2 inhibited the ES cells motility and induced apoptosis in which the AKT/mTOR signaling pathway involved. The enhanced understanding to this molecular mechanism has provided a strong basis for the development of novel therapeutic strategies for ES.

scholarly journals Angiotensin‐(1‐7) Alleviates Autophagy Response Through the PI3K/Akt/mTOR Signaling Pathway in Severe Acute Pancreatitis

2021 ◽  
Author(s):  
Chunyun Li ◽  
Xiaozheng Yu ◽  
Yinan Guo ◽  
Xueyan Wang ◽  
Ruixia Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Signaling Pathway ◽  
Severe Acute Pancreatitis ◽  
Underlying Mechanism ◽  
Mtor Signaling ◽  
Medical Emergency ◽  
Protein Markers ◽  
Mtor Signaling Pathway ◽  
Ar42j Cells ◽  
The Impact

Abstract Background: Severe acute pancreatitis (SAP) is a fatal medical emergency. The autophagy response is essential for cellular homeostasis, and plays an important role in SAP. We aimed to determine if angiotensin‐(1‐7), abbreviated as Ang1‐7, regulates the autophagy response in SAP and to elucidate the underlying mechanism.Methods: We used a rat model to investigate the effects of Ang1-7 on pancreatic pathomorphological damage and the autophagy response, which were evaluated using histological scoring and the quantification of the autophagy markers microtubule-associated protein 1 light chain 3 (LC3) and p62/SQSTM (p62) by western blotting and immunohistochemistry. We treated rat pancreatic acinar AR42J cells with caerulein (CAE) to build an in vitro model. To prevent degradation of the autophagy markers, so that we could determine the increase in autophagic vacuolization, we used chloroquine to inhibit autophagosome and lysosome fusion. The PI3K inhibitor BEZ235 was used to suppress PI3K/Akt/mTOR signaling. We observed the impact of Ang1-7 on the autophagy response and evaluated the underlying mechanism by detecting protein expressions of LC3 and p62.Results: In the rat SAP model, Ang1-7 significantly relieved pancreatic pathological damage. Ang1-7 also reduced autophagy protein markers, including the LC3-Ⅱ to LC3-Ⅰ ratio and the p62 level. In AR42J cells, the autophagy markers significantly increased after treatment with CAE and chloroquine. The autophagy response was significantly alleviated after treatment of the cells with Ang1-7, while blocking the PI3K/Akt/mTOR pathway remarkably counteracted this effect.Conclusions: Our results indicated that Ang1-7 alleviated the autophagy response in SAP via the PI3K/Akt/mTOR signaling pathway.

scholarly journals Hypoxia-Induced Glioma-Derived Exosomal miRNA-199a-3p Promotes Ischemic Injury of Peritumoral Neurons by Inhibiting the mTOR Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Jian-Lan Zhao ◽  
Bo Tan ◽  
Gong Chen ◽  
Xiao-Ming Che ◽  
Zhuo-Ying Du ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Ischemic Injury ◽  
Neuronal Injury ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
C6 Glioma Cells ◽  
Mtor Signaling Pathway ◽  
Exosomal Mirna

The underlying molecular mechanisms that the hypoxic microenvironment could aggravate neuronal injury are still not clear. In this study, we hypothesized that the exosomes, exosomal miRNAs, and the mTOR signaling pathway might be involved in hypoxic peritumoral neuronal injury in glioma. Multimodal radiological images, HE, and HIF-1α staining of high-grade glioma (HGG) samples revealed that the peritumoral hypoxic area overlapped with the cytotoxic edema region and directly contacted with normal neurons. In either direct or indirect coculture system, hypoxia could promote normal mouse hippocampal neuronal cell (HT22) injury, and the growth of HT22 cells was suppressed by C6 glioma cells under hypoxic condition. For administrating hypoxia-induced glioma-derived exosomes (HIGDE) that could aggravate oxygen-glucose deprivation (OGD)/reperfusion neuronal injury, we identified that exosomes may be the communication medium between glioma cells and peritumoral neurons, and we furtherly found that exosomal miR-199a-3p mediated the OGD/reperfusion neuronal injury process by suppressing the mTOR signaling pathway. Moreover, the upregulation of miRNA-199a-3p in exosomes from glioma cells was induced by hypoxia-related HIF-1α activation. To sum up, hypoxia-induced glioma-derived exosomal miRNA-199a-3p can be upregulated by the activation of HIF-1α and is able to increase the ischemic injury of peritumoral neurons by inhibiting the mTOR pathway.

scholarly journals STYX/FBXW7 axis participates in the development of endometrial cancer cell via Notch–mTOR signaling pathway

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Liheng Liu ◽  
Haili Jiang ◽  
Xiaoxin Wang ◽  
Xin Wang ◽  
Liying Zou
Keyword(s):  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Notch Pathway ◽  
Mtor Signaling ◽  
Expression Level ◽  
Mtor Signaling Pathway ◽  
Ec Cells ◽  
The Impact

Abstract Endometrial cancer (EC) is the most common gynecologic malignancy in world. It has been reported that the mutation rate of FBXW7 is frequent in EC, but the specific functions of FBXW7 remain unknown in EC. In the present study, we revealed the role and mechanism of FBXW7 in EC cells. Compared with adjacent nontumor tissues, the FBXW7 expression level was lower in EC tissues. However, the level of STYX was in contrast with the expression of FBXW7 in EC tissues. And STYX interacted with FBXW7 and then down-regulated its expression level in EC. Over-expression of FBXW7 inhibited cell proliferation and facilitated apoptosis in EC cells, whereas silencing FBXW7 acted an opposite effect on EC cells. And the process of FBXW7 participated the proliferation and apoptosis in EC was regulated by STYX. FBXW7 suppressed the expression of Notch pathway related protein, and further inhibited the phosphorylation of mTOR. In addition, we also found that mTOR activitor (MHY1485) and Notch activator (Jagged-1) reversed the effect of over-expressing FBXW7 on cell proliferation and cell apoptosis. And Notch inhibitor (DAPT) counteracted the impact of over-expressing STYX on cell proliferation and cell apoptosis. Collectively, the present study verified that STYX inhibited the expression level of FBXW7 in EC, and then promoted cell proliferation but suppressed apoptosis through Notch–mTOR signaling pathway, which promoted carcinogenesis and progression of EC.

scholarly journals mTORC1 Signaling Pathway Mediated SIRT6 Overexpression in TGF-β1-Induced Pulmonary Fibrosis

2021 ◽  
Author(s):  
Ji Zhang ◽  
Yi Hu ◽  
Huiping Huang ◽  
Qun Liu ◽  
Yang Du ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Critical Role ◽  
Mtor Signaling ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Mtor Signaling Pathway ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Tgf Β1

Abstract Fibroblast-to-myofibroblast transdifferentiation and myofibroblast hyperproliferation play a major role in Idiopathic pulmonary fibrosis (IPF). It was also reported that mTOR signaling pathway and SIRT6 have a critical role in pulmonary fibrosis. However, the mechanisms whether mTOR signaling pathway and SIRT6 affect the myofibroblasts differentiation in IPF remain unclear. The results show that SIRT6 is significantly upregulated by TGF-β1 with a time and concentration-dependent manner in MRC5 line and primary lung fibroblasts isolated from IPF patients. SIRT6 protein is also increased in IPF fibrotic lung tissues and bleomycin-challenged mice lung tissues. Also, the activity of mTOR signaling is activated in MRC5 and primary lung fibroblasts. Furthermore, the inhibitor of mTOR, rapamycin treatment significantly suppress mTORC1 pathway activity and SIRT6 protein expression. SIRT6 siRNA failed to mediate the activity of mTORC1 pathway and autophagy induction. Finally, deficiency of SIRT6 could promote TGF-β1 induced pro-fibrotic cytokines. In summary, the study have suggested that SIRT6 is a downstream of mTORC1 signaling pathway in the pulmonary fibrosis caused by TGF-β1-induced. Deficiency of SIRT6 mediated myofibroblasts differentiation through induced pro-fibrotic cytokines production but not induced-autophagy. It was indicated that manipulations of SIRT6 expression may provide a new therapeutic strategy to reverse the progression of pulmonary fibrosis.

scholarly journals Shikonin suppresses proliferation and induces apoptosis in endometrioid endometrial cancer cells via modulating miR-106b/PTEN/AKT/mTOR signaling pathway

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Caimei Huang ◽  
Guohua Hu
Keyword(s):  
Endometrial Cancer ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mtor Signaling ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Mtor Signaling Pathway ◽  
Chinese Medicinal Herb ◽  
Anticancer Effects ◽  
Endometrioid Endometrial Cancer

Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicinal herb, which exerts anticancer effects in various cancers. However, the molecular mechanisms underlying the therapeutic effects of shikonin against endometrioid endometrial cancer (EEC) have not yet been fully elucidated. Herein, we investigated anticancer effects of shikonin on EEC cells and explored the underlying molecular mechanism. We observed that shikonin inhibits proliferation in human EEC cell lines in a dose-dependent manner. Moreover, shikonin-induced apoptosis was characterized by the up-regulation of the pro-apoptotic proteins cleaved-Caspase-3 and Bax, and the down-regulation of the anti-apoptotic protein Bcl-2. Microarray analyses demonstrated that shikonin induces many miRNAs’ dysregulation, and miR-106b was one of the miRNAs being most significantly down-regulated. miR-106b was identified to exert procancer effect in various cancers, but in EEC remains unclear. We first confirmed that miR-106b is up-regulated in EEC tissues and cells, and knockdown of miR-106b suppresses proliferation and promotes apoptosis. Meanwhile, our results validated that the restored expression of miR-106b abrogates the antiproliferative and pro-apoptotic effects of shikonin. We also identified that miR-106b targets phosphatase and tensin homolog (PTEN), a tumor suppressor gene, which in turn modulates AKT/mTOR signaling pathway. Our findings indicated that shikonin inhibits proliferation and promotes apoptosis in human EEC cells by modulating the miR-106b/PTEN/AKT/mTOR signaling pathway, suggesting shikonin could act a potential therapeutic agent in the EEC treatment.

UPF1 Impacts on mTOR Signaling Pathway and Autophagy in Endometrioid Endometrial Carcinoma

2020 ◽  
Author(s):  
Minfen Zhang ◽  
Hui Chen ◽  
Ping Qin ◽  
Tonghui Cai ◽  
Lingjun Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

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