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Epithelial‐mesenchymal transition (EMT) plays an important role in idiopathic pulmonary fibrosis (IPF). Astragaloside IV (ASV), a natural saponin from astragalus membranaceus, has shown anti‐fibrotic property in bleomycin (BLM)‐induced pulmonary fibrosis. The current study was undertaken to determine whether EMT was involved in the beneficial of ASV against BLM‐induced pulmonary fibrosis and to elucidate its potential mechanism. As expected, in BLM‐induced IPF, ASV exerted protective effects on pulmonary fibrosis and ASV significantly reversed BLM‐induced EMT. Intriguing, transforming growth factor‐β1 (TGF‐β1) was found to be up‐regulated, whereas Forkhead box O3a (FOXO3a) was hyperphosphorylated and less expressed. However, ASV treatment inhibited increased TGF‐β1 and activated FOXO3a in lung tissues. TGF‐β1 was administered to alveolar epithelial cells A549 to induce EMT in vitro. Meanwhile, stimulation with TGF‐β1‐activated phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway and induced FOXO3a hyperphosphorylated and down‐regulated. It was found that overexpression of FOXO3a leading to the suppression of TGF‐β1‐induced EMT. Moreover, ASV treatment, similar with the TGF‐β1 or PI3K/Akt inhibitor, reverted these cellular changes and inhibited EMT in A549 cells. Collectively, the results suggested that ASV significantly inhibited TGF‐β1/PI3K/Akt‐induced FOXO3a hyperphosphorylation and down‐regulation to reverse EMT during the progression of fibrosis.

Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of α v integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α v β 6 integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a ‘straitjacket’ that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis. Key growth factor structure determined Members of the transforming growth factor-β (TGF-β) superfamily of growth factors are of fundamental importance in development and tissue homeostasis. TGF-β is secreted as an inactive complex that has to be activated to enable receptor binding and activation of downstream signalling events. Cell surface adhesion receptors of the integrin family are essential for the activation of TGF-β. Shi et al . present the structure of latent TGF-β and provide mechanistic insights into latency and force-dependent activation by integrins.

The incidence and mortality of breast cancer (BC) continue to increase, making it a matter of public health concern worldwide. Despite the various strides made in breast cancer (BC) research, the molecular mechanisms driving its progression remain incompletely understood, particularly the role of key regulatory genes in tumor development and therapy resistance. TGFβ-1, IL19, CXCR4, BMP1, VCAN, and WNT2 have been implicated to be instrumental to critical oncogenic pathways; however, their cumulative contribution toward the pathophysiology of BC has not yet been investigated. Therefore, the present study utilizes an integrative bioinformatics approach to decipher their functional relevance, providing a basis for targeted therapies. TGF-β1, IL19, CXCR4, BMP1, VCAN, and WNT2 are among the important genes in BC that we have studied in great detail using bioinformatics techniques that detail differential gene expression analysis for their dysregulation in BC. Their broader oncogenic implications were then clarified by performing pan-cancer and pathway enrichment analyses. Molecular docking studies were employed to comprehend the functional interactions and potential therapeutic targets in protein-protein interaction (PPI) networks. It is demonstrated by our study that TGFβ-1 and CXCR4 are critical factors in the tumorigenesis of BC and their inhibition shows interference with tumor-associated pathways in a synergistic way. Computational modelling suggests that concomitant inhibition of these two targets, with D4476 and AMD3100, may show therapeutic value through modulation of certain key signalling cascades. This study provide new insights into the molecular basis of BC and support the idea of targeting TGFβ-1 and CXCR4 together for therapy. The above findings lay the foundation for future in vitro and in vivo experiments aimed at demonstrating that inhibition of both factors would be a viable strategy to improve the therapeutic outcome in BC.

Chronic allograft dysfunction (CAD) induced by kidney interstitial fibrosis is the main cause of allograft failure in kidney transplantation. Endothelial‐to‐mesenchymal transition (EndMT) may play an important role in kidney fibrosis. We, therefore, undertook this study to characterize the functions and potential mechanism of EndMT in transplant kidney interstitial fibrosis. Proteins and mRNAs associated with EndMT were examined in human umbilical vein endothelial cells (HUVECs) treated with transforming growth factor‐beta1 (TGF‐β1) at different doses or at different intervals with western blotting, qRT‐PCR and ELISA assays. Cell motility and migration were evaluated with motility and migration assays. The mechanism of EndMT induced by TGF‐β1 was determined by western blotting analysis of factors involved in various canonical and non‐canonical pathways. In addition, human kidney tissues from control and CAD group were also examined for these proteins by HE, Masson's trichrome, immunohistochemical, indirect immunofluorescence double staining and western blotting assays. TGF‐β1 significantly promoted the development of EndMT in a time‐dependent and dose‐dependent manner and promoted the motility and migration ability of HUVECs. The TGF‐β/Smad and Akt/mTOR/p70S6K signalling pathways were found to be associated with the pathogenesis of EndMT induced by TGF‐β1, which was also proven in vivo by the analysis of specimens from the control and CAD groups. EndMT may promote transplant kidney interstitial fibrosis by targetting the TGF‐β/Smad and Akt/mTOR/p70S6K signalling pathways, and hence, result in the development of CAD in kidney transplant recipients.

BackgroundHereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) can be caused by SMAD4 pathogenic variants. SMAD4 is a common transcription factor of the BMP/TGFβ signalling pathway. In this study, we developed a cell-based functional assay to address the pathogenicity of SMAD4 variants identified in the French HHT cohort.MethodsSMAD4 variants were generated by site-directed mutagenesis. A functional assay was developed in a cell line that does not express SMAD4, and the different SMAD4 variants were tested for their capacity to activate the BMP and TGFβ response using luciferase reporter assays.ResultsTwelve SMAD4 variants were identified and studied. We were able to develop a robust functional assay for these variants. All the expressed variants resulted in loss of function (LOF) in response to BMP9 or TGFβ1 stimulation. SMAD4 variants within the MH2 domain expressed SMAD4 mutated proteins that were unable to hetero-oligomerise with other SMADs, which could explain their LOF. Finally, we tested primary human endothelial cells isolated from patients with HHT carrying SMAD4 heterozygous pathogenic variants and observed that they behaved like the control cells at rest or when stimulated with BMP9.ConclusionWe developed a SMAD4 functional assay that allows discrimination between benign and pathogenic SMAD4 variants. We demonstrated that the underlying molecular mechanism of this pathogenicity is due mostly to a loss of hetero-oligomerisation. This assay will be transferable to clinical genetic laboratories and will improve the diagnosis of patients with HHT–JPS.

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health 1 , it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease 2 , 3 . Resident microglia in the central nervous system are identified as the specific macrophage population that regulates myelin growth and integrity.

Objectives To compare the effect of lung recruitment using high frequency ventilation versus volume targeted ventilation on duration of intubation as well as its effect on lung inflammation in preterm infants with respiratory distress syndrome. Methods The study was conducted on a total of 40 preterm infants, 34 weeks gestational age or less, having RDS that needed intubation and mechanical ventilation within the first 72 h after their birth at the NICU of Mansoura University Children’s Hospital during the period from July 2020 to July 2022. Infants included were randomly assigned into two groups, Group A who were subjected to LRM using HFOV (20 cases) and Group B who were subjected to LRM using VTV/AC (20 cases). TGF-β1 level was measured in BAL samples of all studied infants at two time points; before lung recruitment maneuver and at day 5 after lung recruitment or just before extubation if extubation occurs earlier than 5 days. Results Lung recruitment maneuver had no significant effect on time to extubation. Both groups showed no significant difference in rate of prematurity complications nor delta change of TFG-β1 level in tracheal aspirate of those preterm infants measured before lung recruitment and five days after recruitment or at extubation when extubation occurred earlier. Conclusions Lung recruitment maneuver was not associated with significant difference between both groups of preterm infants. The results obtained from our study, being the first of its kind to compare the effect of lung recruitment, provide a promising research area for further investigations.

Background 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. Aims To evaluate the safety and tolerability of STP705 for localized fat reduction in subjects undergoing abdominoplasty. Methods 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. Results 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. Conclusion 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. Trial Registration ClinicalTrials.gov identifier: NCT05422378

Background Paracetamol and ibuprofen are commonly prescribed pain relievers used in dental treatments, but their use can delay wound healing and lead to malunion and weaken the strength of newly formed bones. This randomized controlled clinical trial aimed to evaluate the wound healing (WH) and anti-inflammatory effects of paracetamol and ibuprofen on tooth extraction wounds in patients. Methods This study involved a total of 20 patients who required removal of their fully erupted upper third molar under local anaesthesia at the Oral and Maxillofacial Surgery Clinic, Faculty of Dentistry, Chiang Mai University. The study subjects were divided into two groups of 10 patients each who were prescribed 400 mg of ibuprofen or 500 mg of paracetamol for seven days. Subsequently, WH was evaluated and the resulting proportions were compared using Landry Turnbull and Howley Index (LTHI) scores. Salivary matrix metalloproteinase 9 (MMP-9) and transforming growth factor beta1 (TGF-β1) concentrations were used as proinflammatory indicators. Accordingly, the WH values and the resulting proportions were compared using Fisher’s exact test with a confidence interval (CI) of 95% ( P  < 0.05). The concentrations of MMP-9 and TGF-β1 were measured using ELISA and compared using the Mann‒Whitney U test at 95% CI ( P  < 0.05). The obtained statistical values were then analysed and interpreted accordingly. Results LTHI values on days 3 and 7 after tooth extraction were not significantly different between the two treatment groups. Salivary MMP-9 levels were lower in the paracetamol-treated group than in the ibuprofen-treated group ( P  < 0.01) on day 3 only. The LTHI concentration was also negatively correlated ( r = -0.433) with the MMP-9 concentration ( P  < 0.05) but was positively correlated ( r  = 0.369) with the salivary TGF-β1 concentration ( P  < 0.05). Interestingly, MMP-9 was negatively correlated with TGF-β1 in the ibuprofen treatment group (r 2 = -0.351). Conclusion Ibuprofen can inhibit the inflammatory process and delay healing in the extraction socket. After discontinuation of medication, no differences were observed in the healing effects between the paracetamol and ibuprofen groups. Trial registration The clinical trial was retrospectively registered at the Australian New Zealand Clinical Trial Registry (ANZCTR) NHMRC Clinical Trials Centre, Camperdown, Australia (Registry URL: https://www.anzctr.org.au ) (Registration number: ACTRN12624000595516 Date: 9/5/2024).

The appearance and growth of malignant tumors is a complicated process that is regulated by a number of genes. In recent years, studies have revealed that the transforming growth factor-β (TGF-β) signaling pathway serves an important role in cell cycle regulation, growth and development, differentiation, extracellular matrix synthesis and immune response. Notably, two members of the TGF-β signaling pathway, TGF-β1 and TGF-β receptor 1 (TGF-βR1), are highly expressed in a variety of tumors, such as breast cancer, colon cancer, gastric cancer and hepatocellular carcinoma. Moreover, an increasing number of studies have demonstrated that TGF-β1 and TGF-βR1 promote proliferation, migration and epithelial-mesenchymal transition of tumor cells by activating other signaling pathways, signaling molecules or microRNAs (miRs), such as the NF-κB signaling pathway and miR-133b. In addition, some inhibitors targeting TGF-β1 and TGF-βR1 have exhibited positive effects in in vitro experiments. The present review discusses the association between TGF-β1 or TGF-βR1 and tumors, and the development of some inhibitors, hoping to provide more approaches to help identify novel tumor markers to restrain and cure tumors.