Exploring the role of TNF-α, TGF-ß, and IL-6 serum levels in categorical and noncategorical models of mood and psychosis.

Psychotic and mood disorders are discussed as part of the same continuum. The potential role of immune dysregulation in defining their clinical presentations, however, remains unclear. Differences in TNF-α, IL-6 and TGF-ß levels were investigated in 143 patients with schizophrenia (SCH = 63) and bipolar disorder (BD = 80), in remission. Cytokines were evaluated against the dimensional assessment of psychosis and affective symptoms using the schizo-bipolar scale, together with the severity of the same symptom domains measured by the brief psychiatric rating scale (BPRS). Lower TGF-ß was associated with more lifetime episodes, family risk for psychosis, and more severe mood and psychotic symptoms in all patients. BPRS Affect symptoms domain correlated with lower TGF-ß levels in BD, and higher TGF-ß levels in SCH patients. Using moderated mediation analysis, TGF-ß was a relevant predictor only in the setting of non-categorical symptom distribution, with familial risk for psychosis confirmed as a significant moderator. Severity of BPRS Affect symptoms domain was an independent predictor of inclination towards the psychosis spectrum. The underlying immune dysregulation may be shared by the disorders, rather than a unique characteristic of each, having significant implications for our understanding of the continuum vs. categorical approach to psychosis and mood disorders.

Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis.

Breast disseminated cancer cells (DCCs) can remain dormant in the lungs for extended periods, but the mechanisms limiting their expansion are not well understood. Research indicates that tissue-resident alveolar macrophages suppress breast cancer metastasis in lung alveoli by inducing dormancy. Through ligand-receptor mapping and intravital imaging, it was found that alveolar macrophages express transforming growth factor (TGF)-ß2. This expression, along with persistent macrophage-cancer cell interactions via the TGF-ßRIII receptor, maintains cancer cells in a dormant state. Depleting alveolar macrophages or losing the TGF-ß2 receptor in cancer cells triggers metastatic awakening. Aggressive breast cancer cells are either suppressed by alveolar macrophages or evade this suppression by avoiding interaction and downregulating the TGF-ß2 receptor. Restoring TGF-ßRIII in aggressive cells reinstates TGF-ß2-mediated macrophage growth suppression. Thus, alveolar macrophages act as a metastasis immune barrier, and downregulation of TGF-ß2 signaling allows cancer cells to overcome macrophage-mediated growth suppression.

PCSK9 inhibitor attenuates cardiac fibrosis in reperfusion injury rat by suppressing inflammatory response and TGF-ß1/Smad3 pathway.

Progressive cardiac fibrosis, a hallmark of heart failure, remains poorly understood regarding Proprotein convertase subtilisin/kexin type 9 (PCSK9) 's role. This study aims to elucidate PCSK9's involvement in cardiac fibrosis. After ischemia/reperfusion (I/R) injury surgery in rats, PCSK9 inhibitors were used to examine their effects on the transforming growth factor-ß1 (TGF-ß1)/small mother against decapentaplegic 3 (Smad3) pathway and inflammation. Elevated PCSK9, TGF-ß1, and Smad3 levels were observed in cardiac tissues post-I/R injury, indicating fibrosis. PCSK9 inhibition reduced pro-fibrotic protein expression, protecting the heart and mitigating I/R-induced damage and fibrosis. Additionally, it ameliorated cardiac inflammation and reduced post-myocardial infarction (MI) size, improving cardiac function and slowing heart failure progression. PCSK9 inhibitors significantly attenuate myocardial fibrosis induced by I/R via the TGF-ß1/Smad3 pathway.

CD27 is not an ideal marker for human memory B cells and can be modulated by IL-21 upon stimulated by Anti-CD40.

B cells play a key role in humoral immune responses by producing antibodies. Although there are numerous research on memory B cells definition markers and cytokines on B cell development, different studies have yielded contradictory conclusions due to species studied, the different cells and stimulating agents used. In the current study, we conducted a detailed characterization of B cells in human CBMCs, PBMCs and tonsil, including expression of Igs, activation and memory markers. Furthermore, we found that considerable amounts of IgA and IgG were expressed by CD27- B cells. These "Atypical" memory B cells corresponded to approximately 50% of IgG+ and IgA+B cells in blood, this proportion even reached 90% in tonsil. In addition, we investigated the effect of IL-21 and TGF-ß1 on the membrane-bound form and secreted form of Igs using PBMCs and purified blood B cells. There were actual differences between the effect of cytokines on Igs secretion and surface expression. Our study will be helpful to advance the knowledge and understanding of humoral memory.

The mechanism of TGF-ß mediating BRD4/STAT3 signaling pathway to promote fibroblast proliferation and thus promote keloid progression.

The purpose of this study was to investigate the effect of TGF-ß on keloid and its molecular mechanism in fibroblasts. METHODS: The difference between normal tissue and keloid tissue can be detected using HE staining. Fibroblasts were treated with TGF-ß, and then treated with the BRD4 inhibitor JQ1 and the STAT3 activator Colivelin TFA. Western blot was used to measure the relative protein expression of TGF-ß, BRD4, p-STAT3, p-EZH2, C-myc, KLF2, KLF4, α-SMA, and Collagen-I. Immunofluorescence staining was used to measure the relative fluorescence intensity of BRD4, p-STAT3, α-SMA, and Collagen-I. Cell proliferation ability was evaluated by CCK-8 assay and colony formation assay. RESULTS: The expression of TGF-ß and BRD4 was significantly higher in keloid tissue compared to normal tissue. TGF-ß mediated the BRD4/STAT3 signaling pathway to inhibit p-EZH2 and promote the expression of C-myc, KLF2, KLF4, α-SMA, and Collagen-I. Additionally, TGF-ß mediated the BRD4/STAT3 signaling pathway to enhance fibroblast proliferation. CONCLUSION: TGF-ß mediates the BRD4/STAT3 signaling pathway to promote fibroblast proliferation and contribute to the progression of keloid.

Soy Peptide Ameliorate TGF-ß1-Mediated Osteoblast Differentiation through Smad and MAPK Signaling Pathways.

The aim of this study was to determine the osteogenic activity and mechanism of soybean peptide VVELLKAFEEKF (SOP) and the potential relationship between SOP and transforming growth factor-ß1 (TGF-ß1). The results show that SOP promotes MC3T3-E1 cell proliferation by altering cell progression. SOP induced cell differentiation and mineralization in a dose-dependent manner at 0.7-7 µM. Moreover, SOP stimulates osteoblast differentiation, which may be achieved through the activation of p38-MAPK and Smad2/3 signaling pathways. Furthermore, treatment with a TßRI inhibitor (SB525334) inhibited the phosphorylation levels of p38 and Smad2/3, which indicates the involvement of TßRI in the process of osteoblast differentiation caused by SOP. Besides, in non-FBS-cultured MC3T3-E1 cells, SOP and TGF-ß1 promoted the phosphorylation of Smad2/3 and alkaline phosphatase (ALP) activity, but the effect was lost when SOP was incubated separately, indicating that SOP stimulated osteoblast differentiation by promoting TGF-ß1 activity. In vivo, SOP significantly restores bone mineral density loss and behavioral deficits in a model of glucocorticoid-induced osteoporosis (GIOP) in zebrafish. These results suggest that SOP may have the function of promoting bone remodeling and may be used as a potential active factor for functional food development to prevent osteoporosis.

TGF-ß and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: implications in breast cancer metastasis.

Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-ß and TNF-α levels are elevated in TME, we asked whether these two agents interacted to induce/augment MMP-9 expression. Using a well-established MDA-MB-231 breast cancer model, we found that the synergy between TGF-ß and TNF-α led to MMP-9 upregulation at the transcriptional and translational levels, compared to treatments with each agent alone. Our in vitro findings are corroborated by co-expression of elevated MMP-9 with TGF-ß and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-ß/TNF-α cooperativity was attenuated by selective inhibition of the TGF-ßRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-ß-induced phosphorylation of Smad2/3 and p38. As expected, the cells defective in Smad2/3 or p38-mediated signaling did not exhibit this synergistic induction of MMP-9. Importantly, the inhibition of histone methylation but not acetylation dampened the synergistic MMP-9 expression. Histone modification profiling further identified the H3K36me2 as an epigenetic regulatory mark of this synergy. Moreover, TGF-ß/TNF-α co-stimulation led to increased levels of the transcriptionally permissive dimethylation mark at H3K36 in the MMP-9 promoter. Comparable outcomes were noted in cells deficient in NSD2 histone methyltransferase. In conclusion, our findings support a cooperativity model in which TGF-ß could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis.

Transformation of macrophages into myofibroblasts in fibrosis-related diseases: emerging biological concepts and potential mechanism.

Macrophage-myofibroblast transformation (MMT) transforms macrophages into myofibroblasts in a specific inflammation or injury microenvironment. MMT is an essential biological process in fibrosis-related diseases involving the lung, heart, kidney, liver, skeletal muscle, and other organs and tissues. This process consists of interacting with various cells and molecules and activating different signal transduction pathways. This review deeply discussed the molecular mechanism of MMT, clarified crucial signal pathways, multiple cytokines, and growth factors, and formed a complex regulatory network. Significantly, the critical role of transforming growth factor-ß (TGF-ß) and its downstream signaling pathways in this process were clarified. Furthermore, we discussed the significance of MMT in physiological and pathological conditions, such as pulmonary fibrosis and cardiac fibrosis. This review provides a new perspective for understanding the interaction between macrophages and myofibroblasts and new strategies and targets for the prevention and treatment of MMT in fibrotic diseases.

The Role of Dicrocoelium dendriticum Egg Antigen in Colitis: A Molecular, Pathological and Serological Study in an Experimental Model of C57BL/6 Mice.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic and recurrent disease of the gastrointestinal tract that enhances the chance of developing colorectal cancer. Since standard treatments such as Mesalazine have limited effectiveness and are often accompanied by numerous side effects, the use of immune modulators derived from worms has been proposed as a new immunotherapy method for inflammatory diseases such as ulcerative colitis. The aim of this study is to investigate the protective effects of D. dendriticum egg antigen on DSS-induced colitis in C57BL/6 mice. METHODS: D. dendriticum egg antigen was extracted and DSS (3.5%) was used to induce colitis in mice. Treatment and prophylaxis included intraperitoneal injections of D. dendriticum egg antigen. Histopathological indicators and the disease activity index (DAI), including weight loss, rectal bleeding, stool consistency, and rectal prolapse, were used to assess the severity of colitis. Real-time PCR measured the expression of transforming growth factor-ß (TGF-ß) and interleukin-17 (IL-17), while ELISA determined the concentration of these cytokines. RESULTS: Treatment with D. dendriticum egg antigen significantly improved the clinical symptoms and decreased the severity of DSS-induced colitis. Furthermore, D. dendriticum egg antigen increased the expression of TGF-ß mRNA and reduced the expression of IL-17 mRNA, leading to a positive adjustment in the regulation of proteins and reduction of inflammatory proteins. As a result, the macroscopic, microscopic inflammation and activity index (DAI) of DSS-induced decreased. CONCLUSION: D. dendriticum egg antigen provides a promising new way to modulate the immune system and improve ulcerative colitis.

The contribution of the sphingosine 1-phosphate signaling pathway to chronic kidney diseases: recent findings and new perspectives.

Chronic kidney disease (CKD) is a multifactorial condition with diverse etiologies, such as diabetes mellitus, hypertension, and genetic disorders, often culminating in end-stage renal disease (ESRD). A hallmark of CKD progression is kidney fibrosis, characterized by the excessive accumulation of extracellular matrix components, for which there is currently no effective anti-fibrotic therapy. Recent literature highlights the critical role of sphingosine 1-phosphate (S1P) signaling in CKD pathogenesis and renal fibrosis. This review provides an in-depth analysis of the latest findings on S1P metabolism and signaling in renal fibrosis and in specific CKDs, including diabetic nephropathy (DN), lupus nephritis (LN), focal segmental glomerulosclerosis (FSGS), Fabry disease (FD), and IgA nephropathy (IgAN). Emerging studies underscore the therapeutic potential of modulating S1P signaling with receptor modulators and inhibitors, such as fingolimod (FTY720) and more selective agents like ozanimod and cenerimod. Additionally, the current knowledge about the effects of established kidney protective therapies such as glucocorticoids and SGLT2 and ACE inhibitors on S1P signaling will be summarized. Furthermore, the review highlights the potential role of S1P as a biomarker for disease progression in CKD models, particularly in Fabry disease and diabetic nephropathy. Advanced technologies, including spatial transcriptomics, are further refining our understanding of S1P's role within specific kidney compartments. Collectively, these insights emphasize the need for continued research into S1P signaling pathways as promising targets for CKD treatment strategies.

Increased peritoneal TGF-ß1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer.

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-ß1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-ß1 exposure. Moreover, inhibition of TGF-ß1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-ß1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-ß1 signaling could increase NK cell immune responses in high-grade EOC patients.

TGF-ß effects on adipogenesis of 3T3-L1 cells differ in 2D and 3D cell culture conditions.

The TGF-ß superfamily plays a pivotal role in the regulation of adipogenesis, but little is known about the potential differential role of the three isoforms of TGF-ß, TGF-ß-1~3. To further elucidate their role, two-dimensionally (2D) and three-dimensionally (3D) cultured 3T3-L1 mouse preadipocytes were subjected to the following analyses: (a) qPCR analysis of adipogenesis-related factors and major extracellular matrix protein (2D and /or 3D), (b) lipid staining by Oil Red O (2D) or BODIPY (3D), (c) Seahorse cellular metabolic measurement (2D), and (d) size and stiffness measurements of 3D 3T3-L1 spheroids. In the 2D cultured 3T3-L1 cells, mRNA expression levels of adipogenesis-related genes and Oil Red O lipid staining intensity were significantly increased by adipogenesis and they were substantially decreased following treatment with 0.1 nm TGF-ß isoforms, with TGF-ß2 having the greater effects. Consistent with these results, treatment with TGF-ß2 resulted in suppression of mitochondrial and glycolytic functions in 2D cultured 3T3-L1 cells. However, the inhibitory effect of TGF-ß on adipogenesis decreased under 3D spheroid culture conditions and TGF-ß isoforms did not affect adipogenesis-induced (a) enlargement and downsizing of 3T3-L1 spheroids, (b) increase in BODIPY lipid staining intensity, and (c) up-regulation of the mRNA expression of adipogenesis-related genes. The findings presented herein suggest that the three TGF-ß isoforms have different suppressive effects on adipogenesis-related cellular properties of 2D cultured 3T3-L1 cells and that their effects decrease under 3D spheroid culture conditions.

Fibroblast-specific TGF-ß signaling mediates cardiac dysfunction, fibrosis, and hypertrophy in obese diabetic mice.

AIMS: Transforming growth factor (TGF)-ß is up-regulated in the diabetic myocardium and may mediate fibroblast activation. We aimed at examining the role of TGF-ß-induced fibroblast activation in the pathogenesis of diabetic cardiomyopathy. METHODS AND RESULTS: We generated lean and obese db/db mice with fibroblast-specific loss of TbR2, the Type 2 receptor-mediating signaling through all three TGF-ß isoforms, and mice with fibroblast-specific Smad3 disruption. Systolic and diastolic function, myocardial fibrosis, and hypertrophy were assessed. Transcriptomic studies and in vitro experiments were used to dissect mechanisms of fibroblast activation. Fibroblast-specific TbR2 loss attenuated systolic and diastolic dysfunction in db/db mice. The protective effects of fibroblast TbR2 loss in db/db mice were associated with attenuated fibrosis and reduced cardiomyocyte hypertrophy, suggesting that in addition to their role in fibrous tissue deposition, TGF-ß-stimulated fibroblasts may also exert paracrine actions on cardiomyocytes. Fibroblast-specific Smad3 loss phenocopied the protective effects of fibroblast TbR2 loss in db/db mice. Db/db fibroblasts had increased expression of genes associated with oxidative response (such as Fmo2, encoding flavin-containing monooxygenase 2), matricellular genes (such as Thbs4 and Fbln2), and Lox (encoding lysyl oxidase). Ingenuity pathway analysis (IPA) predicted that neurohumoral mediators, cytokines, and growth factors (such as AGT, TGFB1, and TNF) may serve as important upstream regulators of the transcriptomic profile of diabetic mouse fibroblasts. IPA of scRNA-seq data identified TGFB1, p53, MYC, PDGF-BB, EGFR, and WNT3A/CTNNB1 as important upstream regulators underlying fibroblast activation in db/db hearts. Comparison of the transcriptome of fibroblasts from db/db mice with fibroblast-specific Smad3 loss and db/db Smad3 fl/fl controls identified Thbs4 [encoding thrombospondin-4 (TSP-4), a marker of activated fibroblasts] as a candidate diabetes-induced fibrogenic mediator. However, in vitro experiments showed no significant activating effects of matricellular or intracellular TSP-4 on cardiac fibroblasts. CONCLUSION: Fibroblast-specific TGF-ß/Smad3 signaling mediates ventricular fibrosis, hypertrophy, and dysfunction in Type 2 diabetes.

The role and mechanism of CRISPLD2 in skin fibrosis of systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune connective tissue disease involving multiple organs. The most common clinical symptom of SSc is progressive fibrosis of the skin, and the pathologically manifestations of skin were activation and proliferation of fibroblasts and continuous proliferation of extracellular matrix. Transforming growth factor ß (TGFß) can promote the proliferation and activation of fibroblasts, causing excessive deposition of collagen and structural proteins. Therefore, exploring the specific mechanism of TGFß-related pathway on fibrosis is of great significance for improving skin fibrosis in SSc. METHODS: Genes related to TGFß pathway were screened through bioinformatics analysis, and SSc phenotypes were verified in vivo and vitro. The relevant molecular mechanisms were preliminarily discussed in combination with transcriptome sequencing. RESULTS: Human cysteine-rich secreted protein LCCL domain protein 2 (CRISPLD2) was found increased reactivity in TGFß induced fibroblasts, and the expression of ACTA2 (ɑ-SMA) decreased significantly in TGFß-mediated fibroblasts with up-regulation of CRISPLD2. CONCLUSION: CRISPLD2 was found increased reactivity in TGFß induced fibroblasts, and we further confirmed that CRISPLD2 can participate in TGFß induced fibroblast fibrosis from multiple perspectives and levels in negative feedback regulation, and investigated the mechanism of CRISPLD2 in fibrosis.

CD151 identifies a NK cell subset that is enriched in COVID-19 patients and correlates with disease severity.

Severe coronavirus disease 2019 (COVID-19) often lead to acute respiratory distress syndrome and multi-organ dysfunction, driven by a dysregulated immune response, including a cytokine storm with elevated proinflammatory cytokine levels. Natural killer (NK) cells are part of the innate immune system with a fundamental role in the defense against viral infections. However, during COVID-19 acute infection, they exhibit an altered phenotype and impaired functionality contributing to the immunopathogenesis of the disease. In this work, we have studied a cohort of patients with COVID-19 (ranging from mild to severe) by analyzing IL-15, TGF-ß, PlGF and GDF-15 plasma levels and performing multiparametric flow cytometry studies. Our results revealed that severe COVID-19 patients exhibited high levels of IL-15, PlGF and GDF-15, along with an enrichment of a NK cell subset expressing the CD151 tetraspanin, which correlated with IL-15 plasma levels and disease severity. In patients, these CD151+ NK cells displayed a more activated phenotype characterized by an increased expression of HLA-DR, CD38 and granzyme B, a distinct receptor repertoire, with lower levels of CD160 and CD31 and higher levels of CD55 and, remarkably, a higher expression of tissue-resident markers CD103 and the NK cell decidual marker CD9. Last of all, in individuals with severe disease, we identified an expansion of a CD151brightCD9+ NK cell subset, suggesting that these cells play a specific role in COVID-19. Altogether, our findings suggest that CD151+ NK cells may have a relevant role in COVID-19 immunopathogenesis.

Isoliensinine suppressed gastric cancer cell proliferation and migration by targeting TGFBR1 to regulate TGF-ß-smad signaling pathways.

Background: Gastric cancer (GC) ranks as the fifth most prevalent cancer globally, and its pronounced invasiveness and propensity to spread provide significant challenges for therapy. At present, there are no efficacious medications available for the treatment of patients with GC. Isoliensinine (ISO), a bisbenzylisoquinoline alkaloid, was isolated from Nelumbo nucifera Gaertn. It possesses anti-tumor, antioxidant, and other physiological effects. Nevertheless, there is currently no available study on the impact of ISO on GC, and further investigation is needed to understand its molecular mechanism. Methods: ISO target points and GC-related genes were identified, and the cross-target points of ISO and GC were obtained. We then examined cross-targeting and found genes that were differentially expressed in GCs. Kaplan-Meier survival curves were used to screen target genes, and the STRING database and Cytoscape 3.9.1 were used to construct protein-protein interactions and drug-target networks. In addition, molecular docking studies confirmed the interactions between ISO screen targets. Finally, in vitro tests were used to establish the impact of ISO on GC cells. Results: Through bioinformatics research, we have identified TGFBR1 as the target of ISO in GC. In addition, we noticed a substantial inhibition in GC cell proliferation, migration, and invasion activities following ISO treatment. Moreover, we noticed that ISO treatment effectively suppressed TGF-ß-induced epithelial-mesenchymal transition (EMT) and activation of the TGF-ß-Smad pathway. Furthermore, we discovered that siTGFBR1 nullified the impact of ISO on TGF-ß-triggered migration, invasion, and activation of the TGF-ß-Smad pathway. Conclusion: Our research suggests that ISO specifically targets TGFBR1 and regulates the TGF-ß-Smad signaling pathway to suppress the proliferation and migration of GC cells.

Transforming growth factor-ß in tumor microenvironment: Understanding its impact on monocytes and macrophages for its targeting.

TGF-ß is a pivotal cytokine that orchestrates various aspects of cancer progression, including tumor growth, metastasis, and immune evasion. In this review, we present a comprehensive overview of the multifaceted role of transforming growth factor ß (TGF-ß) in cancer biology, focusing on its intricate interactions with monocytes and macrophages within the tumor microenvironment (TME). We specifically discuss how TGF-ß modulates monocyte and macrophage activities, leading to immunosuppression and tumor progression. We conclude with the current translational and clinical efforts targeting TGF-ß, recognizing the promising role of this strategy in immunooncology.

Transforming growth factor ß (TGF-ß), a pivotal cytokine, plays a crucial role in maintaining homeostasis and influencing cancer development by affecting various cell types. In cancer, TGF-ß initially suppresses tumor cell growth but later contributes to tumor progression and metastasis, presenting challenges in developing therapeutics targeting this cytokine. Mechanistically, TGF-ß impacts diverse cellular processes through canonical Smad and non-Smad pathways, that explains its diverse regulation of different, sometimes opposing, cellular processes.In the context of immunity, exposure to TGF-ß renders immune cells immunosuppressive, hindering their ability to fight tumor development. This article explores the effects of TGF-ß on monocytes and macrophages, highlighting its role in creating an immunosuppressive tumor microenvironment (TME) required for tumor survival and growth. The article provides an update on recent studies that underscore the potential of TGF-ß inhibition in modulating the immune response within the TME, thereby enhancing the effectiveness of cancer immunotherapy.Overall, this review article delves into the multifaceted role of TGF-ß in cancer biology, with a specific focus on its interactions with monocytes and macrophages. It underscores the knowledge gaps and the importance of targeting TGF-ß signaling in tumor-associated monocytes and macrophages as a promising therapeutic approach in TGF-ß secreting tumors.

Qianggan Ruanjian Pill ameliorates liver fibrosis through regulation of the TGF-ß1/Smad and PI3K/AKT signalling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is a critical pathological process in the progression of chronic liver injury, ultimately resulting in cirrhosis, for which currently available therapeutic interventions remain inadequate. Among these, the Qianggan Ruanjian Pill (QGRJP) has emerged as a clinically experienced formula with notable therapeutic efficacy against liver fibrosis. However, the precise underlying mechanisms require further investigation. AIM OF THE STUDY: In this study, we investigated the key pathways and target genes of QGRJP that attenuate liver fibrosis and elucidated the underlying mechanisms. MATERIALS AND METHODS: High-performance liquid chromatography-mass spectrometry (HPLC-MS) was used to identify the major components of the QGRJP. Mouse models of liver fibrosis were established by injecting olive oil containing 25% carbon tetrachloride (CCl4), which was administered at different doses of QGRJP by gavage. Liver damage and function were assessed using serum biochemical detection, ultrasound imaging, and histopathological examination. The anti-fibrosis effect was assessed using immunohistochemistry, western blotting, and quantitative real-time PCR (qRT-PCR). The in vivo safety of the QGRJP was evaluated using weight monitoring and biopsy. Potential anti-liver fibrosis signalling pathways and key targets of QGRJP were identified using RNA-seq analysis and network pharmacology. The predicted targets and pathways were validated using in vitro and in vivo experiments. RESULTS: QGRJP significantly ameliorated CCl4-induced liver fibrosis, and its mechanism was correlated with the inhibition of hepatic stellate cell (HSC) activation and the inflammatory response via inhibition of the TGF-ß1/Smad and PI3K/AKT pathways, leading to a significant reduction in the expression of collagen and other fibrosis-related proteins. Additionally, no obvious toxic side effects were observed in the major organs of the mice or in activated HSCs (aHSCs). CONCLUSION: This study demonstrated that QGRJP mitigated liver injury, inflammation, and fibrosis by inhibiting the TGF-ß1/Smad and PI3K/AKT signalling pathways.

Quercetin regulates pulmonary vascular remodeling in pulmonary hypertension by downregulating TGF-ß1-Smad2/3 pathway.

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-ß1 (TGF-ß1)/ 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-ß1/Smad2/Smad3 pathway, thereby reducing right ventricular hyperplasia (RVH) and pulmonary vascular remodeling, providing potential pharmacological and molecular explanations for the treatment of PAH.