S-Equol Protects Chondrocytes against Sodium Nitroprusside-Caused Matrix Loss and Apoptosis through Activating PI3K/Akt Pathway.
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ABSTRACT:
SUBMITTER: Huang LW
PROVIDER: S-EPMC8268809 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIcariin (ICA) is one of the major active flavonoids extracted from the traditional Chinese herb Epimedium brevicornum Maxim and has been shown to have neuroprotective effects. This study was designed to investigate the effect of ICA on sodium azide (NaN3)-induced rat adrenal pheochromocytoma (PC12) cell damage and to further examine the underlying mechanisms.MethodsTo explore its possible mechanism, we used NaN3 (50 mM)-induced neuronal PC12 cell damage. Cell viability was evaluated by CCK-8 and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (MMP) was detected by JC-1. Glucose concentration was assessed by the glucose oxidase method. The role of ICA in the PI3K/Akt/GSK-3? signaling pathway was explored by Western blotting.ResultsThe results indicate that pretreatment with ICA reduced NaN3-induced cell damage and significantly reduced the leakage rate of LDH in PC12 cells. ICA pretreatment increased the MMP and a decrease in glucose concentration indicate increased glucose consumption. Furthermore, the protein levels of p-PI3K (p85), PI3K-110?, p-Ser473-Akt and p-Ser9-GSK-3? were markedly decreased in PC12 cells after NaN3 treatment for 24 h, whereas these effects were reverted after pretreatment with ICA. Tau phosphorylation at the Ser396/404 and Thr217 sites was significantly decreased by pretreatment with ICA.ConclusionsThese results suggest that ICA protects against NaN3-induced neurotoxicity in PC12 cells by activating the PI3K/Akt/GSK-3? signaling pathway.
| S-EPMC7179568 | biostudies-literature
Project description:The chronic overexpression of matrix metalloproteases leading to consequent degradation and loss of the elastic matrix with the reduction in tissue elasticity is central to the pathophysiology of proteolytic disorders, such as abdominal aortic aneurysms (AAAs), which are localized rupture-prone aortic expansions. Effecting tissue repair to alleviate this condition is contingent on restoring elastic matrix homeostasis in the aortic wall. This is naturally irreversible due to the poor elastogenicity of adult and diseased vascular cells, and the impaired ability to assemble mature elastic fibers, more so in the context of phenotypic changes to medial smooth muscle cells (SMCs) owing to the loss of nitric oxide (NO) signaling in the AAA wall tissue. In this study, we report the benefits of the exposure of primary human aneurysmal SMCs (aHASMCs) to NO donor drug, sodium nitroprusside (SNP), in improving extracellular matrix homeostasis, particularly aspects of elastic fiber assembly, and inhibition of proteolytic degradation. SNP treatment (100 nM) upregulated elastic matrix regeneration at both gene (p < 0.05) and protein levels (p < 0.01) without affecting cell proliferation, improved gene, and protein expression of crosslinking enzyme, lysyl oxidase (p < 0.05), inhibited the expression of MMP2 (matrix metalloprotease 2) significantly (p < 0.05) and promoted contractile SMC phenotypes in aHASMC culture. In addition, SNP also attenuated the expression of mitogen-activated protein kinases, a significant player in AAA formation and progression. Our results indicate the promise of SNP for therapeutic augmentation of elastic matrix regeneration, with prospects for wall repair in AAAs. Impact Statement Chronic and naturally irreversible enzymatic degradation and loss of elastic fibers are centric to proteolytic disorders such as abdominal aortic aneurysms (AAAs). This is linked to poor elastogenicity of adult and diseased vascular cells, compromising their ability to assemble mature elastic fibers. Toward addressing this, we demonstrate the phenotype-modulatory properties of a nitric oxide donor drug, sodium nitroprusside on aneurysmal smooth muscle cells, and its dose-specific proelastogenic and antiproteolytic properties for restoring elastic matrix homeostasis. Combined with the development of vehicles for site-localized, controlled drug delivery, this can potentially lead to a new nonsurgical approach for AAA wall repair in the future.
| S-EPMC10122248 | biostudies-literature
Project description:Our pilot studies have shown that clemastine fumarate (CLE) can protect against myocardial ischemia-reperfusion injury (MIRI) through regulation of toll like receptor 4 (TLR4). However, the protective mechanism of CLE and related signaling pathways for MIRI remains unclear. The objective of this study is to determine the mechanism by which CLE relieves MIRI in cardiomyocytes and its relationship with the TLR4/PI3K/Akt signaling pathway. CCK8 analysis was used to test the optimal concentration of TLR4 inhibitor CLI-095 and TLR4 agonist lipopolysaccharide (LPS) on MIRI. The expression of inflammatory factors, oxidative stress response, cell damage, and intracellular calcium redistribution of cardiomyocytes were examined using the ELISA kits, Total Superoxide Dismutase Assay Kit with WST-8 and Lipid Peroxidation MDA Assay Kit, LDH Cytotoxicity Assay Kit, and laser scanning confocal microscope. The expression of TLR4/PI3K/Akt and cleaved caspase-3 were determined by Western blotting and immunofluorescent staining. Our results showed that MIRI aggravated the inflammatory response, oxidative stress, cellular damage of cardiomyocytes, and caused redistribution of intracellular calcium, upregulated the expression of TLR4 protein, cleaved caspase-3 protein, and down-regulated the expression of PI3K/Akt protein. After treatment with CLE, the inflammatory response, oxidative stress, and cellular damage of cardiomyocytes were alleviated, and intracellular calcium ion accumulation decreased. The expression of TLR4 protein, cleaved caspase-3 protein declined, but PI3K/Akt protein expression increased in cardiomyocytes treated with CLE. In addition, after treatment with the TLR4 inhibitor CLI-095, the results were similar to those of CLE treatment. The TLR4 agonist LPS aggravated the reactions caused by MIRI. The role of LPS was reversed after CLE treatment. These results suggested that CLE can attenuate MIRI by activating the TLR4/PI3K/Akt signaling pathway.
| S-EPMC7025565 | biostudies-literature
Project description:BackgroundPaeonia lactiflora Pall. (PLP), a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by activating NF-E2-related factor 2 (Nrf2) via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.Materials and methodsLiquid chromatography-mass spectrometry (LC-MS) was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bile acid (TBA) were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed. In addition, validation of PLP putative target network was also performed in silico.ResultsFour major compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were identified by LC-MS analysis in water extract of PLP. Moreover, PLP could remarkably downregulate serum levels of TBIL, DBIL, AST, ALT, ALP, γ-GT, and TBA, and alleviate the histological damage of liver tissue caused by ANIT. It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression. The putative targets network validation also confirmed the important role of PLP in activating Akt expression.ConclusionThe potential mechanism of PLP in alleviating ANIT-induced cholestasis could to be related to the induction of GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. This indicates that PLP might be a potential therapeutic agent for cholestasis.
| S-EPMC4562737 | biostudies-literature
Project description:Osteoarthritis (OA) is a degenerative joint disorder causing pain and functional disability. Emerging evidence reveals that circular RNAs (circRNAs) play essential roles in OA progression and development. This study aimed to investigate the role of a novel circRNA factor, circFOXO3, in the progression of OA and elucidate its underlying molecular mechanism. The function of circFOXO3 in OA and interaction between circFOXO3 and its downstream mRNA target, forkhead box O3 (FOXO3), were evaluated by western blot (WB), immunofluorescence (IF), RNA immunoprecipitation, reverse transcription-quantitative PCR (RT-qPCR), and fluorescence in situ hybridization (FISH). Upregulation of circFOXO3 and autophagic flux were detected both in vivo and in vitro by WB, transmission electron microscopy (TEM), IF, and immunohistochemistry (IHC). A mouse model of OA was also used to confirm the role of circFOXO3 in OA pathogenesis in vivo. Decreased expression of circFOXO3 in OA cartilage tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of the extracellular matrix (ECM). Mechanistically, circFOXO3 functioned in cartilage by targeting its parental gene FOXO3 and activating autophagy. Intra-articular injection of lentivirus-circFOXO3 alleviated OA in the mouse model. In conclusion, our results reveal the key role played by circFOXO3 in OA progression; circFOXO3 overexpression may alleviate apoptosis of chondrocytes and promote anabolism of the ECM via activation of FOXO3 and autophagy, providing a potentially effective novel therapeutic strategy for OA.
| S-EPMC9640610 | biostudies-literature
Project description:Osteoporosis bears an imbalance between bone formation and resorption, which is strongly related to oxidative stress. The function of leonurine on bone marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress is still unclear. Therefore, this study was aimed at identifying the protective effect of leonurine on H2O2 stimulated rat BMSCs. We found that leonurine can alleviate cell apoptosis and promote the differentiation ability of rat BMSCs induced by oxidative stress at an appropriate concentration at 10 μM. Meanwhile, the intracellular ROS level and the level of the COX2 and NOX4 mRNA decreased after leonurine treatment in vitro. The ATP level and mitochondrial membrane potential were upregulated after leonurine treatment. The protein level of PINK1 and Parkin showed the same trend. The mitophage in rat BMSCs blocked by 3-MA was partially rescued by leonurine. Bioinformatics analysis and leonurine-protein coupling provides a strong direct combination between leonurine and the PI3K protein at the position of Asp841, Glu880, Val882. In conclusion, leonurine protects the proliferation and differentiation of BMSCs from oxidative stress by activating mitophagy, which depends on the PI3K/Akt/mTOR pathway. The results showed that leonurine may have potential usage in osteoporosis and bone defect repair in osteoporosis patients.
| S-EPMC9179429 | biostudies-literature
Project description:FOXC1 is a member of Forkhead box family transcription factors. We showed that FOXC1 level was increased in melanoma cells and tissues and correlated with hypomethylation of the FOXC1 gene. Overexpression of FOXC1 promoted proliferation, migration, invasion, colony formation and growth in 3D Matrigel of melanoma cells. FOXC1 increased MST1R and activated the PI3K/AKT pathway. Also, FOXC1 expression was associated with disease progression and poor prognosis of melanoma. We suggest that FOXC1 is a potential prognostic biomarker for treating melanoma and predicting outcome of patients.
| S-EPMC5356666 | biostudies-literature
Project description:Glioma is the most malignant primary brain cancer which frequently occurred in adults. In recent years, long-non coding RNAs (lncRNAs) have been demonstrated to play pivotal roles in human cancers. However, the role of most lncRNAs in gliomagenesis has not been probed. Presently, through TCGA, a novel lncRNA LINC01198 was found to be up-regulated and associated with clinical outcomes in glioblastoma multiforme (GBM). In our study, LINC01198 was proved to be up-regulated in glioma cell lines, and silenced LINC01198 curbed glioma cell proliferation and accelerated cell apoptosis. Importantly, we corroborated that LINC01198 activated the PI3 K/AKT pathway to aggravate glioma progression by targeting PIK3 CA and PTEN. Subsequently, LINC01198 was validated to localize in both cytoplasm and nucleus of glioma cells. Through mechanistic exploration, we illustrated that LINC01198 increased PIK3CA expression by sponging miR-129-5p in the cytoplasm. Furthermore, PTEN was transcriptionally repressed by REST/RCOR1/HDAC2 complex. More importantly, LINC01198 accelerated the assembly of REST/RCOR1/HDAC2 complex and recruited such complex to PTEN promoter so as to impair PTEN expression in glioma. Finally, we further verified that LINC01198 hindered glioma tumour growth in vivo through AKT-dependent manner. Jointly, LINC01198 activates PI3 K/AKT signalling to exert oncogenic function in gliomagenesis by regulating PIK3CA and PTEN, which highlights a new approach for glioma treatment.
| S-EPMC7549703 | biostudies-literature
Project description:ObjectiveTo investigate the ameliorative effect of Semaglutide-loaded PEG-nanoliposomes (Sem-PEG-lips) combined with ultrasound-targeted microbubble destruction (UTMD) on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) in rodents and its potential mechanisms.MethodsSem-PEG-lips were prepared by the reverse phase evaporation method. Fifty STZ-induced diabetic rats were randomly divided into DCM model group, Sem or Sem-PEG-lips alone treatment group, UTMD + Sem group and UTMD + Sem-PEG-lips group (n = 10), respectively, and used the healthy rats as normal control. During the 12-week intervention, the weight and blood glucose levels of all rats were recorded. Myocardial injury and fibrosis were observed by using H&E and Masson staining. The activity of antioxidant enzymes and the expression levels of oxidative stress-related signaling pathway markers in myocardial tissues were measured by ELISA and western blotting method, respectively.ResultsCompared with DCM rats, the body weight and blood glucose levels of those in the UTMD + Sem-PEG-lips group were significantly increased and decreased, respectively (both p < 0.05). The results of H&E and Masson staining showed that myocardial fibrosis and apoptosis were both significantly improved in combination group (both p < 0.001). Further results of ELISA and Western blot analysis showed that the activity of antioxidant enzymes in ones received combination therapy were significantly higher than that in DCM model group (all p < 0.001), and the expression of PI3K/Akt/Nrf2 signaling pathway related proteins were significantly up-regulated (all p < 0.001), and all these changes were reversed by the treatment of PI3K inhibitor. results.ConclusionUTMD combined Sem-PEG-lips can reduce the oxidative stress of myocardial tissue in DCM rats by activating PI3K/Akt/Nrf2 signaling pathway, thereby improving diabetic myocardial injury.
| S-EPMC10559235 | biostudies-literature
Project description:MicroRNAs (miRNAs) play a pivotal role in cartilage development and homeostasis in osteoarthritis (OA). While the fundamental roles of miRNAs in cartilage degeneration have been extensively studied, their effects on chondrogenic differentiation induced by human adipose-derived stem cells (hADSCs) and the underlying mechanisms remain largely elusive. Here, we investigated the roles and mechanisms of miRNAs in hADSC chondrogenic differentiation and chondrocyte homeostasis. Using microarray analysis, we screened miRNAs expressed in the chondrogenic differentiated hADSCs and identified miR-490-5p as the most significantly down-regulated miRNA. We analyzed its expression patterns during chondrogenesis in vivo and in vitro. Our study showed that miR-490-5p overexpression promoted the transition of hADSCs from chondrogenesis to osteogenesis. In addition, based on miRNA-mRNA prediction analysis and dual-luciferase reporter assay, we proposed and proved that miR-490-5p targeted PITPNM1 by binding to its 3'-UTR and inhibiting its translation. Moreover, loss- and gain-of-function experiments identified the involvement of the PI3K/AKT signaling pathway, and a rescue experiment determined the effect and specific mechanism of the miR-490-5p/PITPNM1/PI3K/AKT axis in hADSC chondrogenic differentiation and chondrocyte homeostasis. Inhibition of miR-490-5p alleviated cartilage injury in vivo as demonstrated using the destabilization of the medial meniscus (DMM) OA model. We identified miR-490-5p as a novel modulator of hADSC-mediated chondrogenesis and chondrocyte phenotype. This study highlighted that miR-490-5p attenuated hADSC chondrogenesis and accelerated cartilage degradation through activation of the PI3K/AKT signaling pathway by targeting PITPNM1. Inhibition of miR-490-5p facilitated hADSC chondrogenic differentiation and protected chondrocyte phenotype via the PITPNM1/PI3K/AKT axis, thus providing a novel stem cell potential therapeutic target for OA treatment.
| S-EPMC7680841 | biostudies-literature