Explore the vast range of titles available.

This study aimed to investigate the protective effect of curcumin against carbon tetrachloride (CCl4)-induced acute liver injury in a mouse model, and to explain the underlying mechanism. Curcumin at doses of 50, 100 and 200 mg/kg/day were administered orally once daily for seven days prior to CCl4 exposure. At 24 h, curcumin-attenuated CCl4 induced elevated serum transaminase activities and histopathological damage in the mouse’s liver. Curcumin pre-treatment at 50, 100 and 200 mg/kg significantly ameliorated CCl4-induced oxidative stress, characterized by decreased malondialdehyde (MDA) formations, and increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) content, followed by a decrease in caspase-9 and -3 activities. Curcumin pre-treatment significantly decreased CCl4-induced inflammation. Furthermore, curcumin pre-treatment significantly down-regulated the expression of TGF-β1 and Smad3 mRNAs (both p < 0.01), and up-regulated the expression of nuclear-factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both p < 0.01) in the liver. Inhibition of HO-1 attenuated the protective effect of curcumin on CCl4-induced acute liver injury. Given these outcomes, curcumin could protect against CCl4-induced acute liver injury by inhibiting oxidative stress and inflammation, which may partly involve the activation of Nrf2/HO-1 and inhibition of TGF-β1/Smad3 pathways.

Myocardial fibrosis after myocardial infarction (MI) is a leading cause of heart diseases. MI activates cardiac fibroblasts (CFs) and promotes CF to myofibroblast transformation (CMT). This study aimed to investigate the role of miR‐21 in the regulation of CMT and myocardial fibrosis. Primary rat CFs were isolated from young SD rats and treated with TGF‐β1, miR‐21 sponge or Jagged1 siRNA. Cell proliferation, invasion and adhesion were detected. MI model was established in male SD rats using LAD ligation method and infected with recombinant adenovirus. The heart function and morphology was evaluated by ultrasonic and histological analysis. We found that TGF‐β1 induced the up‐regulation of miR‐21 and down‐regulation of Jagged1 in rat CFs. Luciferase assay showed that miR‐21 targeted 3′‐UTR of Jagged1 in rat CFs. miR‐21 sponge inhibited the transformation of rat CFs into myofibroblasts, and abolished the inhibition of Jagged1 mRNA and protein expression by TGF‐β1. Furthermore, these effects of miR‐21 sponge on rat CFS were reversed by siRNA mediated knockdown of Jagged1. In vivo, heart dysfunction and myocardial fibrosis in MI model rats were partly improved by miR‐21 sponge but were aggravated by Jagged1 knockdown. Taken together, these results suggest that miR‐21 promotes cardiac fibroblast‐to‐myofibroblast transformation and myocardial fibrosis by targeting Jagged1. miR‐21 and Jagged1 are potential therapeutic targets for myocardial fibrosis.

Liver fibrosis is a necessary stage in the development of chronic liver diseases to liver cirrhosis. This study aims to investigate the anti‐fibrotic effects of levo‐tetrahydropalmatine (L‐THP) on hepatic fibrosis in mice and cell models and its underlying mechanisms. Two mouse hepatic fibrosis models were generated in male C57 mice by intraperitoneal injection of carbon tetrachloride (CCl4) for 2 months and bile duct ligation (BDL) for 14 days. Levo‐tetrahydropalmatine was administered orally at doses of 20 and 40 mg/kg. An activated LX2 cell model induced by TGF‐β1 was also generated. The results showed that levo‐tetrahydropalmatine alleviated liver fibrosis by inhibiting the formation of extracellular matrix (ECM) and regulating the balance between TIMP1 and MMP2 in the two mice liver fibrosis models and cell model. Levo‐tetrahydropalmatine inhibited activation and autophagy of hepatic stellate cells (HSCs) by modulating PPARγ/NF‐κB and TGF‐β1/Smad pathway in vivo and in vitro. In conclusion, levo‐tetrahydropalmatine attenuated liver fibrosis by inhibiting ECM deposition and HSCs autophagy via modulation of PPARγ/NF‐κB and TGF‐β1/Smad pathway.

Systemic Sclerosis (SSc) is a rare fibrotic autoimmune disorder for which no curative treatments currently exist. Metabolic remodelling has recently been implicated in other autoimmune diseases; however, its potential role in SSc has received little attention. Here, we aimed to determine whether changes to glycolysis and glutaminolysis are important features of skin fibrosis. TGF‐β1, the quintessential pro‐fibrotic stimulus, was used to activate fibrotic pathways in NHDFs in vitro. Dermal fibroblasts derived from lesions of SSc patients were also used for in vitro experiments. Parameters of glycolytic function were assessed using by measuring extracellular acidification in response to glycolytic activators/inhibitors, whilst markers of fibrosis were measured by Western blotting following the use of the glycolysis inhibitors 2‐dg and 3PO and the glutaminolysis inhibitor G968. Succinate was also measured after TGF‐β1 stimulation. Itaconate was added to SSc fibroblasts and collagen examined. TGF‐β1 up‐regulates glycolysis in dermal fibroblasts, and inhibition of glycolysis attenuates its pro‐fibrotic effects. Furthermore, inhibition of glutamine metabolism also reverses TGF‐β1‐induced fibrosis, whilst glutaminase expression is up‐regulated in dermal fibroblasts derived from SSc patient skin lesions, suggesting that enhanced glutamine metabolism is another aspect of the pro‐fibrotic metabolic phenotype in skin fibrosis. TGF‐β1 was also able to enhance succinate production, with increased succinate shown to be associated with increased collagen expression. Incubation of SSc cells with itaconate, an important metabolite, reduced collagen expression. TGF‐β1 activation of glycolysis is a key feature of the fibrotic phenotype induced by TGF‐B1 in skin cells, whilst increased glutaminolysis is also evident in SSc fibroblasts.

Background Idiopathic pulmonary fibrosis (IPF) bears high mortality due to unclear pathogenesis and limited therapeutic options. Therefore, identifying novel regulators is required to develop alternative therapeutic strategies. Methods The lung fibroblasts from IPF patients and Reticulocalbin 3 (RCN3) fibroblast-selective knockdown mouse model were used to determine the importance of Rcn3 in IPF; the epigenetic analysis and protein interaction assays, including BioID, were used for mechanistic studies. Results Reticulocalbin 3 (RCN3) upregulation is associated with the fibrotic activation of lung fibroblasts from IPF patients and Rcn3 overexpression blunts the antifibrotic effects of pirfenidone and nintedanib. Moreover, repressing Rcn3 expression in mouse fibroblasts ameliorates bleomycin-induced lung fibrosis and pulmonary dysfunction in vivo. Mechanistically, RCN3 promotes fibroblast activation by maintaining persistent activation of TGFβ1 signalling via the TGFβ1-RCN3-TGFBR1 positive feedback loop, in which RCN3 upregulated by TGFβ1 exposure detains EZH2 (an epigenetic methyltransferase) in the cytoplasm through RCN3-EZH2 interaction, leading to the release of the EZH2-H3K27me3 epigenetic repression of TGFBR1 and the persistent expression of TGFBR1. Conclusions These findings introduce a novel regulating mechanism of TGFβ1 signalling in fibroblasts and uncover a critical role of the RCN3-mediated loop in lung fibrosis. RCN3 upregulation may cause resistance to IPF treatment and targeting RCN3 could be a novel approach to ameliorate pulmonary fibrosis. Graphical Abstract

Background Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear. Methods CRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils. Results Our study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition . Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor- β1 (TGF-β1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF- β1 axis. Conclusion Our study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.

Stress-induced premature cellular senescence is a significant factor in the onset of age-dependent disease in the cardiovascular system. Plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1/p53 target gene and negative regulator of the plasmin-based pericellular proteolytic cascade, is elevated in arterial plaques, vessel fibrosis, arteriosclerosis, and thrombosis, correlating with increased tissue TGF-β1 levels. Additionally, PAI-1 is necessary and sufficient for the induction of p53-dependent replicative senescence. The mechanism of PAI-1 transcription in senescent cells appears to be dependent on caveolin-1 signaling. Src kinases are upstream effectors of both FAK and caveolin-1 activation as FAKY577,Y861 and caveolin-1Y14 phosphorylation are not detected in TGF-β1-stimulated src family kinase (pp60c-src, Yes, Fyn) triple-deficient (SYF−/−/−) cells. However, restoration of pp60c-src expression in SYF-null cells rescued both caveolin-1Y14 phosphorylation and PAI-1 induction in response to TGF-β1. Furthermore, TGF-β1-initiated Src phosphorylation of caveolin-1Y14 is critical in Rho-ROCK-mediated suppression of the SMAD phosphatase PPM1A maintaining and, accordingly, SMAD2/3-dependent transcription of the PAI-1 gene. Importantly, TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells, correlating with reductions in both Rho-GTP loading and SMAD2/3 phosphorylation. These findings implicate caveolin-1 in expression controls on specific TGF-β1/p53 responsive growth arrest genes. Indeed, up-regulation of caveolin-1 appears to stall cells in G0/G1 via activation of the p53/p21 cell cycle arrest pathway and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene. Although the mechanism is unclear, caveolin-1 inhibits p53/MDM2 complex formation resulting in p53 stabilization, induction of p53-target cell cycle arrest genes (including PAI-1), and entrance into premature senescence while stimulating the ATM→p53→p21 pathway. Identification of molecular events underlying senescence-associated PAI-1 expression in response to TGF-β1/src kinase/p53 signaling may provide novel targets for the therapy of cardiovascular disease.

This study investigated the effects of Golgi membrane protein 73 (GP73) on the epithelial–mesenchymal transition (EMT) and on bladder cancer cell invasion and metastasis through the TGF‐β1/Smad2 signalling pathway. Paired bladder cancer and adjacent tissue samples (102) and normal bladder tissue samples (106) were obtained. Bladder cancer cell lines (T24, 5637, RT4, 253J and J82) were selected and assigned to blank, negative control (NC), TGF‐β, thrombospondin‐1 (TSP‐1), TGF‐β1+ TSP‐1, GP73‐siRNA‐1, GP73‐siRNA‐2, GP73‐siRNA‐1+ TSP‐1, GP73‐siRNA‐1+ pcDNA‐GP73, WT1‐siRNA and WT1‐siRNA + GP73‐siRNA‐1 groups. Expressions of GP73, TGF‐β1, Smad2, p‐Smad2, E‐cadherin and vimentin were detected using RT‐qPCR and Western blotting. Cell proliferation, migration and invasion were determined using MTT assay, scratch testing and Transwell assay, respectively. Compared with the blank and NC groups, levels of GP73, TGF‐β1, Smad2, p‐Smad2, N‐cadherin and vimentin decreased, and levels of WT1 and E‐cadherin increased in the GP73‐siRNA‐1 and GP73‐siRNA‐2 groups, while the opposite results were observed in the WT1 siRNA, TGF‐β, TSP‐1 and TGF‐β + TSP‐1 groups. Cell proliferation, migration and invasion notably decreased in the GP73‐siRNA‐1 and GP73‐siRNA‐2 groups in comparison with the blank and NC groups, while in the WT1 siRNA, TGF‐β, TSP‐1 and TGF‐β + TSP‐1 groups, cell migration, invasion and proliferation showed the reduction after the EMT. These results suggest that GP73 promotes bladder cancer invasion and metastasis by inducing the EMT through down‐regulating WT1 levels and activating the TGF‐β1/Smad2 signalling pathway.