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The epithelial-mesenchymal transition (EMT) is a biological process in which epithelial cells change into mesenchymal cells with fibroblast-like characteristics. EMT plays a crucial role in the progression of fibrosis. Classical inducers associated with the maintenance of EMT, such as TGF-β1, have become targets of several anti-EMT therapeutic strategies. Natural products from the pentacyclic triterpene class have emerged as promising elements in inhibiting EMT. Uvaol is a pentacyclic triterpene found in olive trees (Olea europaea L.) known for its anti-inflammatory, antioxidant, and antiproliferative properties. Yet, its effect on the TGF-β1-induced EMT in alveolar epithelial cells is unknown. The present study aimed to investigate the impact of uvaol upon TGF-β1-induced EMT in a cultured A549 human alveolar epithelial cell line, a classic in vitro model for studies of EMT. Changes in cell shape were measured using phase-contrast and confocal microscopy, whereas protein expression levels were measured using immunofluorescence, flow cytometry, and Western blotting. We also performed wound scratch experiments to explore its effects on cell migration. Uvaol had no significant cytotoxic effects on A549 cells. By contrast, the changes in the cell morphology consistent with TGF-β1-induced EMT were largely suppressed by treatment with uvaol. In addition, increased contents of mesenchymal markers, namely, vimentin, N-cadherin, and fibronectin in TGF-β1-induced A549 cells, were downregulated by uvaol treatment. Furthermore, the TGF-β1-induced migration of A549 cells was significantly suppressed by uvaol. Mechanistically, uvaol prevented the nuclear translocation of β-catenin and reduced the TGF-β1-induced levels of ZEB1 in A549 cells. These results provide compelling evidence that uvaol inhibits EMT by regulating proteins related to the mesenchymal profile in human alveolar epithelial cells, likely by modulating β-catenin and ZEB1 levels. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Trial Registration Airway remodelling is a feature of severe asthma with airway epithelial damage observed frequently. We evaluated the role of WNT5a and TGF‐β1 in asthmatic airway biopsies and in sputum and bronchial brushings assessed their role in remodelling.WNT5a and TGF‐β1 protein expression were assessed in the lamina propria epithelium of people with asthma (GINA 1–3, n‐8 and GINA 4–5, n‐14) and healthy subjects (n‐9), alongside relevant remodelling markers. The effects of WNT5a and TGF‐β1 on BEAS‐2B epithelial cell wound healing and differentiation were assessed in vitro. Replication was performed in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U‐BIOPRED) study in sputum (n = 120) and bronchial brushes (n = 147).WNT5a and TGF‐β1 protein expression were significantly increased in the airway epithelium and lamina propria in asthma patients with concurrent airflow limitation or severe disease. Furthermore, WNT5a protein expression in the lamina propria correlated with tissue eosinophils and vascular remodelling. Airway epithelial WNT5a was co‐localised predominantly to airway basal cells and correlated with Th17 gene expression (r = 0.40, p = 0.025) and both the % intact (rs = 0.54, p = 0.001) and % denuded epithelium (rs = −0.39, p = 0.003). Experiments in BEAS‐2B cells confirmed that WNT5a at maximal physiological concentrations (1 μg/mL), promoted epithelial wound healing, independently of TGF‐β1, as well as induction of EMT‐like morphology. WNT5a mRNA was associated with severe asthma, airflow limitation, sputum eosinophilia and Th2, and Th17 and neutrophil activation transcriptomes in sputum in U‐BIOPRED.WNT5a is associated with both airway remodelling and severe asthma.ClinicalTrials.gov identifier: NCT01982162 [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis is a worldwide disease that develops from activation and propagation of hepatic stellate cells, and subsequent extracellular matrix accumulation. Liver fibrosis is associated with multiple pathways, however, the dysregulation of GIPC1 gene (GIPC PDZ domain containing family member 1) and disruption in the balance of MMPs (matrix metalloproteinases) and TIMPs (tissue inhibitor of metalloproteinases) remain as key factors in this disease. Curcuminoids, especially curcumin (CURC), are medicinal extracts that proved their antioxidative, anti-inflammatory, antifibrotic actions, and showed wide epigenetic regulatory effects. We aimed to explore CURC's effect on declining the inflammatory cytokines TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), TGF-β1 (transforming growth factor beta1), regulating GIPC1 expression, and adjusting MMP-8/TIMP-3 balance mediated by miRNA-483-5p (microRNA-483-5p) in TAA (thioacetamide)-induced liver fibrotic albino Wistar rat model. Results: The attained results revealed significant regressions in livers' relative weights, serum ALT (alanine aminotransferase), AST (aspartate aminotransferase), ALP (alkaline phosphatase) and LDH (lactate dehydrogenase), plasma PDGF (platelet-derived growth factor), liver TOC (total oxidative capacity), TNF-α, IL-6, TGF-β1, and downregulation in GIPC1 gene expression, besides, significant elevation in liver TAC (total antioxidant capacity) in CURC-treated rats. Surprisingly, significant upregulation in miRNA-483 expression was obtained in CURC-treated rats which consequentially enhanced MMP-8/TIMP-3 balance in the form of an elevation in MMP-8/reduction in TIMP-3 levels, along with confirming this novel pathway through conducting bioinformatics analysis. All these enhancements were mirrored in Annexin V/PI (Annexin V Propidium Iodide) assay as massive improvements in % of apoptotic and necrotic cells, plus, in H&E (hematoxylin and eosin) and Masson's trichrome histopathological examinations that showed near to normal liver architecture with no collagen bands deposition. Conclusions: This study concludes that CURC can modulate the novel miRNA-483-5p/MMP-8/TIMP-3 pathway and regulate GIPC1 expression, thus providing new perception of CURC as an effective therapeutic agent capable of lowering inflammation and remodeling liver damage. [ABSTRACT FROM AUTHOR]

Peyronie's disease (PD) is a disorder characterized by fibrous plaque formation in the penile tissue that leads to curvature and complications in advanced stages. In this study, we aimed to compare four injectable induction agents for the establishment of a robust rat model of PD: transforming growth factor-β1 (TGF-β1), fibrin, sodium tetradecyl sulfate (STS) combined with TGF-β1, and polidocanol (POL) combined with TGF-β1. The results showed that injection of TGF-β1 or fibrin into the tunica albuginea induced pathological endpoints without causing penile curvature. The STS + TGF-β1 combination resulted in both histological and morphological alterations, but with a high incidence of localized necrosis that led to animal death. The POL + TGF-β1 combination produced pathological changes and curvature comparable to STS + TGF-β1 and led to fewer complications. In conclusion, fibrin, STS + TGF-β1, and POL + TGF-β1 all induced PD with a certain degree of penile curvature and histological fibrosis in rats. The POL + TGF-β1 combination offered comparatively greater safety and clinical relevance and may have the greatest potential for PD research using model rats. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion The cancer cell marker poliovirus receptor‐like protein 4 (PVRL4) has been shown to be highly expressed in many cancers, including lung cancer. Myeloid‐derived suppressor cells (MDSCs) are a population of immature myeloid cells with immunosuppressive roles that can attenuate the anticancer response. Here, the precise functions and the relationship between PVRL4 and MDSCs in lung adenocarcinoma (LUAD) progression were investigated.Detection of levels of mRNAs and proteins was conducted using qRT‐PCR and western blotting. The CCK‐8, colony formation, transwell, wound healing assays, and flow cytometry were used to explore cell growth, invasion, migration, and apoptosis, respectively. ELISA analysis detected TGF‐β1 contents. LUAD mouse models were established for in vivo assay. Exosomes were isolated by ultracentrifugation. MDSCs were induced from peripheral blood mononuclear cells (PBMCs) by cytokine or co‐culture with cancer cells.LUAD tissues and cells showed high PVRL4 expression, and PVRL4 deficiency suppressed LUAD cell proliferation, invasion, migration, and induced cell apoptosis in vitro, and impeded LUAD growth in vivo. Thereafter, we found that PVRL4 was packaged into exosomes in LUAD cells, and could be transferred into PBMCs to promote MDSC induction and the expression of MDSC‐secreted TGF‐β1. Functionally, the silencing of exosomal PVRL4 impaired LUAD cell proliferation, invasion, migration, and evoked cell apoptosis, which could be reversed by the incubation of TGF‐β1‐overexpressed MDSCs.Exosomal PVRL4 promoted LUAD progression by inducing the secretion of TGF‐β1 in MDSCs, indicating a novel direction for LUAD immunotherapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusion Trial Registration Rising demand for non‐invasive body contouring is driven by aesthetics and the obesity epidemic. Deoxycholic acid (DCA) is the only FDA‐approved injectable for fat reduction but can cause side effects and significant local skin reactions (LSR). RNA interference, using small interfering RNA (siRNA) molecules, offers targeted fat reduction by silencing genes involved in fat maintenance. STP705, a siRNA injectable targeting TGF‐β1 and COX‐2, has shown promising preclinical results both in vitro and in animal models.To evaluate the safety and tolerability of STP705 for localized fat reduction in subjects undergoing abdominoplasty.This phase I dose‐ranging, randomized, vehicle‐controlled trial involved eight females undergoing abdominoplasty who received subcutaneous STP705 injections at varying concentrations and volumes in designated abdominal zones. Safety assessments, including physical exams, lab tests, ECGs, and local skin reactions (LSRs), were conducted at baseline and follow‐ups. Histopathologic evaluations of biopsies collected during abdominoplasty assessed adipocyte apoptosis and tissue remodeling.STP705 demonstrated a favorable safety profile with no clinically significant changes in lab values, vital signs, or ECGs. Adverse events (AEs) were rare and transient. The incidence, intensity, and duration of LSRs were low throughout the study. Histological analysis revealed adipocyte destruction, fat remodeling, and necrosis.STP705 was safe and very well‐tolerated and showed preliminary efficacy in inducing adipocyte apoptosis and tissue remodeling, suggesting a safer alternative or adjunct to existing fat reduction therapies. These findings support further trials to establish the safety and efficacy of STP705 for targeted fat reduction and body contouring.ClinicalTrials.gov identifier: NCT05422378 [ABSTRACT FROM AUTHOR]

Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice. We examined whether arketamine can improve both depression-like behaviors and demyelination in the brains of CRS-exposed mice. Additionally, we investigated the role of transforming growth factor β1 (TGF-β1) in the beneficial effects of arketamine. A single dose of arketamine (10 mg/kg) improved both depression-like behavior and demyelination in the corpus callosum of CRS-exposed mice. Correlations were found between depression-like behaviors and demyelination in this region. Furthermore, pretreatment with RepSox, an inhibitor of TGF-β1 receptor, significantly blocked the beneficial effects of arketamine on depression-like behaviors and demyelination in CRS-exposed mice. Finally, a single intranasal administration of TGF-β1 ameliorated both depression-like behaviors and demyelination in CRS-exposed mice. The precise mechanisms by which TGF-β1 contributes to the effects of arketamine remain unclear. These data suggest that CRS-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and that arketamine can mitigate these changes through a TGF-β1-dependent mechanism. • Chronic restrain stress (CRS) induces demyelination in the brain. • Arketamine mitigated depression-like behaviors and demyelination in CRS-exposed mice. • TGF-β1 receptor inhibitor blocked the effects of arketamine in CRS-exposed mice. • Intranasal injection of TGF-β1 improved depression-like behaviors and demyelination in CRS-exposed mice [ABSTRACT FROM AUTHOR]

Background/Objectives: Pterygium is a nonneoplastic elastotic degeneration characterized by subepithelial growth. It manifests as an ocular lesion originating from the bulbar conjunctiva, extending to the corneal surface, and reaching the visual axis in some cases. Although the exact cause is unknown, prolonged exposure to ultraviolet radiation is considered the most significant contributing factor. Chronic irritation and actinic damage are likely responsible for the typical fibrovascular reactions observed in pterygium. Additionally, growth factors, cytokines, and matrix metalloproteinases play roles in the pathogenesis of pterygium. This study compared recurrent and primary pterygium cases at the molecular level to gain new insights into the etiology of pterygium. Methods: Total protein was extracted from surgical samples of patients with primary and recurrent pterygium, and the levels of transforming growth factor beta 1 (TGF-β1), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), IL-8, and IL-10 were analyzed using the enzyme-linked immunosorbent assay technique. Target gene expression levels were analyzed using the ΔΔCt method after cDNA synthesis from isolated RNA, with normalization to GAPDH and quantification performed with SYBR Green PCR Master Mix. Results: Among the studied cytokines, IL-10 levels were higher in primary pterygium than in recurrent pterygium (722.0 ± 600.9/421.4 ± 266.8) (p = 0.0054). Other cytokines (IL-6, IL-8, IL-1β, and TGF-β1) were detected at similar levels in both primary and recurrent pterygium (p = 0.2986). Additionally, the TGF-β1 gene expression was found to be significantly upregulated in recurrent pterygium tissue compared to primary pterygium tissue (p = 0.034). Conclusions: This increase suggests that TGF-β1 may contribute to the recurrence mechanisms of pterygium through processes such as fibroblast activation and tissue remodeling. The higher levels of IL-10 in primary pterygium compared to recurrent pterygium indicate an enhanced early protective response aimed at limiting pterygium progression and controlling the inflammatory process. [ABSTRACT FROM AUTHOR]

There are some natural products from plants that can prevent and treat disease. Metformin, a derivative of galegine, is the basic drug to treat diabetes. Moreover, this molecule has anticancer properties that inhibit cancer cell growth and proliferation. In this study, the main interactions of galegine and metformin with various cancer‐involved proteins, including mitochondrial alpha‐glycerophosphate dehydrogenase, yeast NADH dehydrogenase, and transforming growth factor‐β1, were surveyed by molecular docking and molecular dynamics simulations. The results showed that each of the proteins makes complexes with the ligands via favorable non‐bonded interactions, especially hydrogen bond interactions. There is greater stability for complexes containing galegine based on the root mean square deviation results. The higher structure compactness is also found in galegine receptors than in metformin receptors. Calculation of ΔGbinding, using the MM/PBSA methodology, shows that the binding energy values for metformin and galegine in interaction with each of the receptors are almost the same, and galegine has similar binding properties with metformin in interaction with the studied protein receptors. Therefore, galegine, a natural ingredient with better binding properties to cancer‐involved proteins than metformin (with various side effects), can be applied as a new drug for cancer treatment. [ABSTRACT FROM AUTHOR]

The progression of monoclonal gammopathies is affected by a range of factors, including the microenvironment surrounding plasma cells. It is recognized that TGF‐β1 plays a distinct role in stimulating IgA production. Hence, this study aims to investigate whether individuals with serum IgA monoclonal immunoglobulins (paraproteins) exhibit elevated total TGF‐β1 levels compared to those with IgG or IgM paraproteins. To achieve this goal, individuals with a positive laboratory finding of monoclonal gammopathy were segregated according to the paraprotein class as well as according to the type of the light chain. Total TGF‐β1 levels were assessed in blood serum samples containing IgG (n = 50), IgA (n = 46), and IgM (n = 31) paraproteins. Elevated level of TGF‐β1 was confirmed in sera with IgA paraproteins (median 25.8 ng/mL; interquartile range IQR: 19.0–33.7) compared to those having IgG (median: 18.2 ng/mL; IQR: 14.3–22.1; p < 0.001) or IgM paraproteins (21.5 ng/mL; IQR: 15.0–27.4; p = 0.043). Also, a higher TGF‐β1 level was detected in sera with IgMλ than those with IgMκ paraproteins (p = 0.043). This research affirms the role of TGF‐β1 in the pathophysiology of IgA monoclonal gammopathies and the potential switch towards the IgA isotype, known for a less favourable prognosis. [ABSTRACT FROM AUTHOR]

Prolonged exposure to environments with high concentrations of crystalline silica (CS) can lead to silicosis. Macrophages play a crucial role in the pathogenesis of silicosis. In the process of silicosis, silica (SiO2) invades alveolar macrophages (AMs) and induces mitophagy which usually exists in three states: normal, excessive, and/or deficiency. Different mitophagy states lead to corresponding toxic responses, including successful macrophage repair, injury, necrosis, apoptosis, and even pulmonary fibrosis. This is a complex process accompanied by various cytokines. Unfortunately, the details have not been fully systematically summarized. Therefore, it is necessary to elucidate the role of macrophage mitophagy in SiO2‐induced pulmonary fibrosis by systematic analysis on the literature reports. In this review, we first summarized the current data on the macrophage mitophagy in the development of SiO2‐induced pulmonary fibrosis. Then, we introduce the molecular mechanism on how SiO2‐induced mitophagy causes pulmonary fibrosis. Finally, we focus on introducing new therapies based on newly developed mitophagy‐inducing strategies. We conclude that macrophage mitophagy plays a multifaceted role in the progression of SiO2‐induced pulmonary fibrosis, and reprogramming the macrophage mitophagy state accordingly may be a potential means of preventing and treating pulmonary fibrosis. Inhalation of crystalline silica (CS) can cause alveolar macrophage mitophagy that usually exists in three states: normal, excessive, and/or deficiency. Among them, mitophagy deficiency induced by high‐dose silica (SiO2) plays a special role in the development of silicosis. Its appearance means that dysfunctional mitochondria damaged by SiO2 cannot be perfectly repaired through autophagy mechanisms, which will cause a series of toxic reactions in macrophages and ultimately lead to pulmonary fibrosis via various mechanisms. [ABSTRACT FROM AUTHOR]