ACSL1 Inhibits ALV-J Replication by IFN-I Signaling and PI3K/Akt Pathway
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ABSTRACT:
SUBMITTER: Zhang Q
PROVIDER: S-EPMC8585972 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To explore the influence of hyperhomocysteinemia (hHcys) on the tibial fracture healing in rats and its effect on the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT) signaling pathway. A total of 36 Sprague-Dawley rats were randomly divided into sham group (n=12), tibial fracture group (n=12) and hHcys + fracture group (n=12). The rats in tibial fracture group underwent the tibial fracture surgery, while the model of tibial fracture and hHcys was established in hHcys + fracture group. The level of plasma homocysteine (Hcy) in each group was analyzed using the full-automatic biochemical analyzer, the fracture stress biomechanical measurement was performed, and the ultimate bending strength and torque were calculated. Moreover, the protein expressions of PI3K and phosphorylated (p)-AKT in tibial tissues were detected using western blotting, the messenger ribonucleic acid (mRNA) levels of Bcl-2 associated X protein (Bax) and caspase-3 were detected using quantitative polymerase chain reaction (qPCR), the apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and the expressions of inflammatory factors were detected via immunohistochemistry. Compared with sham group, tibial fracture group and hHcys + fracture group had a significantly increased level of plasma Hcy, significantly decreased ultimate bending strength and torque, obviously decreased relative protein expressions of PI3K and p-AKT, increased mRNA levels of Bax and caspase-3 and an increased expression of pro-inflammatory factor tumor necrosis factor-? (TNF-?). Compared with tibial fracture group, hHcys + fracture group had a higher level of plasma Hcy, lower ultimate bending strength and torque, lower relative protein expressions of PI3K and p-AKT, higher mRNA levels of Bax and caspase-3, a higher apoptosis rate and a higher expression of TNF-?. hHcys blocks the downstream apoptotic signal transduction, promotes apoptosis and inflammatory response, and affects fracture healing through affecting the PI3K/AKT signaling pathway.
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Project description:Skeletal muscle is the dominant executant in locomotion and regulator in energy metabolism. Embryonic myogenesis and postnatal muscle growth are controlled by a cascade of transcription factors and epigenetic regulatory mechanisms. MicroRNAs (miRNAs), a family of non-coding RNA of 22 nucleotides in length, post-transcriptionally regulates expression of mRNA by pairing the seed sequence to 3' UTR of target mRNA. Increasing evidence has demonstrated that miRNAs are important regulators in diverse myogenic processes. The profiling of miRNA expression revealed that miR-432 is more enriched in the longissimus dorsi of 35-day-old piglets than that of adult pigs. Our gain of function study showed that miR-432 can negatively regulate both myoblast proliferation and differentiation. Mechanically, we found that miR-432 is able to down-regulate E2F transcription factor 3 (E2F3) to inactivate the expression of cell cycle and myogenic genes. We also identified that phosphatidylinositol 3-kinase regulatory subunit (P55PIK) is another target gene of miR-432 in muscle cells. downregulation of P55PIK by miR-432 leads to inhibition of P55PIK-mediated PI3K/AKT/mTOR signaling pathway during differentiation. The blocking effect of miR-432 on this pathway can be rescued by insulin treatment. Taken together, our findings identified microRNA-432 as a potent inhibitor of myogenesis which functions by targeting E2F3 and P55PIK in muscle cells.
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Project description:Pancreatic stellate cells (PSCs) have a vital role in pancreatic fibrosis accompanied by pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). Any agents which can affect the activation of PSCs could become potential candidates for treatment strategies in PDAC and CP. Our aim was to explore the effect of Coenzyme Q10 (CoQ10) in the process of PSCs activation.Isolated PSCs from C57BL/6 mice were treated with various dosages of CoQ10 (1, 10, and 100?M) and different time (24h, 48h, and 72 h). Effect of CoQ10 on autophagy, apoptosis, senescence and oxidative stress, as well as the activation of PSCs were analyzed by immunocytofluorescent staining, quantitative real time RT-PCR, western blotting, SA-?-galactosidase staining, malondialdehyde and reactive oxygen species (ROS) assay.Expression of ?-smooth muscle actin, LC3II, Beclin1, Cleaved caspases-3 and Bax levels were significantly reduced in CoQ10 treatment groups. Meanwhile, compared with the control group, significant differences for the expression of desmin, P62, Bcl-2, p-PI3K, p-AKT and p-mTOR levels in CoQ10 treatment groups were found. Moreover, CoQ10 affected the secretion of extracellular matrix components for PSCs. Few SA-?-gal positive cells were found in CoQ10 treated groups. A significant decrease in ROS positive cells and malondialdehyde levels were observed after 72 h exposure to CoQ10.Our finding suggests that CoQ10 inhibits the activation of PSCs by suppressing autophagy through activating the PI3K/AKT/mTOR signaling pathway. CoQ10 may act as a therapeutic agent in PSC-relating pathologies and/or anti-fibrotic approaches.
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Project description:The present study investigated the inhibitory effects and the associated mechanism of the compound 25-OH-PPD (PPD) on cardiac hypertrophy, fibrosis and inflammation. The signaling pathways associated with diabetic mellitus cardiomyopathy (DMCM) were investigated using a rat model. DMCM Sprague-Dawley rats were induced by injection of streptozotocin. The animals were divided into 5 groups as follows: Normal group (NG group), diabetic group, PPD treatment group, PPD/LY294002 group (inhibitor of PI3K/Akt) and PPD/LiCl group [inhibitor of glycogen synthase kinase (GSK) 3?]. The studies were carried out during the 12 weeks following induction of diabetes and the levels of plasma brain natriuretic peptide (BNP), creatine phosphokinase isoenzyme (CK-MB) were measured. In addition, the volume of myocardial collagen fraction (CVF) was tested. The expression levels of the inflammatory cytokines, including transforming growth factor beta 1 (TGF-?1), connective tissue growth factor (CTGF), cell adhesion molecules ?-smooth muscle actin (?-SMA) and vascular adhesion molecule 1 (VCAM-1) and associated signaling proteins (Akt, GSK-3?) were measured by biochemical analyses. The levels of BNP and CK-MB, the volume of CVF, the expression levels of TGF-?1, CTGF, ?-SMA and VCAM-1 in the diabetic group were higher compared with those of the normal control group (P<0.05). Conversely, the levels of these molecules were significantly decreased in the PPD treatment groups (P<0.05). The aforementioned effects were partially eliminated in the PPD/LY294002 and PPD/LiCl groups. In addition, PPD treatment significantly increased the expression levels of p-Akt and decreased the levels of phosphorylated GSK-3? compared with those of the DMCM group (P<0.05). The data demonstrated that the protective effects of 25-OH-PPD against DMCM may be attributed to the PI3k/Akt/GSK-3? signaling pathway, via the suppression of the ?-SMA/VCAM axis and the downregulation of TGF-?1 and CTGF expression.
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Project description:Objectives:Flufenamic acid (FFA) is a representative of the fenamic acids, an important group of NSAIDs. In the present study, we study the effects of FFA on adipogenesis of human mesenchymal stem cells (MSCs) and we explore the potential mechanism. Methods:To investigate the effects of FFA on adipogenic differentiation of hMSCs, human adipose-derived stem cells (hASCs) and human bone marrow mesenchymal stem cells (hBMMSCs), representative of hMSCs, were treated with FFA during adipogenic differentiation in vitro. The effects of FFA in vivo were evaluated using a heterotopic adipose formation assay in nude mice as well as ovariectomized (OVX) and aged mice. To explore the mechanism of FFA, Western blot was used to determine activation of the PI3K/AKT signaling pathway. Results:Our results demonstrate that, at certain concentrations, FFA inhibited adipogenesis of human MSCs both in vitro and in vivo. Mechanistically, FFA inhibited adipogenesis of human MSCs by inhibiting the PI3K/AKT pathway. Conclusions:The present study indicated that FFA could be used to inhibit adipogenesis of human MSCs in tissue engineering and diseases related to excessive adipogenic differentiation of MSCs.
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Project description:PurposeTo investigate the anti-tumor effect of Robinin (Toll-like receptor 2 inhibitor) in pancreatic cancer cells via regulating tumor microenvironment.MethodsThe effects of Robinin on cell proliferation or migration in Mia-PACA2 and PANC-1 were determined, using CCK8 or wound healing assay, respectively. The typical markers of EMT (αSMA and snail) and the inflammation markers (IL-6 and TNF-α) were all detected by western blot. CU-T12-9 (TLR2 agonist) was used to rescue Robinin's effect. PI3k-p85α and Phosphorylated-AKT (p-AKT) were evaluated, compared to the β-actin and AKT, using western blot.ResultsRobinin significantly inhibited cell proliferation and migration in Mia-PACA2 and PANC-1, compared to HPNE (**P < 0.01). Robinin also attenuated the expression of α-SMA and snail in Mia-PACA2, and PANC-1 (**P < 0.01). Besides, it was found that expression of IL-6 and TNF-α were diminished in presence of Robinin in Mia-PACA2, and PANC-1 (**P < 0.01). Western blot confirmed that Robinin could target on TLR2, and further downregulated PI3k-AKT signaling pathway to exert biological function.ConclusionsRobinin exerts anti-tumor effect perhaps via downregulating inflammation and EMT in pancreatic cancer cell through inhibiting TLR2-PI3k-AKT signaling pathway. Robinin may be a novel agent in adjuvant therapy of pancreatic cancer.
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Project description:ObjectivesTo investigate the role of immune escape encoding genes on the prognosis of BC, and to predict the novel targeting agents.MethodsHuman immune genes and immune escape encoding genes were obtained from the IMMPORT database and the previous study. Sample information and clinical data on BC were obtained from the TCGA and GTEX databases. Obtaining differentially expressed protein data from cBioportal database. To construct a risk score model by lasso analysis, and nomogram was used to predict score core. GSCA, TIMER and CELLMINER databases were used for immune and drug susceptibility correlation analyses. Cell experiments were verified by MTT, Western blotting, and RT-qPCR.ResultsWe found prognostic models consisting of eleven immune escape related protein-coding genes with ROC curves that performed well in the ontology data (AUC for TCGA is 0.672) and the external data (AUC for GSE20685 is 0.663 and for GES42568 is 0.706). Five core prognostic models are related to survival (EIF4EBP1, BCL2A1, NDRG1, ERRFI1 and BRD4) were summarized, and a nomogram was constructed to validate a C-index of 0.695, which was superior to other prognostic models. Relevant drugs targeting core genes were identified based on drug sensitivity analysis, and found that Vemurafenib downregulates the PI3K-AKT pathway and BCL2A1 protein in BC, as confirmed by external data and cellular assays.ConclusionsBriefly, our work establishes and validates an 11-immune escape risk model, and five core prognostic factors that are mined deeply from this model, and elucidates in detail that Vemurafenib suppresses breast cancer by targeting the PI3K/AKT signaling pathway to inhibit the immune escape biomarker BCL2A1, confirms the validity of the prognostic model, and provides corresponding targeted agents to guide individualized treatment of BC patients.
| S-EPMC9745811 | biostudies-literature