HIV-1 Nef induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC3963078 | biostudies-other | 2014 Mar
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Hepatocellular carcinoma (HCC) is the dominant pathological type of primary liver cancer and no effective methods are available for its treatment. Erianin is a natural product extracted from Dendrobium, which possesses multiple pharmacological activities, including antioxidative and antitumor activity. OBJECTIVE:To evaluate the anti-HCC activities of erianin and explore its underlying mechanism. METHODS:MTT assay and Crystal Violet staining assay were used to select the non-toxic concentrations for the subsequent experiments. The colony formation assay and PCNA fluorescent staining were used to investigate the antiproliferative effects of erianin on human SMMC-7721 and HepG2 cells. Wound healing and transwell test were used to analyze cell migration and invasion. Caspase3 and Tunel staining were used to detect apoptosis. Western blot was used to examine the expression levels of proteins associated with invasion and key proteins in the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), p38 and ERK mitogen-activated protein kinase (MAPK) signaling pathways. RESULTS:Erianin inhibited HCC cell proliferation in a dose-dependent manner. Decreased migration rate and invaded cells were observed with erianin supplement. The expression of invasion-associated proteins in the erianin group was also down-regulated. Besides, more apoptotic cells were observed after erianin treatment. For the molecular mechanism, erianin inhibited the phosphorylation of Akt, ERK and P38 in the PI3K/Akt and ERK/P38 pathway. CONCLUSION:We demonstrated, for the first time, that erianin inhibited the proliferation, migration, invasion and induced the apoptosis of HCC through PI3K/Akt, p38 and ERK MAPK signaling pathway, indicating that erianin is a promising agent for the HCC treatment.
| S-EPMC7385585 | biostudies-literature
Project description:Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1β) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1β on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1β on the changes that can promote VM. The evidence for VM stimulated by IL-1β was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-β. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1β treatment. The increase in VM response was observed in IL-1β treated cells under both normoxia and hypoxia. IL-1β also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1β stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1β stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1β may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.
| S-EPMC8160375 | biostudies-literature
Project description:Due to its rapid onset and high mortality, acute myocardial infarction (AMI) is considered as one of the most fatal diseases among heart diseases. Therefore, exploring its potential pathogenesis and developing effective treatment approaches for AMI have become a research hotspot in the medical community. In the present study, clinical blood samples from patients with AMI were analyzed and the results showed that the expression of microRNA (miR)-124 was significantly increased in peripheral blood of patients with AMI compared with healthy subjects. In addition, miR-124 overexpression notably promoted the apoptosis of HUVECs and attenuated their proliferative ability. Based on these findings, RNA from HUVECs was extracted and sequenced to investigate the changes in the gene expression profile triggered by miR-124 overexpression. The upregulated genes were enriched in several signaling pathways such as PI3K/AKT, while the downregulated ones were mainly enriched in metabolic-related signaling pathways. Additionally, the chromosomal location analysis revealed that the differentially expressed genes (DEGs) were distributed in all chromosomes, except the Y sex chromosome. Furthermore, the characteristic profile of DEGs mediated by miR-124 overexpression was analyzed via Connectivity Map analysis. The analysis revealed that anisomycin and sanguinarine, two agonists of the p38/MAPK signaling pathway involved in the inhibition of angiogenesis, exerted the highest enrichment scores. Additionally, Gene Set Enrichment Analysis demonstrated that DEGs were mainly enriched in the PI3K/AKT signaling pathway, thus inhibiting angiogenesis. Collectively, the present results indicated that miR-124 overexpression could promote AMI by affecting angiogenesis.
2021-07-27 | GSE180765 | GEO
Project description:BACKGROUND:The aim of this study was to investigate the mechanisms of OX40L in regulating helper T (Th) cells differentiation through phosphoinositide 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase signaling pathway in vitro and in vivo experiments. METHODS:Serum samples of patients with asthma and healthy controls were used to explore the association between OX40L and Th cells. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum concentrations of OX40L, IL-4, IFN-?, IL-17 and TGF-?. Flow cytometry method was used to analyze Th1, Th2, Th17 and Treg cells. 3H-thymidine was used to determine the proliferation of T cells. Western Blot was used to detect protein expression and phosphorylation. Immunohistochemistry was used to detect the expression of OX40L in lung tissues. RESULTS:OX40L, IL-4, IL-17 increased in patient serum compared to healthy control and in the ovalbumin (OVA)-primed mononuclear cells compared to normal cells, while IFN-? and TGF-? were decreased. Besides, the OVA-primed CD4+ T cells treated with OX40L-Ig fusion protein promoted the proliferation of T cells and Th2 and Th17 cells differentiation as well as PI3K/AKT and p38 MAPK signaling pathway, but suppressed Th1 and Treg cells differentiation. Moreover, helper T cells differentiation in OVA-primed CD4+ T cells could be markedly reversed by the addition of PI3K/AKT inhibition, p38 MAPK inhibition and anti-OX40L monoclonal antibody. CONCLUSIONS:In this study, we revealed that OX40L could regulate differentiation of helper T cells via PI3K/AKT and p38 MAPK signaling pathway in asthma. Besides, blockade of OX40/OX40L could inhibit the proliferation of CD4+ T cells and regulate polarization of helper T cells.
| S-EPMC5859438 | biostudies-literature
Project description:Background and purposeThe development of antinociceptive morphine tolerance is a clinically intractable problem. Earlier work has demonstrated the pivotal roles of PDGF and its receptor PDGFRβ in morphine tolerance. Here, we have investigated the role of spinal heat shock protein 27 (HSP27) in morphine tolerance and its relationship with PDGFRβ activation.Experimental approachRats were treated with morphine for 9 days, and its anti-nociceptive effect against thermal pain was evaluated by a tail-flick latency test. Western blot, real-time PCR, immunofluorescent staining, and various antagonists, agonists, and siRNA lentiviral vectors elucidated the roles of HSP27, PDGFRβ, and related signalling pathways in morphine tolerance.Key resultsChronic morphine administration increased expression and phosphorylation of HSP27 in the spinal cord. Down-regulating HSP27 attenuated the development of morphine tolerance. PDGFRβ antagonism inhibited HSP27 activation and attenuated and reversed morphine tolerance. PDGFRβ induction increased HSP27 expression and activation and partly decreased morphine analgesia. PDGFRβ inhibition reduced Akt and p38 MAPK activity in morphine tolerance. PI3K and p38 inhibitors reversed morphine tolerance and suppressed morphine-induced HSP27 phosphorylation.Conclusion and implicationsThis study demonstrated for the first time that spinal HSP27 participates in PDGFRβ-mediated morphine tolerance via the PI3K/Akt and p38 MAPK signalling pathways. These findings suggest a potential clinical strategy for prolonging the antinociceptive effects of opioids during long-term pain control.
| S-EPMC7589020 | biostudies-literature
Project description:Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that is sensitive to cell swelling, arachidonic acid and its metabolites, epoxyeicosatrienoic acids, which are associated with cerebral ischemia. The activation of TRPV4 induces cytotoxicity in many types of cells, accompanied by an increase in the intracellular free calcium concentration. TRPV4 activation modulates the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)/ protein kinase B (Akt) signaling pathways that regulate cell death and survival. Herein, we examined TRPV4-induced neuronal apoptosis by intracerebroventricular (ICV) injection of a TRPV4 agonist (GSK1016790A) and assessed its involvement in cerebral ischemic injury. ICV injection of GSK1016790A dose-dependently induced apoptosis in the mouse hippocampi (GSK-injected mice). The protein level of phosphorylated p38 MAPK (p-p38 MAPK) was markedly increased and that of phosphorylated c-Jun N-terminal protein kinase (p-JNK) was virtually unchanged. TRPV4 activation also decreased Bcl-2/Bax protein ratio and increased the cleaved caspase-3 protein level, and these effects were blocked by a PI3K agonist and a p38 MAPK antagonist, but were unaffected by a JNK antagonist. ICV injection of the TRPV4 antagonist HC-067047 reduced brain infarction after reperfusion for 48 h in mice with middle cerebral artery occlusion (MCAO). In addition, HC-067047 treatment attenuated the decrease in the phosphorylated Akt protein level and the increase in p-p38 MAPK protein level at 48 h after MCAO, while the increase in p-JNK protein level remained unchanged. Finally, the decreased Bcl-2/Bax protein ratio and the increased cleaved caspase-3 protein level at 48 h after MCAO were markedly attenuated by HC-067047. We conclude that activation of TRPV4 induces apoptosis by downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways, which is involved in cerebral ischemic injury.
| S-EPMC4669828 | biostudies-other
Project description:BackgroundPancreatic cancer (PDAC) is a highly invasive cancer with poor prognosis. Recent research has found that the transcription factor Yin Yang 1 (YY1) plays an inhibitory role in the development of pancreatic cancer. It has been reported that tubulin polymerisation-promoting protein (TPPP) plays an indispensable role in a variety of tumours, but its expression and role in pancreatic cancer have not yet been elucidated.MethodsIn this study, we performed ChIP-sequencing and found that YY1 directly binds to the promoter region of TPPP. The expression of TPPP in pancreatic cancer was detected by western blotting and immunohistochemistry. Four-week-old male BALB/c-nude mice were used to assess the effect of TPPP on pancreatic cancer.ResultsImmunohistochemistry revealed that TPPP was expressed at low levels in pancreatic cancer tissues, and was associated with blood vessel invasion. The results from vivo experiments have showed that TPPP could enhance the migration and invasion of pancreatic cancer. Further experiments showed that YY1 could inhibit the migration, invasion and angiogenesis of pancreatic cancer cells by downregulating TPPP via p38/MAPK and PI3K/AKT pathways.ConclusionOur study demonstrates that TPPP may act as a promoter and may serve as a novel target for the treatment of pancreatic cancer.
| S-EPMC6888832 | biostudies-literature
Project description:Porcine circovirus type 2 (PCV2) infection caused PCV2-associated diseases (PCVAD) is one of the major emerging immunosuppression diseases in pig industry. In this study, we investigated how PCV2 inoculation increases interleukin (IL)-10 expression in porcine alveolar macrophages (PAMs). PCV2 inoculation significantly upregulated IL-10 expression compared with PCV1. Upon initial PCV2 inoculation, PI3K/Akt cooperated with NF-?B pathways to promote IL-10 transcription via p50, CREB and Ap1 transcription factors, whereas inhibition of PI3K/Akt activation blocked Ap1 and CREB binding to the il10 promoter, and decreased the binding level of NF-?B1 p50 with il10 promoter, leading to great reduction in early IL-10 transcription. In the later phase of inoculation, PCV2 further activated p38 MAPK and ERK pathways to enhance IL-10 production by promoting Sp1 binding to the il10 promoter. For PCV2-induced IL-10 production in macrophages, PCV2 capsid protein Cap, but not the replicase Rep or ORF3, was the critical component. Cap activated PI3K/Akt, p38 MAPK, and ERK signaling pathways to enhance IL-10 expression. In the whole process, gC1qR mediated PCV2-induced PI3K/Akt and p38 MAPK activation to enhance IL-10 induction by interaction with Cap. Depletion of gC1qR blocked PI3K/Akt and p38 MAPK activation, resulting in significant decrease in IL-10 production in PCV2-inoculated cells. Thus, gC1qR might be a critical functional receptor for PCV2-induced IL-10 production. Taken together, these data demonstrated that Cap protein binding with host gC1qR induction of PI3K/Akt and p38 MAPK signalings activation is a critical process in enhancing PCV2-induced IL-10 production in porcine alveolar macrophages.
| S-EPMC4951228 | biostudies-literature
Project description:T-cell acute lymphoblastic leukemia (T-ALL) as a prevalent hematologic malignancy is one of the most common malignant tumors worldwide in children. Andrographolide (Andro), the major active component from Andrographis paniculata, has been shown to possess antitumor activities in several types of cancer cells. However, whether Andro would inhibit T-ALL cell growth remains unclear. In this study, we investigated the cytotoxic effect of Andro on human T-ALL Jurkat cells and explored the mechanisms of cell death. Cell apoptosis was assayed by flow cytometry, and the signaling transduction for Andro was analyzed by Western blotting. The results indicated 10 ?g/mL Andro could significantly induce Jurkat cells' apoptosis, depending on the inhibition of PI3K/AKT pathway. Moreover, Andro-induced apoptosis is enhanced by AKT-selective inhibitor LY294002. ERK- or JNK-selective inhibitors PD98059 and SP600125 had no effect on Andro-induced apoptosis. In addition, p38 inhibitor SB203580 could reverse Andro-induced apoptosis in Jurkat cells. We also found that the protein expression of p-p53 and p-p38 were increased after Andro treatments. The result of an in vivo study also demonstrated Andro's dose-dependent inhibition in subcutaneous Jurkat xenografts. In conclusion, our findings explained a novel mechanism of drug action by Andro in Jurkat cells and suggested that Andro might be developed into a new candidate therapy for T-ALL patients in the coming days.
| S-EPMC4833376 | biostudies-literature
Project description:Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.
| S-EPMC5371332 | biostudies-literature