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Intrahepatic cholangiocarcinoma (ICC) is a highly invasive malignant tumor. The prognosis of patients with ICC after radical surgical resection remains poor, due to local infiltration, distant metastasis, a high recurrence rate and lack of effective treatment strategies. E26 transformation-specific sequence variant 4 (ETV4) is a pro-carcinogenic factor that is upregulated in several tumors; however, the role of ETV4 in ICC is relatively unknown. The present study aimed to determine the role of ETV4 in the Hccc9810 ICC cell line and to assess how it contributes to epithelial-mesenchymal transition (EMT) in ICC. Hccc9810 cells were infected with lentiviruses to construct stable ETV4-overexpressing cells, stable ETV4 knockdown cells and corresponding control groups. The Cell Counting Kit-8 and Transwell assays were used to quantify cell proliferation, invasion and migration, and the effects on cell cycle progression and apoptosis were detected by flow cytometry. ETV4 was identified as a driver of cell growth, invasion, migration and cell cycle progression, while restraining apoptosis in Hccc9810 cells. Reverse transcription-quantitative PCR and western blotting revealed that increased ETV4 levels may drive EMT by triggering the TGF-β1/Smad signaling pathway. This cascade, in turn, may foster tumor cell proliferation, migration, invasion and cell cycle advancement, and hinder apoptosis.

Cardiac fibrosis is a pathological consequence of radiation-induced fibroblast proliferation and fibroblast-to-myofibroblast transition (FMT). Mesenchymal stem cell (MSC) transplantation has been revealed to be an effective treatment strategy to inhibit cardiac fibrosis. We identified a novel MSC-driven mechanism that inhibited cardiac fibrosis, via the regulation of multiple fibrogenic pathways. Hypoxia pre-conditioned MSCs (MSCsHypoxia) were co-cultured with fibroblasts using a Transwell system. Radiation-induced fibroblast proliferation was assessed using an MTT assay, and FMT was confirmed by assessing the mRNA levels of various markers of fibrosis, including type I collagen (Col1) and alpha smooth muscle actin (α-SMA). α-SMA expression was also confirmed via immunocytochemistry. The expression levels of Smad7 and Smad3 were detected by western blotting, and Smad7 was silenced using small interfering RNAs. The levels of oxidative stress following radiation were assessed by the detection of reactive oxygen species (ROS) and the activity of superoxide dismutase (SOD), malondialdehyde (MDA), and 4-hydroxynonenal (HNE). It was revealed that co-culturing with MSCsHypoxia could inhibit fibroblast proliferation and FMT. In addition, the present results indicated that MSCs are necessary and sufficient for the inhibition of fibroblast proliferation and FMT by functionally targeting TGF-β1/Smad7/Smad3 signaling via the release of hepatocyte growth factor (HGF). Furthermore, it was observed that MSCs inhibited fibrosis by modulating oxidative stress. Co-culturing with MSCsHypoxia alleviated fibroblast proliferation and FMT via the TGF-β1/Smad7/Smad3 pathway. MSCs may represent a novel therapeutic approach for the treatment of radiation-related cardiac fibrosis.

Metastasis is the primary cause of death in prostate cancer (PCa) patients. Effective therapeutic intervention in metastatic PCa is undermined by our poor understanding of its molecular aetiology. Defining the mechanisms underlying PCa metastasis may lead to insights into how to decrease morbidity and mortality in this disease. Glyoxalase 1 (Glo1) is the detoxification enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). Hydroimidazolone (MG‐H1) and argpyrimidine (AP) are AGEs originating from MG‐mediated post‐translational modification of proteins at arginine residues. AP is involved in the control of epithelial to mesenchymal transition (EMT), a crucial determinant of cancer metastasis and invasion, whose regulation mechanisms in malignant cells are still emerging. Here, we uncover a novel mechanism linking Glo1 to the maintenance of the metastatic phenotype of PCa cells by controlling EMT by engaging the tumour suppressor miR‐101, MG‐H1‐AP and TGF‐β1/Smad signalling. Moreover, circulating levels of Glo1, miR‐101, MG‐H1‐AP and TGF‐β1 in patients with metastatic compared with non‐metastatic PCa support our in vitro results, demonstrating their clinical relevance. We suggest that Glo1, together with miR‐101, might be potential therapeutic targets for metastatic PCa, possibly by metformin administration.

Background Postinfarction cardiac remodeling presents a compensatory mechanism aimed at mitigating congestive heart failure. It is distinguished by progressive dilatation and hypertrophy of the ventricular chambers, fibrotic alterations, and prolonged apoptosis of cardiomyocytes. The primary objective of this study was to assess the effects of icariin on myocardial fibrosis and ventricular remodeling in rats subjected to myocardial infarction (MI). Methods Male Sprague‒Dawley (SD) rats were subjected to randomization and subsequently divided into distinct groups: the control group, the sham group (undergoing sham operation), the MI group (experiencing ligation of the left anterior descending artery), and the icariin group. Within the icariin group, rats were further categorized into three different dose groups based on the administered icariin dosage: the MI30 group (30 mg/kg/day), the MI60 group (60 mg/kg/day), and the MI120 group (120 mg/kg/day). Cardiac function evaluation was carried out using echocardiography. Histological examinations, including hematoxylin and eosin (HE) staining, Masson staining, and immunohistochemistry studies, were conducted 90 days after the occurrence of MI. Additionally, Western blotting was employed to assess TGF‐β1, p-Smad2, and p-Smad3 levels. Results The administration of icariin revealed a noteworthy enhancement in cardiac function among rats afflicted with left anterior descending coronary artery (LAD) ligation. In comparison to the icariin groups, the MI group exhibited reduced EF and FS, along with elevated LVEDD and LVESD. Furthermore, the cardiac fibrosis levels in the MI group rats exhibited a considerable increase compared to those in the icariin group. Notably, the levels of Collagen I, Collagen III, MMP2, and MMP9 were significantly higher in the MI group than in the icariin group, with evident distinctions. Moreover, the expression levels of TGF-β, IL-13, p-Smad2, and p-Smad3 were notably upregulated in the MI group compared to the icariin group. Conclusions In an experimental rat model of MI, the administration of icariin resulted in the amelioration of both cardiac function and remodeling processes, operating through the intricate TGF-β1/Smad signaling pathway.

Skin wounds may threaten quality of life and cause serious complications. This study aimed to investigate the effects of lyophilized exopolysaccharide (L-EPS) obtained from the probiotic strain Lactiplantibacillus plantarum GD2 on various stages of wound healing. The results revealed that L-EPS accelerated in vitro wound healing and increased COL1A1 in L929 cells. L-EPS affected the TGF-β1/Smad signaling pathway by increasing the expression of the TGF-β1, Smad2, Smad3, and Smad4 genes. L-EPS also exerted anti-inflammatory effects by reducing the gene expression of IL-1β, IL-6 and iNOS in TNF-α-induced fibroblasts. Additionally, L-EPS demonstrated fibroproliferative effect on both healthy and TNF-α-induced fibroblasts. Furthermore, L-EPS was found to have a proangiogenic effect in ovo chorioallantoic membrane (CAM) model. This study presents the first-ever characterization of the multifaceted effects of L-EPS derived from the probiotic strain L. plantarum GD2 on wound healing. Our findings highlight the potential of L-EPS as effective agent for wound healing and suggest possible application in the development of wound healing biomaterials. By elucidating the mechanism of action of L-EPS in wound healing, this research may provide new perspectives for advanced treatment strategies in the field of wound care.

The inflammatory response of lung tissue and abnormal proliferation of pulmonary artery smooth muscle cells are involved in the pathogenesis of high-altitude pulmonary hypertension (HAPH). Halofuginone (HF), an active ingredient derivative of Chang Shan ( Dichroa febrifuga Lour. [Hydrangeaceae]), has antiproliferative, antihypertrophic, antifibrotic, and other effects, but its protective effects on HAPH remains unclear. In the present study, we evaluated the efficacy of HF on HAPH by establishing a 6000 m HAPH rat model. Male Sprague–Dawley rats were divided into normoxia, normoxia + halofuginone (1 mg/kg), hypoxia, and hypoxia + halofuginone (1 mg/kg) groups. The results showed that HF (1 mg/kg) could prevent hypoxia-induced hemodynamic abnormalities, right ventricular hypertrophy, and pulmonary vascular remodeling in rats. We further detected the expression levels of inflammatory factors interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and proliferative/antiproliferative indicators proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 6 (CDK6), Cyclin D1, p21 in lung tissue, and found that HF could attenuate the lung tissue inflammatory response and proliferative response in HAPH rats. In addition, we also examined the expression levels of transforming growth factor-β1 (TGF-β1), Smad2/3 and p-Smad2/3 in lung tissue, and found that HF exerted therapeutic effects by inhibiting the TGF-β1/Smad signaling pathway.

Myocardial fibrosis, characterized by increased reactive oxygen species (ROS), is a key pathological feature of diabetic cardiomyopathy (DCM). Although oral edaravone (EDA) shows therapeutic potential in ameliorating myocardial fibrosis in DCM, the precise mechanisms remain unclear. Transcriptome analysis of myocardial tissues revealed a dramatic up-regulation of the TGF-β1/Smad pathway, which was reversed by oral EDA treatment. In vitro studies showed that oral EDA attenuated myocardial fibrosis by inhibiting the TGF-β1/Smad signaling pathway and its downstream fibrosis key factors, Col3a1 and α-SMA. These findings suggest that oral EDA improves myocardial fibrosis in Type 2 diabetes mellitus (T2DM) by inhibiting the TGF-β1/Smad signaling pathway and holds promise as an effective treatment for myocardial fibrosis in DCM. •Transcriptome analysis of myocardial tissues revealed a dramatic up-regulation of the TGF-β1/Smad pathway•In vitro studies showed that EDA attenuated myocardial fibrosis by inhibiting the TGF-β1/Smad signaling pathway and its downstream fibrosis key factors, Col3a1 and α-SMA.

Hypoxia is one of the factors severely affect renal function, and, in severe cases, it can lead to renal fibrosis. Although much progress has been made in identifying the molecular mediators of fibrosis, the mechanisms that govern renal fibrosis remain unclear, and there have been no effective therapeutic anti-fibrotic strategies to date. Mammals exposed to low oxygen in the plateau environment for a long time are prone to high-altitude disease, while yaks have been living in the plateau for generations do not develop kidney fibrosis caused by low oxygen. It has been suggested that metabolic reprogramming occurs in renal fibrosis and that pyruvate dehydrogenase kinase 1 (PDK1) plays a crucial role in metabolic reprogramming as an important node between glycolysis and the tricarboxylic acid cycle. The aim of this study was to investigate the effects of hypoxia on the renal tissues and renal interstitial fibroblasts of yaks. We found that, at the tissue level, HIF-1α, PDK1, TGF-β1, Smad2, Smad3, and α-SMA were mainly distributed and expressed in tubular epithelial cells but were barely present in the renal mesenchymal fibroblasts of healthy cattle and yak kidneys. Anoptical density analysis showed that in healthy cattle kidneys, TGF-β1, Smad2, and Smad3 expression was significantly higher than in yak kidneys (p < 0.05), and HIF-1α and PDK1 expression was significantly lower than in yak kidneys (p < 0.05). The results at the protein and gene levels showed the same trend. At the cellular level, prolonged hypoxia significantly elevated PDK1 expression in the renal mesangial fibroblasts of cattle and yak kidneys compared with normoxia (p < 0.05) and was proportional to the degree of cellular fibrosis. However, PDK1 expression remained stable in yaks compared with renal interstitial fibroblast-like cells in cattle during the same hypoxic time period. At the same time, prolonged hypoxia also promoted changes in cellular phenotype, promoting the proliferation, activation, glucose consumption, lactate production, and anti-apoptosis in the both of cattle and yaks renal interstitial fibroblasts The differences in kidney structure and expression of PDK1 and HIF-1α in kidney tissue and renal interstitial fibroblasts induced by different oxygen concentrations suggest that there may be a regulatory relationship between yak kidney adaptation and hypoxic environment at high altitude. This provides strong support for the elucidation of the regulatory relationship between PDK1 and HIF-1α, as well as a new direction for the treatment or delay of hypoxic renal fibrosis; additionally, these findings provide a basis for further analysis of the molecular mechanism of hypoxia adaptation-related factors and the adaptation of yaks to plateau hypoxia.

Background Liver fibrosis can progress to end-stage cirrhosis and liver cancer. Mesenchymal stem cells (MSCs) were considered the most promising therapeutic strategy, but most of the MSCs injected intravenously traditionally are trapped in the lungs, rapidly reducing their survival ability. MSC spheroids cultured in 3D have shown higher tolerance to fluid shear stress and better survival than dissociated MSCs. Simulating the route of orthotopic liver transplantation, transplanting MSC spheroids into the liver via hepatic portal vein may impact superior therapeutic effects. Methods In the present study, human umbilical cord-derived MSC spheroids (hUC-MSC sp ) were transplanted into rhesus monkey models of liver fibrosis via B-ultrasound-guided percutaneous portal vein puncture with minimized body invasion. The therapeutic effect is evaluated through hematology, ultrasound, and pathology. To study the effect of hUC-MSC sp on gene expression in rhesus monkeys with liver injury, transcriptome sequencing analysis was performed on the livers of rhesus monkeys. The distribution of transplanted hUC-MSC sp was traced with RNA scope technology. Results We found that hUC-MSC sp significantly restored liver function, including ALT, AST, ALB, GLOB and bilirubin. hUC-MSC sp also significantly reduced liver collagen deposition and inflammatory infiltration, and promote dismission of liver ascites. Subsequently, the therapeutic effects were further validated in TGF-β1/Smad pathway by global transcription profile. The distribution of transplanted hUC-MSC sp were also tracked, and we found that hUC-MSC sp distributed in the liver in a sphere status at 1 h after transplantation. After 16 days, the hUC-MSC sp were dispersed into dissociated cells that were predominantly distributed in the spleen, and a significant number of dissociated cells were still present in the liver. Conclusions This study reveals the distributions of transplanted hUC-MSC sp after liver portal vein transplantation, and provides a novel approach and new insights into the molecular events of potential molecular events underlying the treatment of liver fibrosis with hUC-MSC sp .

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal, and chronic lung disease, lacking a validated and effective therapy. Blueberry has demonstrated multiple pharmacological activities including anti-inflammatory, antioxidant, and anticancer. Therefore, the objective of this study was to investigate whether blueberry juice (BBJ) could ameliorate IPF. Experiments in vitro revealed that BBJ could significantly reduce the expressions of TGF-β1 modulated fibrotic protein, which were involved in the cascade of fibrosis in NIH/3T3 cells and human pulmonary fibroblasts. In addition, for rat primary lung fibroblasts (RPLFs), BBJ promoted the cell apoptosis along with reducing the expressions of α-SMA, vimentin, and collagen I, while increasing the E-cadherin level. Furthermore, BBJ could reverse epithelial–mesenchymal transition (EMT) phenotypic changes and inhibit cell migration, along with inducing the upregulation of E-cadherin in A549 cells. Compared with the vehicle group, BBJ treatment alleviated fibrotic pathological changes and collagen deposition in both bleomycin-induced prevention and treatment pulmonary fibrosis models. In fibrotic lung tissues, BBJ remarkably suppressed the expressions of collagen I, α-SMA, and vimentin and improved E-cadherin, which may be related to its inhibition of the TGF-β1/Smad pathway and anti-inflammation efficacy. Taken together, these findings comprehensively proved that BBJ could effectively prevent and attenuate idiopathic pulmonary fibrosis via suppressing EMT and the TGF-β1/Smad signaling pathway.