Circ_0020014 mediates CTSB expression and participates in IL-1β-prompted chondrocyte injury via interacting with miR-24-3p
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ABSTRACT:
SUBMITTER: Zhang C
PROVIDER: S-EPMC10657024 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundOsteoarthritis (OA) is a chronic disease that involves chondrocyte injury and dysfunction. CircRNAs participate in OA progression, but the roles of circRNAs in the occurrence of OA are unclear. In this study, we explore the role of circ_0008365 in OA.MethodsCHON-001 cells were treated with interleukin-1β (IL-1β) to construct an in vitro OA cell model. The levels of circ_0008365, SRY-related high mobility group-box gene9 (SOX9) mRNA, and microRNA-338-3p (miR-338-3p) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Western blot (WB) assay was used to measure protein levels. Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EDU) assay, and flow cytometry analysis were used to detect cell viability, proliferation, and apoptosis, respectively. Dual-luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation (RIP) assays were used to confirm the interaction between miR-338-3p with circ_0008365 or SOX9.ResultsCirc_0008365 expression was reduced in OA tissues and IL-1β-induced CHON-001 cells. Functionally, circ_0008365 inhibited viability, proliferation, and ECM degradation and promoted apoptosis of IL-1β-induced CHON-001 cells. Mechanistically, circ_0008365 acted as a sponge of miR-338-3p to regulate SOX9 expression, thus exerting its functions in IL-1β-induced CHON-001 cells. Moreover, exosomal circ_0008365 had great value in diagnosing OA.ConclusionCirc_0008365 alleviates IL-1β-induced CHON-001 cell damage through the miR-338-3p/SOX9 axis, which suggested that circ_0008365 might be a new therapeutic target for OA.
| S-EPMC9569125 | biostudies-literature
Project description:As part of the pathogenesis of osteoarthritis (OA), chondrocytes lose their phenotype and become hypertrophic, or dedifferentiate, mainly driven by interleukin-1β (IL-1β). The contribution of other factors to the dedifferentiation process is not completely understood. Recent studies suggested a dose-dependent role for the sympathetic neurotransmitter norepinephrine (NE) in OA chondrocyte metabolism. Therefore, the aim of this study was to analyze the contribution of NE (10-8 M, 10-6 M) to human articular OA chondrocyte dedifferentiation in the absence or presence of IL-1β (0.5 ng/mL). Here, we demonstrate that OA chondrocytes express α2A-, α2C- and β2-adrenoceptors (AR) and show the characteristic shift towards a fibroblast-like shape at day 7 in physioxic monolayer culture. NE alone did not affect morphology but, in combination with IL-1β, markedly accelerated this shift. Moderate glycosaminoglycan (GAG) staining was observed in untreated and NE-treated cells, while IL-1β strongly decreased GAG deposition. IL-1β alone or in combination with NE decreased SOX9, type II collagen, COMP, and aggrecan, and induced MMP13 and ADAMTS4 gene expression, indicating an accelerated dedifferentiation. NE alone did not influence gene expression and did not modulate IL-1β-mediated effects. In conclusion, these results indicate that low-grade inflammation exerts a dominant effect on chondrocyte dedifferentiation and should be targeted early in OA therapy.
| S-EPMC6429278 | biostudies-literature
Project description:Introduction: Mathematical model can be used to model complex biological processes, and have shown potential in describing apoptosis in chondrocytes. Method: In order to investigate the regulatory mechanisms of TNF signaling pathway in regulating chondrocyte apoptosis, a fractional-order differential equation model is proposed to describe the dynamic behavior and mutual interaction of apoptosis-related genes under the activation of TNF signaling pathway. Compared with the traditional molecular biology techniques, the proposed mathematical modeling has advantages to providing a more comprehensive understanding of the regulatory mechanisms of TNF signaling pathway in chondrocyte apoptosis. Result: In this paper, differentially expressed genes induced by IL-1β in human chondrocyte apoptosis are screened using high-throughput sequencing. It is found that they were significantly enriched in the TNF signaling pathway. Therefore, a mathematical model of the TNF signaling pathway is built. Using real-time PCR experiments, mRNA data is measured and used to identify the model parameters, as well as the correlation coefficient. Finally, the sensitivity of the model parameters is discussed by using numerical simulation methods, which can be used to predict the effects of different interventions and explore the optimal intervention strategies for regulating chondrocyte apoptosis. Discussion: Therefore, fractional-order differential equation modeling plays an important role in understanding the regulatory mechanisms of TNF signaling pathway in chondrocyte apoptosis and its potential clinical applications.
| S-EPMC10652750 | biostudies-literature
Project description:BackgroundOsteoarthritis (OA) is the most prevalent degenerative joint disease. In vitro experiments are an intuitive method used to investigate its early pathogenesis. Chondrocyte inflammation models in rats and mice are often used as in vitro models of OA. However, similarities and differences between them in the early stages of inflammation have not been reported.ObjectiveThis paper seeks to compare the chondrocyte phenotype of rats and mice in the early inflammatory state and identify chondrocytes suitable for the study of early OA.MethodsUnder similar conditions, chondrocytes from rats and mice were stimulated using the same IL-1β concentration for a short period of time. The phenotypic changes of chondrocytes were observed under a microscope. The treated chondrocytes were subjected to RNA-seq to identify similarities and differences in gene expression. Chondrocytes were labelled with EdU for proliferation analysis. Cell proliferation-associated proteins, including minichromosome maintenance 2 (MCM2), minichromosome maintenance 5 (MCM5), Lamin B1, proliferating cell nuclear antigen (PCNA), and Cyclin D1, were analysed by immunocytochemical staining, cell immunofluorescence, and Western blots to verify the RNA-seq results.ResultsRNA-seq revealed that the expression patterns of cytokines, chemokines, matrix metalloproteinases, and collagen were similar between the rat and mouse chondrocyte inflammation models. Nonetheless, the expression of proliferation-related genes showed the opposite pattern. The RNA-seq results were further verified by subsequent experiments. The expression levels of MCM2, MCM5, Lamin B1, PCNA, and Cyclin D1 were significantly upregulated in rat chondrocytes (P < 0.05) and mouse chondrocytes (P < 0.05).ConclusionsBased on the findings, the rat chondrocyte inflammation model may help in the study of the early pathological mechanism of OA.
| S-EPMC8815127 | biostudies-literature
Project description:Excessive chondrocyte apoptosis is mostly responsible for the progression of osteoarthritis (OA). It has been shown that circular RNAs (circRNAs) are differentially expressed in OA cartilage and participate in various pathological processes during OA. Here, this study was designed to explore the effect and molecular mechanism of hsa_circ_0005567 on IL-1β-induced chondrocyte apoptosis. The results showed that hsa_circ_0005567 knockdown aggravated the IL-1β-induced chondrocyte apoptosis. In contrast, hsa_circ_0005567 overexpression attenuated the IL-1β-induced chondrocyte apoptosis, but this effect could be abrogated by 3-methyladenine (an inhibitor of autophagy), suggesting that hsa_circ_0005567 overexpression inhibited chondrocyte apoptosis by inducing autophagy. Furthermore, hsa_circ_0005567 competitively bound to miR-495 and derepressed the expression of ATG14, an early autophagy marker that was a direct target of miR-495. Moreover, both miR-495 mimic and ATG14 knockdown counteracted the autophagy-promoting and anti-apoptotic effects of hsa_circ_0005567 overexpression in IL-1β-treated chondrocytes. Taken together, hsa_circ_0005567 activates autophagy by regulating the miR-495/ATG14 axis and thereby suppresses IL-1β-induced chondrocyte apoptosis. These findings suggest that hsa_circ_0005567 may serve as a therapeutic target for the treatment of OA.
| S-EPMC7477291 | biostudies-literature
Project description:Regulation of hippocampal neurogenesis is poorly understood, but appears to contribute to mood and cognition. Ethanol and neuroinflammation are known to reduce neurogenesis. We have found that ethanol induces neuroinflammation supporting the hypothesis that ethanol induction of neuroinflammation contributes to ethanol inhibition of neurogenesis. To identify the key proinflammatory molecule that may be responsible for ethanol-impaired neurogenesis we used an ex vivo model of organotypic hippocampal-entorhinal cortex brain slice cultures. Here, we demonstrated a key role of proinflammatory cytokine IL-1β signaling in mediating ethanol inhibition of neurogenesis. Ethanol inhibition of neurogenesis was reversed by neutralizing antibody to IL-1β or blockade of the IL-1β receptor with antagonist IL-1RIa. Ethanol-impaired neurogenesis is associated with strong induction of IL-1β and inflammasome proteins NALP1 and NALP3 in both neurons and astrocytes. Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis. Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain. Together, these novel findings demonstrate that targeting inflammasome-IL-1β signaling can normalize ethanol-impaired hippocampal neurogenesis, which may have therapeutic implications for treatment of cognitive impairment associated with hippocampal dysfunction in alcoholics.
| S-EPMC3362805 | biostudies-literature
Project description:Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high-fat diet to induce type II DM and were subjected to IL-1β antibodies, macrophage depletion by clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor 2 (RyR2) stabilizer (S107). All tests were performed at 36-38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria, as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1β levels. Signs of aberrant RyR2 Ca2+ leak were observed in the atria of DM mice. IL-1β neutralization, macrophage depletion, and exposure to mitoTEMPO and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1β contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca2+ leak.
| S-EPMC11383594 | biostudies-literature
Project description:Caspase 8, the initiator caspase for death receptor-induced apoptosis, functions as a negative regulator of receptor interacting protein kinase 3 (RIPK3), an essential factor for TNF-, TLR3-, and TLR4-induced necroptosis. In certain situations, caspase 8 can also participate in pro-IL-1β processing. However, the biochemical complex that mediates caspase 8-mediated processing is not defined. In this study, we show that RIPK3 is crucial for caspase 1- and caspase 8-mediated pro-IL-1β and pro-IL-18 processing in bone marrow-derived dendritic cells (BMDCs) in response to LPS stimulation. Caspase 8-mediated pro-IL-1β processing requires intact RIPK1, RIPK3, TRIF, and FADD. In response to LPS, a complex that contains RIPK1, RIPK3, FADD, and caspase 8 is formed. Surprisingly, RIPK3-specific kinase inhibitors strongly enhanced caspase 8 activation and pro-IL-1β processing in LPS-stimulated BMDCs. However, studies in BMDCs expressing the kinase-inactive RIPK3-K51A mutant or RIPK1-K45A mutant showed that the kinase activity of neither RIPK1 nor RIPK3 is required for LPS-induced caspase 8 activation and IL-1β secretion. Hence, RIPK3 is an unexpected positive regulator of caspase 8 activity that promotes IL-1β maturation in BMDCs.
| S-EPMC4324020 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death. Cytokines, including interleukin 24 (IL-24), play an important role in HCC. IL-24 inhibits HCC metastasis but the molecular mechanism by which this occurs is still unknown. MicroRNAs (miRNAs) are regulators of cancers including hepatocellular carcinoma (HCC). However, the role that miRNAs play in the regulation of IL-24 in HCC is unclear. The aim of this study was to investigate the effects of regulation of IL-24 by miR-203a-3p.1 on liver cancer cell proliferation and metastasis. IL-24 mRNA and miR-203a-3p.1 were detected by real-time RT-PCR, and IL-24 protein in the cell growth medium was measured by ELISA. A luciferase assay was used to verify that the IL-24 gene was the target of miR-203a-3p.1. Cell survival ability was detected by the MTT assay and colony formation. Cell metastasis was assayed by the Transwell system. The results showed that IL-24 could be down-regulated by miR-203a-3p.1 in HCC cells and that miR-203a-3p.1 acted as an onco-miRNA by targeting IL-24. Inhibition of miR-203a-3p.1 in cells could lead to the reversal of HCC cell proliferation and metastasis. The study highlights a novel molecular interaction between miR-203a-3p.1 and IL-24, which indicates that IL-24 and miR-203a-3p.1 may constitute potential therapeutic targets for HCC.
| S-EPMC5536994 | biostudies-other
Project description:In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1β in PNAC. Pharmacological antagonism of IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1β) prevents PNAC in mice. IL-1β increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes (Abcc2, Abcb11, and Abcg5/8), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1β, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC.
| S-EPMC5895696 | biostudies-literature