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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]

Adhesion seriously affects the recovery of tendon gliding function. Our group previously found that inhibition of TGF-β1, which is closely related to adhesion formation, effectively attenuated adhesions but did not eliminate them, suggesting that there may be other mechanisms involved in adhesion formation. In this study, we considered that uncontrolled and excessively proliferating fibroblasts undergo immune escape, which aggravates the deposition of extracellular matrix during the adhesion formation. We found that the expression of the immune checkpoint PD-L1 was significantly elevated after injury and may be involved in adhesion formation. Therefore, we intended to silence both TGF-β1 and PD-L1 to improve the immune advantage in the microenvironment after flexor tendon injury to further reduce adhesion. We constructed the nanoparticle/TGF-β1 or/and PD-L1 siRNAs complexes and verified their high biocompatibility and high transfection efficiency. We found that CD8+ T cells had a greater killing effect on the excessively proliferating cells that were transfected with nanoparticle/TGF-β1 or/and PD-L1 siRNAs. The hydrogel-nanoparticle/TGF-β1 or/and PD-L1 siRNAs system could effectively improve the gliding function of the tendons without weakening the mechanical properties in injured rat FDL tendon and chicken FDP tendon models. In addition, the potential of CD8+ T cells to encircle the adhesion cells on the tendon surface was observed, which resulted in increased levels of cell apoptosis. Thus, our study confirmed that combined knockdown of TGF-β1 and PD-L1 could activate immunodominance after flexor tendon repair and provided a potential treatment to limit adhesion formation and improve gliding function. Adhesion seriously affects the recovery of tendon gliding function. TGF-β1 is related to adhesion formation as it regulates the production of extracellular matrix. We found that excessively proliferated fibroblasts might undergo immune escape, which aggravated the deposition of extracellular matrix. Therefore, we constructed a hydrogel-nanoparticle/TGF-β1 and PD-L1 siRNAs system for silencing TGF-β1 and PD-L1 to improve the immune advantage in the microenvironment after tendon injury. This system could improve the gliding function of tendons without weakening the mechanical property and increase the killing effect of CD8+ T cells. Combined knockdown of TGF-β1 and PD-L1 could activate immunodominance after tendon repair and provide a potential treatment to limit adhesion formation. [Display omitted] [ABSTRACT FROM AUTHOR]

Cytokine(s) pre-activation/licensing is an effective way to enhance the immunomodulatory potency of mesenchymal stromal cells (MSCs). Currently, IFN-γ licensing received the most attention in comparison with other cytokines. After licensing human bone marrow-derived MSCs with pro-/anti-inflammatory cytokines IFN-γ, IL-1β, TNF-α, TGF-β1 alone or in combination, the in vitro immunomodulatory potency of these MSCs was studied by incubating with allogeneic T cells and macrophage-like THP-1 cells. In addition, immunomodulation-related molecules filtered by bioinformatics, complement 1 subcomponent (C1s), and interferon-induced GTP-binding protein Mx2 (MX2), were studied to verify whether to reflect the immunomodulatory potency. Herein, we reported that different cytokines cause different effects on the function of MSC. While TGF-β1 licensing enhances the capacity of MSCs to induce T cells with an immunosuppressive phenotype, IFN-γ-licensing strengthens the inhibitory effect of MSC on T cell proliferation. Both TGF-β1 and IFN-γ licensing can enhance the effect of MSC on reducing the expression of pro-inflammatory cytokines by M1 macrophage-like THP-1 cells. Interestingly, IFN-γ upregulates potential potency markers extracellular C1s and kynurenine (KYN) and intracellular MX2. These 3 molecules have the potential to reflect mesenchymal stromal cell immunomodulatory potency. In addition, we reported that there is a synergistic effect of TGF-β1 and IFN-γ in immunomodulation. [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]

Purpose: Hashimoto's thyroiditis (HT) is one of the most common causes of thyroid dysfunction in iodine sufficient worldwide areas, but its molecular mechanisms are not completely understood. To this regard, this study aimed to assess serum levels of miRNA-29a (miR-29a) and transforming growth factor beta 1 (TGFβ1) in HT patients with different patterns of thyroid function. Methods: A total of 29 HT patients, with a median age of 52 years (21–68) were included. Of these, 13 had normal thyroid function (Eu-HT); 8 had non-treated hypothyroidism (Hypo-HT); 8 had hypothyroidism on replacement therapy with LT4 (subst-HT). All patients had serum miR-29a assayed through qRT-PCR and serum TGFβ1 assayed by ELISA. Results: Serum miR-29a levels were significantly down-regulated in patients with Hypo-HT compared to Eu-HT patients (P < 0.01) and subst-HT patients (P < 0.05). A significant negative correlation was detected between serum miR-29a levels and TSH levels (r = −0.60, P < 0.01). Serum TGFβ1 levels were significantly higher in Hypo-HT than both Eu-HT (P < 0.01) and subst-HT patients (P < 0.05). A negative correlation was observed between serum miR-29a and TGFβ1 (r = −0.75, P < 0.01). Conclusions: In conclusion, Hypo-HT patients had lower levels of serum miR-29a and higher levels of TGFβ1 in comparison with Eu-HT patients. Worthy of note, subst-HT patients showed restored serum miR-29a levels compared with Hypo-HT group, associated with lower serum TGFβ1. These novel findings may suggest a possible impact of replacement therapy with levothyroxine on serum miR-29a levels in HT. [ABSTRACT FROM AUTHOR]

Background: Patients with Triple Negative Breast Cancer (TNBC) currently lack targeted therapies, and consequently face higher mortality rates when compared to patients with other breast cancer subtypes. The tumor microenvironment (TME) cytokine Oncostatin M (OSM) reprograms TNBC cells to a more stem-like/mesenchymal state, conferring aggressive cancer cell properties such as enhanced migration and invasion, increased tumor-initiating capacity, and intrinsic resistance to the current standards of care. In contrast to OSM, Interferon-β (IFN-β) promotes a more differentiated, epithelial cell phenotype in addition to its role as an activator of anti-tumor immunity. Importantly, OSM suppresses the production of IFN-β, although the mechanism of IFN-β suppression has not yet been elucidated. Methods: IFN-β production and downstream autocrine signaling were assessed via quantitative real-time PCR (qRT-PCR) and Western blotting in TNBC cells following exposure to OSM. RNA-sequencing (RNA-seq) was used to assess an IFN-β metagene signature, and to assess the expression of innate immune sensors, which are upstream activators of IFN-β. Cell migration was assessed using an in vitro chemotaxis assay. Additionally, TNBC cells were exposed to TGF-β1, Snail, and Zeb1, and IFN-β production and downstream autocrine signaling were assessed via RNA-seq, qRT-PCR, and Western blotting. Results: Here, we identify the repression of Toll-like Receptor 3 (TLR3), an innate immune sensor, as the key molecular event linking OSM signaling and the repression of IFN-β transcription, production, and autocrine IFN signaling. Moreover, we demonstrate that additional epithelial-mesenchymal transition-inducing factors, such as TGF-β1, Snail, and Zeb1, similarly suppress TLR3-mediated IFN-β production and signaling. Conclusions: Our findings provide a novel insight into the regulation of TLR3 and IFN-β production in TNBC cells, which are known indicators of treatment responses to DNA-damaging therapies. Furthermore, strategies to stimulate TLR3 in order to increase IFN-β within the TME may be ineffective in stem-like/mesenchymal cells, as TLR3 is strongly repressed. Rather, we propose that therapies targeting OSM or OSM receptor would reverse the stem-like/mesenchymal program and restore TLR3-mediated IFN-β production within the TME, facilitating improved responses to current therapies. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a type of stroke in which blood vessel blockage prevents blood supply to the brain. Transforming growth factor beta 1 (TGF-β1) is involved in the pathophysiology of several inflammatory diseases, including ischemic stroke. This study aimed to examine the relationship between rs1800470 (T869C) genetic variation in TGF-β1 gene and the risk of stroke in a meta-analysis approach. In a systematic review, we evaluated trustworthy databases and ultimately included nine eligible studies involving a total of 13,609 participants in our meta-analysis. The strength of association of rs1800470 variation with stroke risk evaluated using the odds ratio and 95% confidence interval. Stratified assessment was also performed according to ethnicity, type of stroke, and genotyping methods. Our data demonstrated substantial correlation between rs1800470 variation and elevated risk of stroke in overall analysis. Also, significant correlations were observed after ethnicity-based stratified analysis and genotyping methods. TGFβ1-rs1800470 could be regarded as a molecular biomarker for identifying at-risk individuals. [ABSTRACT FROM AUTHOR]

Background: Ficolins were originally identified as proteins that bind to transforming growth factor-β1 (TGF-β1). They are capable of activating the complement system through lectin pathway for immune system protection. Ficolin-2 and 3 have been identified in patients with interstitial lung diseases (ILD) and their function in these diseases is currently being explored. In contrast, the functional role of ficolin-1 in pulmonary fibrosis is still elusive and remains to be elucidated. Methods: The expression of ficolin-1 in the plasma of idiopathic pulmonary fibrosis (IPF) and connective tissue disease (CTD)-ILD patients was first determined. As the orthologue of human ficolin-1, ficolin-B knockout and ficolin-B overexpression were used to establish bleomycin (BLM)-induced pulmonary fibrosis mouse model. Co-immunoprecipitation, immunofluorescence and RNA sequencing were utilized to explore and expound on the expression and the functional mechanism of ficolin-1 in pulmonary fibrosis. Results: Compared with healthy controls, plasma ficolin-1 was significantly decreased in patients with IPF and CTD-ILD. In the bleomycin (BLM)-induced mice model, ficolin-B deficiency aggravated lung injury and fibrosis. There was also observed increase in TGF-β1 levels and enhanced downstream signaling. However, the overexpression of ficolin-B showed preventative and therapeutic efficacy against lung fibrosis. Furthermore, coimmunoprecipitation studies revealed the direct interaction between ficolin-1 and TGF-β1 in human plasma, which was further confirmed by the colocalization of ficolin-1 and TGF-β1 in lung tissues. Conclusions: Ficolin-1 inhibits pulmonary fibrosis by directly binding to the key profibrogenic factor TGF-β1, marking it as a potential target for therapy in the treatment of fibrotic lung diseases. [ABSTRACT FROM AUTHOR]

Tilapia is a kind of fish with a huge amount of aquaculture, and a lot of byproducts are wasted in processing. Of these, fish skin is the most valued due to its high content of gelatin, which has good characteristics such as low hypoallergenic, biocompatibility, and permeability. In this study, a novel pentapeptide (Leu‐Ser‐Gly‐Tyr‐Gly, LYG) was isolated from gelatin gastrointestinal digests of tilapia skin and verified the anti‐inflammatory and antiangiogenic activity of LYG, which can inhibit scar formation. In addition, the active sites were analyzed using molecular docking. The key active amino acids Leu and Tyr of LYG were able to form hydrogen bonds and good hydrophobic structures with transforming growth factor β1 (TGF‐β1). Hyperplastic scar (HS) is a common fibrous proliferative disorder of the skin, and fibrosis is the process of scar formation. It is well known that the inhibition of collagen and angiogenesis is an effective way to combat HS. The results of this study show that LYG inhibited collagen synthesis and inflammatory stress in mouse fibroblasts (L929), suppressed the angiogenic signaling pathway in vascular endothelial cells (HUVECs), and reduced scar formation after wound healing in mice. This study provides new ideas for improving the diversified use of tilapia resources. [ABSTRACT FROM AUTHOR]

Objective: To investigate the diagnostic value of EMI ultrasound parameters combined with serum TGF-β1 and COX-2 for adenomyosis. Methods: Retrospective selection of 110 patients with adenomyosis from January 2021 to March 2023 as the observation group and 110 healthy women as the control group during the same period. All subjects underwent the same examinations and surgical procedures. Compare the diagnostic value of relevant indicators between two groups of subjects for adenomyosis. Results: The age of the observation group was significantly higher than that of the control group; 73.64% of patients with adenomyosis have ab- normal EMI ultrasound findings; The EMI ultrasound parameters in the observation group were lower than those in the control group, with P values<0.05. The serum levels of TGF-β1 and COX-2 in the observation group were higher than those in the control group, with P<0.05. Increased average thickness, abnormal morphology, and elevated levels of TGF-β1 and COX-2 in EMI were risk factors for adenomyosis, while elevated EMI blood flow index was a protective factor for adenomyosis, with P<0.05 for both. Among them, the average thickness and morphology of EMI; The combination of TGF-β1, COX-2 levels, blood flow index, and above indicators has good diagnostic value for adenomyosis, with P values<0.05. However, the AUC area of the combination of indicators for adenomyosis is larger than other indicators and can be used for the diagnosis of adenomyosis. Conclusion: EMI ultrasound parameters combined with serum TGF-β1 and COX-2 can be used for the diagnosis of adenomyosis. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers (DFUs), a prevalent chronic disease caused by various factors, significantly impact patients' quality of life due to prolonged healing times and increased infection risks. Current treatment modalities, including pharmacological, physical, and surgical interventions, often yield limited efficacy and adverse effects, highlighting the urgent need for novel therapeutic strategies. The objective of this research is to create SIKVAV-modified chitosan hydrogels with the intention of improving the process of skin wound healing in diabetic mice. We synthesized the hydrogels and established a diabetic mice model with skin wounding to evaluate its healing effects and underlying mechanisms. The results of our study indicate that the SIKVAV-modified chitosan hydrogels markedly enhance the wound healing process in diabetic mice. This effect may be attributed to several mechanisms, including differentiation of fibroblasts, proliferation of keratinocytes, the promotion of angiogenesis, stimulation of collagen synthesis, upregulation of growth factor expression, and possible involvement of the TGF-β1/Smad3 signaling pathway. This research not only provides a new biomaterial for the treatment of diabetic wounds but also elucidates the related molecular mechanisms involved in wound healing of DFUs, offering valuable insights for future clinical applications. [ABSTRACT FROM AUTHOR]

At present, the characteristics of double-hit multiple myeloma (DHMM) are unknown. We retrospectively analyzed the clinical data from 433 new diagnosed MM patients and found that DHMM have a higher β2-MG level and percentage of bone marrow plasma cell. Cox regression analysis showed that the prognosis of DHMM was not limited by clinical indicators. The abnormal proliferation of bone marrow in DHMM is obvious, and the proportion of poorly differentiated plasma cell is high. By collecting specimens from our center and performing flow cytometry to analyze the immunophenotypic and functional characteristics of lymphocyte subpopulations, we found that DHMM had a higher ratio of Tregs cells, and the proportion of iTregs cells was also significantly higher than non-DHMM (P < 0.05). Moreover, DHMM had higher levels of TGF-β1 and IL-10, and TGF-β1 and IL-10 were positively correlated with iTregs (P < 0.05). In addition, DHMM was highly expressed PD-1 on CD8 + T cells and had a higher proportion of CD38highTregs cells. In vitro we have shown that the addition of TGF-β1 antibody or CD38 antibody can effectively inhibit the proportion of CD38high Tregs. This study describes the characteristics of DHMM based on bicentric data, which is helpful to better provide theoretical support for the treatment of DHMM. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mechanism of UC intervention on PKC-NF-кВ pathway in the treatment of ulcerative colitis. Methods: In this study, 33 adult male SD rats were selected and divided into five groups according to the research requirements, they were divided into normal group, low-dose group, middle-dose group, high-dose group and UC Group, among which, normal group (N=7), high-dose group (N=6), middle-dose group (N=6), low-dose group (N=9) and UC Group (N=5). The immunohistochemical results, colonic results and hypothalamic results were analyzed. The relative expression levels of cytokines in colon tissue were measured to confirm the mechanism of UC intervention on PKC-NF-кВ pathway in the treatment of ulcerative colitis. Results: The results of immunohistochemistry showed that there were significant differences between UC Group and high-dose group, middle-dose group, low-dose group and normal group (P<0.05), there were significant differences in the results of colonic examination and hypothalamus examination among the five groups (P<0.05), the indexes of UC Group, high dose group, middle dose group and low dose group were higher than those of normal group (P<0.05). The indexes of high dose group were higher than those of middle dose group, low dose group and normal group (P<0.05), the level in the middle dose group was higher than that in the low dose group and the normal group (P<0.05), and the level in the low dose group was higher than that in the normal group (P<0.05). Conclusion: UC intervention of PKC-NF-кВ pathway is effective in the treatment of ulcerative colitis, and can be directly related to the relative expression level of cytokine mRNA in colon tissue, UC intervention can therefore help in the treatment of ulcerative colitis. [ABSTRACT FROM AUTHOR]

Background: Fibrosis is a principal sign of systemic sclerosis (SSc) which can affect several organs including the lung, heart, and dermis. Dermal fibroblasts of SSc patients are characterized by persistent and activated Ras and ERK1/2 signaling which stimulates extreme collagen and extracellular matrix synthesis. Salirasib is a Ras inhibitor that competitively prevents the adherence of GTP‐bound Ras to the plasma membrane, that inhibits Ras signaling. This study intended to clarify whether salirasib can influence fibrotic mediators in SSc fibroblasts. Materials and Methods: Dermal fibroblasts from 10 SSc patients were treated with salirasib in the presence of TGF‐β1, and mRNA levels of H‐Ras and genes related to fibrosis, such as COL1A1, COL1A2, CTGF, TGF‐β1, fibronectin, ACTA2, and MMP1 was measured by real‐time PCR. The α‐SMA protein expression was analyzed by immunofluorescence staining. Results: In dermal fibroblasts of SSc patients, salirasib treatment, markedly downregulated the H‐Ras gene expression. In addition, the protein expression of α‐SMA and gene expression of ACTA2 were inhibited upon salirasib treatment. Salirasib also significantly reduced the expression of COL1A1, and COL1A2 genes and augmented the gene expression of MMP1. The mRNA levels of other genes related to fibrosis such as FN1, CTGF, and TGF‐β1 were significantly decreased upon salirasib treatment. Conclusion: Considering salirasib significantly reduced the expression of genes related to the fibrosis process and α‐SMA gene and protein expression, and given significant upregulation of MMP1 by salirasib, it can be considered as a new curative strategy for fibrotic diseases like SSc. [ABSTRACT FROM AUTHOR]

Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial–mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-β1 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-β1 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-β1 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-β1. Therefore, co-stimulation with TWEAK and TGF-β1 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF-β1) is a critical profibrotic mediator in chronic lung disease, and there are no specific strategies to mitigate its adverse effects. Activation of TGF-β1 signaling is a multipart process involving ligands, transmembrane receptors, and transcription factors. In addition, an intricate network of adaptor proteins fine-tunes the signaling strength, duration, and activity. Namely, Smad7 recruits growth arrest and DNA damage (GADD34) protein that then interacts with the catalytic subunit of phosphoprotein phosphatase 1 (PP1c) to inactivate TGF-β receptor (TβR)-I and downregulate TGF-β1 signaling. Little is known about how TGF-β1 releases TβR-I from the GADD34-PP1c inhibition to activate its signaling. Transmembrane lemur tyrosine kinase 2 (LMTK2) is a PP1c inhibitor, and our published data showed that TGF-β1 recruits LMTK2 to the cell surface. Here, we tested the hypothesis that TGF-β1 recruits LMTK2 to inhibit PP1c, allowing activation of TβR-I. First, LMTK2 interacted with the TGF-β1 pathway in the human bronchial epithelium at multiple checkpoints. Second, TGF-β1 inhibited PP1c by an LMTK2-dependent mechanism. Third, TGF-β1 used LMTK2 to activate canonical Smad3-mediated signaling. We propose a model whereby the LMTK2-PP1c and Smad7-GADD34-PP1c complexes serve as on-and-off switches in the TGF-β1 signaling in human bronchial epithelium. NEW & NOTEWORTHY: Activation of the transforming growth factor (TGF)-β1 signaling pathway is complex, involving many ligands, transmembrane receptors, transcription factors, and modulating proteins. The mechanisms of TGF-β1 signaling activation/inactivation are not fully understood. We propose for the first time a model by which transmembrane lemur tyrosine kinase 2 (LMTK2) forms a complex with phosphoprotein phosphatase 1 (PP1c) to activate TGF-β1 signaling and Smad7, growth arrest and DNA damage (GADD34), and PP1C form a complex to inactivate TGF-β1 signaling in human bronchial epithelium. [ABSTRACT FROM AUTHOR]

Depressive disorder (DD) ranks among the most prevalent, burdensome, and costly psychiatric conditions globally. It manifests through a range of emotional, cognitive, somatic, and behavioral symptoms. Mesenchymal Stem Cells (MSCs) have garnered significant attention due to their therapeutic potential via immunomodulation in neurological disorders. Our research indicates that MSCs treatment demonstrates a notable effect on a Chronic Unpredictable Mild Stress (CUMS)-induced DD model in mice, surpassing even Fluoxetine in its antidepressant efficacy. MSCs mitigate DD by inhibiting central nervous system inflammation and facilitating the conversion of microglial cells into an Arg1high anti-inflammatory state. The MSCs-derived TGF-β1 is crucial for this Arg1high microglial cell transformation in DD treatment. [Display omitted] • Hippocampus transplantation of MSCs alleviates depressive-like behaviors in mice. • MSCs can promote microglial cells convert into an Arg1high anti-inflammation state. • MSCs-derived TGF-β1 is crucial for Arg1high microglial cells conversion. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is the most prevalent form of diabetic cardiomyopathy. Increased levels of transforming growth factor-beta 1 (TGF-ß1) and galectin-3 are present in cardiac fibrosis, and these proteins might be potential therapeutic targets. Researches have shown that Moringa oleifera (MO) display numerous biological activities which could be harnessed for the treatment of a variety of ailments, including cardiovascular diseases. This study is aimed at evaluating the effect of MO on TGF-ß1 and galectin-3 levels in diabetic rat model of cardiac fibrosis. Fifteen (15) Wistar rats were randomly divided into three groups: normal control group, administered normal saline; case group, administered normal saline and streptozotocin; and MO treatment group, administered streptozotocin and MO extract (1000 mg/kg) once daily for 28 days. Cardiac fibrosis was evaluated by histopathological analysis of the rats' myocardium. The levels of TGF-ß1 and galectin-3 were investigated by enzyme-linked immunosorbent assay (ELISA). Histopathological examination revealed fewer cardiac fibrosis features in the myocardium of MO treated group compared to the case group. In addition, MO treatment resulted in a significant reduction in collagen decomposition in the left ventricle myocardium. ELISA revealed a significant decrease in the TGF-ß1 and galectin-3 levels in the MO treated group compared to the case group (641.4±94.0 ng/L vs. 852.3±56.2 ng/L, and 1.53±0.07 ng/L vs. 1.79±0.166 ng/L, respectively). In conclusion, the beneficial effects of MO are likely related to its ability to decrease oxidative stress in the heart tissue and reduce the formation of fibrosis by suppressing the expression of TGF-ß1 and galectin-3. [ABSTRACT FROM AUTHOR]

Objectives: Vocal fold scar remains a therapeutic challenge. Vocal fold fibroblasts (VFFs) secrete extracellular matrix (ECM), and transforming growth factor‐beta 1 (TGF‐β1)‐mediated fibroblast to myofibroblast differentiation is central to the development of fibrosis. The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels, and activation of TRP ankyrin 1 (TRPA1) channel has been shown to have antifibrotic effects through TGF‐β1/Smad signaling in various organs. This study aimed to elucidate expression of TRPA1 and the impact of TRPA1 activation on TGF‐β1/Smad signaling in VFFs. Methods: Vocal folds were dissected from 10‐week‐old, male Sprague‐Dawley rats and primary VFFs were established. TRPA1 was examined in VFFs and lamina propria via immunostaining. VFFs were treated with allyl isothiocyanate (AITC, TRP channel agonist, 10−5 M) ± TGF‐β1 (10 ng/ml) ± A‐967079 (selective TRPA1 channel antagonist, 5.0 × 10−7 M) for 4 or 24 h. Trpa1, Smad3, Smad7, Col1a1, Acta2, and Has1 mRNA expression were quantified via qPCR. Results: TRPA1 was expressed in cultured VFFs and the lamina propria. TGF‐β1 administration significantly increased Trpa1 compared to control. AITC alone did not alter Smad3, Smad7, Acta2, or ECM related genes. However, the combination of AITC and TGF‐β1 significantly increased Smad3 and decreased Smad7 and Acta2 compared to TGF‐β1 alone; A‐967079 significantly reduced this response. Conclusions: VFFs expressed TRPA1, and the activation of TRPA1 regulated TGF‐β1/Smad signaling in VFFs. These findings provide preliminary insights into potential anti‐fibrotic mechanisms of TRPA1 activation through TGF‐β1/Smad signaling in VFFs. Level of Evidence: NA Laryngoscope, 134:4593–4598, 2024 [ABSTRACT FROM AUTHOR]

We aimed to investigate galectin-1 overexpression induces normal fibroblasts (NFs) translates into cancer-associated fibroblasts (CAFs). Galectin-1 overexpression was conducted in Human embryonic lung fibroblasts (HFL1) cell. The motilities of H1299 and A549 cells were measured. Human umbilical vein endothelial cell (HUVEC) proliferation and tube formation ability were assessed. Tumor volume and tumor weight was recorded. Cells motilities were increased, while apoptosis rates were decreased after CMs co-cultured. B-cell lymphoma-2 (Bcl-2) expression level was increased, while Bcl2-associatedX (Bax) and cleaved-caspase3 decreased. CMs treatment enhanced HUVEC proliferation and tube formation. Tumor volume and weight in CMs treated mice were increased, and the sensitivity of anlotinib in co-cultured cells was decreased. Our results revealed that galectin-1 overexpression induced NFs translated into CAFs.

Pancreatic cancer (PC) is an aggressive and metastatic gastrointestinal tumor with a poor prognosis. Persistent activation of the TGF-β/Smad signaling induces PC cell (PCC) invasion and infiltration via epithelial-to-mesenchymal transition (EMT). Hedgehog signaling is a crucial pathway for the development of PC via the transcription factors Gli1/2/3. This study aimed to investigate the underlying molecular mechanisms of action of hedgehog activation in TGF-β1-triggered EMT in PCCs (PANC-1 and BxPc-3). In addition, overexpression and shRNA techniques were used to evaluate the role of Smad4 in TGF-β1-treated PCCs. Our data showed that TGF-β1 promoted PCC invasion and infiltration via Smad2/3-dependent EMT. Hedgehog-Gli signaling axis in PCCs was activated upon TGF-β1 stimulation. Inhibition of hedgehog with cyclopamine effectively antagonized TGF-β1-induced EMT, thereby suggesting that the hedgehog signaling may act as a downstream cascade signaling of TGF-β1. As a key protein that assists the nuclear translocation of Smad2/3, Smad4 was highly expressed in PANC-1 cells, but not in BxPc-3 cells. Conversely, Gli1 expression was low in PANC-1 cells, but high in BxPc-3 cells. Furthermore, knockdown of Smad4 in PANC-1 cells by shRNA inhibited TGF-β1-mediated EMT and collagen deposition. Overexpression of Smad4 did not affect TGF-β1-mediated EMT due to the lack of significant increase in nuclear expression of Smad4. Importantly, Gli1 activity was upregulated by Smad4 knockdown in PANC-1 cells and downregulated by Smad4 overexpression in BxPc-3 cells, indicating that Gli1 may be a negative target protein downstream of Smad4. Thus, Smad4 regulates TGF-β1-mediated hedgehog activation to promote EMT in PCCs by suppressing Gli1 activity.

Abstract Ischemic stroke is a type of stroke in which blood vessel blockage prevents blood supply to the brain. Transforming growth factor beta 1 (TGF-β1) is involved in the pathophysiology of several inflammatory diseases, including ischemic stroke. This study aimed to examine the relationship between rs1800470 (T869C) genetic variation in TGF-β1 gene and the risk of stroke in a meta-analysis approach. In a systematic review, we evaluated trustworthy databases and ultimately included nine eligible studies involving a total of 13,609 participants in our meta-analysis. The strength of association of rs1800470 variation with stroke risk evaluated using the odds ratio and 95% confidence interval. Stratified assessment was also performed according to ethnicity, type of stroke, and genotyping methods. Our data demonstrated substantial correlation between rs1800470 variation and elevated risk of stroke in overall analysis. Also, significant correlations were observed after ethnicity-based stratified analysis and genotyping methods. TGFβ1-rs1800470 could be regarded as a molecular biomarker for identifying at-risk individuals.

Abstract Background Ficolins were originally identified as proteins that bind to transforming growth factor-β1 (TGF-β1). They are capable of activating the complement system through lectin pathway for immune system protection. Ficolin-2 and 3 have been identified in patients with interstitial lung diseases (ILD) and their function in these diseases is currently being explored. In contrast, the functional role of ficolin-1 in pulmonary fibrosis is still elusive and remains to be elucidated. Methods The expression of ficolin-1 in the plasma of idiopathic pulmonary fibrosis (IPF) and connective tissue disease (CTD)-ILD patients was first determined. As the orthologue of human ficolin-1, ficolin-B knockout and ficolin-B overexpression were used to establish bleomycin (BLM)-induced pulmonary fibrosis mouse model. Co-immunoprecipitation, immunofluorescence and RNA sequencing were utilized to explore and expound on the expression and the functional mechanism of ficolin-1 in pulmonary fibrosis. Results Compared with healthy controls, plasma ficolin-1 was significantly decreased in patients with IPF and CTD-ILD. In the bleomycin (BLM)-induced mice model, ficolin-B deficiency aggravated lung injury and fibrosis. There was also observed increase in TGF-β1 levels and enhanced downstream signaling. However, the overexpression of ficolin-B showed preventative and therapeutic efficacy against lung fibrosis. Furthermore, coimmunoprecipitation studies revealed the direct interaction between ficolin-1 and TGF-β1 in human plasma, which was further confirmed by the colocalization of ficolin-1 and TGF-β1 in lung tissues. Conclusions Ficolin-1 inhibits pulmonary fibrosis by directly binding to the key profibrogenic factor TGF-β1, marking it as a potential target for therapy in the treatment of fibrotic lung diseases.

Abstract At present, the characteristics of double-hit multiple myeloma (DHMM) are unknown. We retrospectively analyzed the clinical data from 433 new diagnosed MM patients and found that DHMM have a higher β2-MG level and percentage of bone marrow plasma cell. Cox regression analysis showed that the prognosis of DHMM was not limited by clinical indicators. The abnormal proliferation of bone marrow in DHMM is obvious, and the proportion of poorly differentiated plasma cell is high. By collecting specimens from our center and performing flow cytometry to analyze the immunophenotypic and functional characteristics of lymphocyte subpopulations, we found that DHMM had a higher ratio of Tregs cells, and the proportion of iTregs cells was also significantly higher than non-DHMM (P

Abstract Repair of the damaged meniscus is a scientific challenge owing to the poor self-healing potential of the white area of the meniscus. Tissue engineering provides a new method for the repair of meniscus injuries. In this study, we explored the superiority of 2% hyaluronic acid chitin hydrogel in temperature sensitivity, in vitro degradation, biocompatibility, cell adhesion, and other biological characteristics, and investigated the advantages of hyaluronic acid (HA) and Transforming Growth Factor β1 (TGF-β1) in promoting cell proliferation and a matrix formation phenotype. The hydrogel loaded with HA and TGF-β1 promoted cell proliferation. The HA + TGF-β1 mixed group showed the highest glycosaminoglycan (GAG) content and promoted cell migration. Hydroxypropyl chitin (HPCH), HA, and TGF-β1 were combined to form a composite hydrogel with a concentration of 2% after physical cross-linking, and this was injected into a rabbit model of a meniscus full-thickness tear. After 12 weeks of implantation, the TGF-β1 + HA/HPCH composite hydrogel was significantly better than HPCH, HA/HPCH, TGF-β1 + HPCH, and the control group in promoting meniscus repair. In addition, the new meniscus tissue of the TGF-β1 + HA/HPCH composite hydrogel had a tissue structure and biochemical content similar to that of the normal meniscus tissue.

Abstract To assess the level of both pro-inflammatory and anti-inflammatory cytokines in the aqueous humor (AH) of patients suffering from uveitis, with or without coexisting glaucoma, and compare them with patients diagnosed with primary open-angle glaucoma (POAG) and those with age-related cataract (ARC). By using Luminex xMAP® multiplex assays analyses, we assessed levels of 11 cytokines and chemokines, and compared them across groups, including uveitis-secondary glaucoma (USG) (n = 16), uveitis without glaucoma (UwoG), (n = 16), POAG (n = 16), and ARC (n = 16) to explore the correlation between these cytokines and the presence of uveitis, as well as intraocular pressure (IOP). Pro-inflammatory factors MCP-1, MIP-1β, IL-6, IL-8, and transforming growth factors TGF-β1 and TGF-β2 were significantly elevated in the AH of USG eyes. In the case of enhanced anti-inflammatory in the perioperative period, the pro-inflammatory factors remained notably elevated in the USG group compared to the UwoG group (P

Abstract This study explores the role and potential mechanisms of microRNA-125b-5p (miR-125b-5p) in pulmonary fibrosis (PF). PF is a typical outcome of many chronic lung diseases, with poor prognosis and the lack of appropriate medical treatment because PF’s molecular mechanisms remain poorly understood. In this study, using in vitro and in vivo analyses, we find that miR-125b-5p is likely a potent regulator of lung fibrosis. The findings reveal that, on the one hand, miR-125b-5p not only specifically decreases in the epithelial-mesenchymal transition (EMT) of lung epithelial cells, but also shows a downregulation trend in the lung tissues of mice with PF. On the other hand, overexpression of miR-125b-5p on the cellular and animal levels downregulates EMT and fibrotic phenotypes, respectively. To clarify the molecular mechanism of the “therapeutic” effect of miR-125b-5p, we use the target prediction tool combined with a dual luciferase assay and complete a rescue experiment by constructing the overexpression vector of the target gene Bcl-2 homologous antagonist/ killer (BAK1), thus confirming that miR-125b-5p can effectively inhibit EMT and fibrosis process by targeting BAK1 gene. MiR-125b-5p inhibits the EMT in lung epithelial cells by negatively regulating BAK1, while overexpression of miR-125b-5p can alleviate lung fibrosis. The findings suggest that MiR-125b-5p/BAK1 can serve as a potential treatment target for PF. Graphical abstract

Abstract Background Pulmonary arterial hypertension (PAH) is a worldwide challenging disease characterized by progressive elevation of pulmonary artery pressure. The proliferation, migration and phenotypic transformation of pulmonary smooth muscle cells are the key steps of pulmonary vascular remodeling. Quercetin (3,3', 4', 5, 6-pentahydroxyflavone, Que) is a natural flavonol compound that has antioxidant, anti-inflammatory, anti-tumor and other biological activities. Studies have shown that Que has therapeutic effects on PAH. However, the effect of quercetin on pulmonary vascular remodeling in PAH and its mechanism remain unclear. Methods and results In vivo, PAH rats were constructed by intraperitoneal injection of monocrotaline (MCT) at 60 mg/kg. Human pulmonary artery smooth muscle cells (HPASMCs) were treated with platelet-derived growth factor BB (PDGF-BB) 20 ng/mL to construct PAH cell model in vitro. The results showed that in vivo studies, MCT could induce right ventricular wall hyperplasia, narrow the small and medium pulmonary artery cavity, up-regulate the expression of proliferating and migration-related proteins proliferating cell nuclear antigen (PCNA) and osteopontin (OPN), and down-regulate the expression of alpha-smooth muscle actin (α-SMA). Que reversed the MCT-induced results. This process works by down-regulating the transforming growth factor-β1 (TGF-β1)/ Smad2/3 signaling pathway. In vitro studies, Que had the same effect on PDGF-BB-induced proliferation and migration cell models. Conclusions Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by down-regulating TGF-β1/Smad2/Smad3 pathway, thereby reducing right ventricular hyperplasia (RVH) and pulmonary vascular remodeling, providing potential pharmacological and molecular explanations for the treatment of PAH.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown etiology. Despite the increasing global incidence and poor prognosis, the exact pathogenic mechanisms remain elusive. Currently, effective therapeutic targets and treatment methods for this disease are still lacking. This study tried to explore the pathogenic mechanisms of IPF. We found elevated expression of SULF1 in lung tissues of IPF patients compared to normal control lung tissues. SULF1 is an enzyme that modifies heparan sulfate chains of heparan sulfate proteoglycans, playing a critical role in biological regulation. However, the effect of SULF1 in pulmonary fibrosis remains incompletely understood. Our study aimed to investigate the impact and mechanisms of SULF1 in fibrosis. Methods We collected lung specimens from IPF patients for transcriptome sequencing. Validation of SULF1 expression in IPF patients was performed using Western blotting and RT-qPCR on lung tissues. ELISA experiments were employed to detect SULF1 concentrations in IPF patient plasma and TGF-β1 levels in cell culture supernatants. We used lentiviral delivery of SULF1 shRNA to knock down SULF1 in HFL1 cells, evaluating its effects on fibroblast secretion, activation, proliferation, migration, and invasion capabilities. Furthermore, we employed Co-Immunoprecipitation (Co-IP) to investigate the regulatory mechanisms involved. Results Through bioinformatic analysis of IPF transcriptomic sequencing data (HTIPF) and datasets GSE24206, and GSE53845, we identified SULF1 may potentially play a crucial role in IPF. Subsequently, we verified that SULF1 was upregulated in IPF and predominantly increased in fibroblasts. Furthermore, SULF1 expression was induced in HFL1 cells following exposure to TGF-β1. Knockdown of SULF1 suppressed fibroblast secretion, activation, proliferation, migration, and invasion under both TGF-β1-driven and non-TGF-β1-driven conditions. We found that SULF1 catalyzes the release of TGF-β1 bound to TGFβRIII, thereby activating the TGF-β1/SMAD pathway to promote fibrosis. Additionally, TGF-β1 induces SULF1 expression through the TGF-β1/SMAD pathway, suggesting a potential positive feedback loop between SULF1 and the TGF-β1/SMAD pathway. Conclusions Our findings reveal that SULF1 promotes fibrosis through the TGF-β1/SMAD pathway in pulmonary fibrosis. Targeting SULF1 may offer a promising therapeutic strategy against IPF.

Impaired serum TGF-β1 production is one of the proposed mechanisms for coronavirus disease 2019 (COVID-19).Study objective: to study blood serum TGF-β1 content in children with new coronavirus infection.Materials and methods: a one-stage study was conducted in 119 patients with COVID-19 and compared with 118 healthy children of the same age and sex as a control group. The age range in both groups was 11.0 years. Preschoolers (0–6 years old) and schoolchildren (7–17 years old) in the group with COVID-19 were 21 (18%) and 98 (82%), respectively. Children with COVID-19 were divided into asymptomatic (n=23), mild (n=61), and moderate (n=35) subgroups. Serum samples for TGF-β1 concentration analysis were taken from all patients and tested by flow fluorimetry. The data were processed using the IBM SPSS Statistics Version 25.0 software package (International Business Machines Corporation, license No Z125-3301-14, USA).Results: median serum TGF-β1 levels of children 0–17 years old with COVID-19 regardless of the form of severity were significantly higher than in the control group. The serum concentration of TGF-β1 in children with COVID-19 of preschool age was increased comparing to schoolchildren. Children 0-6 years old with a moderate form of coronavirus infection had high serum TGF-β1 values when compared with school-age patients.Conclusion: elevated serum TGF-β1 levels were found in children both without clinical manifestations and with symptoms of coronavirus infection, reaching maximum values in the moderate form in children 0–6 years old.

Abstract Transforming Growth Factor Beta1 (TGF-β1) signaling is upregulated in Chronic Obstructive Pulmonary disease (COPD), smokers, and people living with HIV. Cigarette smoking and HIV are also independent risk factors for COPD. Chronic inflammation is a hallmark of COPD. However, the underlying mechanisms remain unknown. Previous research has suggested that TGF-β1 alters the airway epithelial microRNAome and transcriptome, potentially contributing to lung inflammation. The Lactoperoxidase (LPO) system is an integral component of innate immunity within the airway. LPO plays a crucial role in host defense by catalyzing the oxidation of thiocyanate to hypothiocyanite in the presence of hydrogen peroxide (H2O2), generating a potent antibacterial and antiviral agent. Additionally, the LPO system potentially aids in maintaining cellular redox balance by reducing the levels of H2O2, thus mitigating oxidative stress within the airway epithelium. LPO dysfunction can impair immune responses and exacerbate inflammatory processes in respiratory diseases. In this study, primary bronchial epithelial cells and bronchial cell lines were treated with TGF-β1 and exposed to cigarette smoke to characterize the effect of these factors on LPO and their downstream effects. RT-qPCR and Western Blot were applied to quantify mRNA and proteins’ expression. The levels of H2O2 were detected using the Amplex Red Assay. Magnetofection and transfection were applied to probe the effect of miR-449b-5p. Staining procedures using the MitoTracker Green and C12FDG dyes were used to establish mitochondria mass and senescence. The levels of pro-inflammatory cytokines were measured via Luminex assays. We found that TGF-β1 and cigarette smoke suppressed airway LPO expression, increasing H2O2 levels. This increase in H2O2 had downstream effects on mitochondrial homeostasis, epithelial cellular senescence, and the pro-inflammatory cytokine response. We demonstrate for the first time that airway LPO is regulated by TGF-β1-induced miRNA-mediated post-transcriptional silencing through miR-449b-5p in the lungs. Further, we identify and validate miR-449-5p as the candidate miRNA upregulated by TGF-β1, which is involved in LPO suppression. This paper demonstrates a new mechanism by which TGF-β1 can lead to altered redox status in the airway.