Search

Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

In the last forty years, the number of people over 60 years of age has increased significantly owing to better nutrition and lower rates of infectious diseases in developing countries. Aging significantly impacts adipose tissue, which plays crucial role in hormone regulation and energy storage. This can lead to imbalances in glucose, and overall energy homeostasis within the body. Aging is irreversible phenomena and potentially causing lipid infiltration in other organs, leading to systemic inflammation, metabolic disorders. This review investigates various pathways contributing to aging-related defects in adipogenesis, such as changes in adipose tissue function and distribution. Polyphenols, a diverse group of natural compounds, can mitigate aging effects via free radicals, oxidative stress, inflammation, senescence, and age-related diseases. Polyphenols like resveratrol, quercetin and EGCG exhibit distinct mechanisms and regulate crucial pathways, such as the TGF-β, AMPK, Wnt, PPAR-γ, and C/EBP transcription factors, and influence epigenetic modifications, such as DNA methylation and histone modification. This review highlights the critical importance of understanding the intricate relationship between aging and adipogenesis for optimizing well-being with increasing age. These findings highlight the therapeutic potential of polyphenols like quercetin and resveratrol in enhancing adipose tissue function and promoting healthy aging. [ABSTRACT FROM AUTHOR]

Platelets are the first to reach the site of tissue damage and secrete substances like platelet growth factors (GFs), which perform many different functions in the human body. Many studies suggest that GFs such as transforming GF (TGF), platelet‐derived GF (PDGF), or insulin‐like GF‐1 (IGF‐1) may be markers of survival, disease severity, and post‐coronavirus disease (COVID) complications. The study aimed to analyze the concentration of TGF‐β, IGF‐1, and PDGF‐BB in COVID‐19 patients compared to the control group (GK). The study group consisted of 50 patients (23 men and 27 women) at the time of COVID‐19 detection, 7 days after detection, then 14 and 28 days after detecting severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. The GK comprised 48 healthy volunteers (25 women and 23 men). IGF‐1, TGF‐β, and PDGF‐BB concentrations in blood serum by enzyme‐linked immunosorbent assay (ELISA) methods. There was a statistically significant relationship between the concentration of IGF‐1, TGF‐β 1, and PDGF‐BB in the study group (I–IV blood draw) and the GK (p < 0.001). Statistical analysis showed a significant effect on the survival of COVID‐19 patients on IGF‐1 (p = 0.013), TGF‐β (p = 0.013), and PGDF‐BB (p = 0.015) levels. The analysis showed a significant effect of COVID‐19 symptom severity on IGF‐1 levels (p = 0.018), as well as TGF‐β (p = 0.044) and PDGF‐BB (p = 0.047). In the future, GF may serve as a predictor of disease severity and the development of new treatments for COVID‐19. In later studies, the focus should be on finding the relationship of COVID‐19 pathomechanism with all the parameters to understand the processes that occur in the body during SARS‐CoV‐2 virus infection. [ABSTRACT FROM AUTHOR]

Introduction: TGFβ is a major immunoinhibitory factor present in the microenvironment of solid tumors. Various cancer types acquire the ability to overexpress TGFβ to escape immune response. Specifically, TGFβ dampens cytotoxic T cell activity, and its presence has been correlated with tumor invasion and poor prognosis. Methods: In this study, we developed two approaches to counteract the effects of TGFβ and provide a functional advantage to genetically engineered T cells in the immunoinhibitory tumor milieu. We designed a TGFβRI-based co-stimulatory switch receptor (CSRI), comprising the TGFβ receptor I extracellular binding domain and a 4-1BB co-stimulatory signaling moiety. Additionally, we tested the efficacy of a TGFβ-binding scFv trap produced by T cells. Results: We demonstrated that both approaches enhanced tumor-specific T cell cytokine secretion, upregulated activation markers, and reduced inhibition markers upon co-culture with melanoma targets. Furthermore, CSRI and the anti-TGFβ trap exhibited improved anti-tumor function in vivo. Conclusion: Overall, we show that targeting the TGFβ pathway can enhance cellular immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Benign prostatic hyperplasia (BPH) is the enlargement of the prostate gland, primarily occurring in aging men, in which transforming growth factor-beta (TGF-β) plays a critical role in prostate cell hyperproliferation and leads to uncomfortable urinary symptoms in BPH patients. Pterocarpus indicus Willd. is well known for its ethnopharmacological applications for treating ailments such as diuresis and bladder stones. Methods: This study aimed to examine the effect of P. indicus extract (PI extract) on TGF-β-induced WPMY-1 cell proliferation, followed by bioassay-guided fractionation to isolate the active metabolites. Angolensin (Ang) and maackiain (Mac) were isolated from bioassay-guided fractionation. Network analysis was performed to investigate the potential mechanisms. Furthermore, network analysis of the Ang-Mac combination in BPH highlighted the potential top ten pathways, including PI3K/AKT signaling pathway. Accordingly, subsequent investigation focused on evaluating the effect of PI extract, Ang, Mac, and Ang-Mac combination on the expression of PCNA, p53, and PI3K/AKT protein localization and expression. Results and discussion: Results revealed inhibition of cell proliferation in TGF-β-induced WPMY-1 cells, correlating with downregulated PCNA expression. While PI extract and Mac induced apoptosis via p53 upregulation, Ang and Ang-Mac combination did not significantly affect apoptosis through the p53 pathway. Additionally, both metabolites exhibited potent inhibition of p-PI3K and p-AKT protein localization and expression in the nucleus of TGF-β-induced WPMY-1 cells. This study suggests that PI extract, Ang, and Mac are promising compounds for treating BPH, as evidenced by in silico and in vitro studies. Additionally, Ang and Mac could be used to standardize PI extract in future investigations. [ABSTRACT FROM AUTHOR]

Although substantial quantities of potent therapies for multiple myeloma (MM) have been established, MM remains an incurable disease. In recent years, our understanding of the initiation, development, and metastasis of cancers has made a qualitative leap. Cancers attain the abilities to maintain proliferation signals, escape growth inhibitors, resist cell death, induce angiogenesis, and more importantly, escape anti-tumor immunity and reprogram metabolism, which are the hallmarks of cancers. Besides, different cancers have different tumor microenvironments (TME), thus, we pay more attention to the TME in the pathogenesis of MM. Many researchers have identified that myeloma cells interact with the components of TME, which is beneficial for their survival, ultimately causing the formation of immunosuppressive and high-metabolism TME. In the process, transforming growth factor-β (TGF-β), as a pivotal cytokine in the TME, controls various cells' fates and influences numerous metabolic pathways, including inhibiting immune cells to infiltrate the tumors, suppressing the activation of anti-tumor immune cells, facilitating more immunosuppressive cells, enhancing glucose and glutamine metabolism, dysregulating bone metabolism and so on. Thus, we consider TGF-β as the tumor promoter. However, in healthy cells and the early stage of tumors, it functions as a tumor suppressor. Due to the effect of context dependence, TGF-β has dual roles in TME, which attracts us to further explore whether targeting it can overcome obstacles in the treatment of MM by regulating the progression of myeloma, molecular mechanisms of drug resistance, and various signaling pathways in the immune and metabolic microenvironment. In this review, we predominantly discuss that TGF-β promotes the development of MM by influencing immunity and metabolism. [ABSTRACT FROM AUTHOR]

Chronic wounds can develop as a result of prolonged inflammation during the healing process, which can happen due to bacterial infection. Therefore, preventing infection and controlling inflammation can accelerate wound healing. Antimicrobial peptides have different protective properties in addition to antimicrobial activity. Some of these activities include the stimulation of cytokine or chemokine synthesis, the facilitation of chemotaxis and cell proliferation, the acceleration of cell proliferation, the induction of anti-inflammatory responses, and the promotion of wound repair. This study aimed to assess the wound healing potential of a novel in silico-designed antimicrobial peptide. Then, its anti-inflammatory activity was investigated by measuring the level of tumor necrosis factor-α (TNF-α) and transforming growth factor beta (TGF-β) as indicators of the wound healing process. In addition, the influence of the peptide on cell migration was evaluated by a scratch test on human dermal fibroblasts (HDF) and HaCaT cells as a human epidermal keratinocyte cell line. The results showed that our new peptide could act well in inhibiting TNF-α over-secretion while increasing the expression of TGF-β as an anti-inflammatory factor. This peptide showed a significant potential to stimulate HDF and HaCaT cell migration and proliferation. Therefore, using this peptide as an anti-inflammatory component of wound dressings may be promising. • A novel antimicrobial peptide was designed from Cathelicidine-2, named as mCHTL (131-140). • The mCHTL (131-140) could inhibit TNF-α over-secretion. • The mCHTL (131-140) could increase the TGF-β expression. • The mCHTL (131-140) could stimulate HDF and HaCaT cells migration and proliferation. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) represents a highly heterogeneous kidney malignancy associated with the poorest prognosis. The metastatic potential of advanced ccRCC tumors is notably high, posing significant clinical challenges. There is an urgent imperative to develop novel therapeutic approaches to address ccRCC metastasis. Recent investigations indicated a potential association between GBP2 and tumor immunity. However, the precise functional role of GBP2 in the progression of ccRCC remains poorly understood. The present study revealed a strong correlation between GBP2 and M2 macrophages. Specifically, our findings demonstrated that the inhibition of GBP2 significantly impedes the migratory and invasive capabilities of ccRCC cells. We observed that the presence of M2 macrophages can reverse the effects of GBP2 knockdown on tumor cell migration and invasion. Mechanistically, we demonstrated that M2 macrophages promote the expression of the GBP2/p‐STAT3 and p‐ERK axis in tumor cells through the secretion of interleukin‐10 (IL‐10) and transforming growth factor‐β (TGF‐β), thereby substantially enhancing the migratory and invasive capacities of the tumor cells. Simultaneously, we have identified that GBP2 promotes the polarization of macrophages to the M2 phenotype by stimulating the secretion of interleukin‐18 (IL‐18). In summary, our investigation anticipates that the GBP2/IL‐18/M2 macrophages/IL‐10 and the TGF‐β/GBP2, p‐STAT3, p‐ERK loop plays a crucial role in ccRCC metastasis. The collective findings from our research underscore the significant role of GBP2 in tumor immunity and emphasize the potential for modulating GBP2 as a promising therapeutic strategy for targeting ccRCC metastasis. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1 , priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth. [Display omitted] • TGF-β and RAS drive expression of EMT and fibrogenic genes that jointly fuel metastasis • Epigenetic determinants segregate different programs within a global TGF-β response • RAS/MAPK-regulated RREB1 primes enhancers for activation by SMAD-recruited INO80 • Targeting RREB1 selectively inhibits LUAD metastasis During carcinoma metastasis, malignant progenitors undergo a TGF-β-dependent EMT associated with fibroblast activation and extracellular matrix remodeling in the tumor microenvironment. RAS-activated RREB1 primes enhancers of EMT and fibrogenic genes in lung adenocarcinoma cells for activation by chromatin remodeling complexes that the TGF-β/SMAD pathway recruits to these enhancers. Inhibiting RREB1 disables this pro-metastatic process. [ABSTRACT FROM AUTHOR]

Myocardial injuries in viral myocarditis (VMC) are caused by viral infection and related autoimmune disorders. Recent studies suggest that IL-9 mediated both antimicrobial immune and autoimmune responses in addition to allergic diseases. However, the role of IL-9 in viral infection and VMC remains controversial and uncertain. In this study, we infected Balb/c mice with Coxsackievirus B3 (CVB3), and found that IL-9 was enriched in the blood and hearts of VMC mice on days 5 and 7 after virus infection. Most of IL-9 was secreted by CD8+ T cells on day 5 and CD4+ T cells on day 7 in the myocardium. Further, IL-9 knockout exacerbated cardiac damage following CVB3 infection, along with a sharp increase in viral replication and IL-17a expression, as well as a decrease in TGF-β. In contrast, the repletion of IL-9 in Balb/c mice with CVB infection induced the opposite effect. Studies in vitro further revealed that IL-9 directly inhibited viral replication in cardiomyocytes by reducing coxsackie and adenovirus receptor expression, which might be associated with upregulation of TGF-β autocrine effect in these cells. However, IL-9 had no direct effect on apoptosis in cardiomyocytes. Our data indicated that IL-9 played a protective role in disease progression by inhibiting CVB3 replication in the early stages of VMC. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the effectiveness of dipeptidyl peptidase IV inhibitors (DPP4-I) against liver damage, especially fibrosis and lipid accumulation, in a rat intestinal failure-associated liver disease (IFALD) model. Methods: SD rats were divided into two groups: the Control (n = 7; normal saline + IFALD model) and DPP4-I (n = 7; DPP4-I + IFALD model; short bowel syndrome (SBS) + total parenteral nutrition) groups. All rats were euthanized 21 days postoperatively to obtain tissue samples. Liver fibrosis was evaluated by Sirius Red and α-SMA staining. Liver damage was assessed using the steatosis, activity, and fibrosis score. Inflammation cytokines were examined by ELISA. Results: The survival rate was comparatively different, being 87.5% in the DPP4-I group and 70.0% in the Control group. Two rats of the Control group showed progressive liver fibrosis in the periportal area with fibrous streaks. Further, the mean area percentage of α-SMA immune-positive cells was significantly lower in the DPP4-I group than in the Control group. TGF-β levels were significantly lower in the DPP4-I group than in the Control group. Conclusion: DPP4-I administration reduced liver fibrosis in IFALD, possibly by inhibiting DPP4-I-induced adipogenesis and suppressing TGF-β. These results may contribute to elucidating the mechanism of IFALD. [ABSTRACT FROM AUTHOR]

Background: Although the representative treatment for colorectal cancer (CRC) is radiotherapy, cancer cells survive due to inherent radioresistance or resistance acquired after radiation treatment, accelerating tumor malignancy and causing local recurrence and metastasis. However, the detailed mechanisms of malignancy induced after radiotherapy are not well understood. To develop more effective and improved radiotherapy and diagnostic methods, it is necessary to clearly identify the mechanisms of radioresistance and discover related biomarkers. Methods: To analyze the expression pattern of miRNAs in radioresistant CRC, sequence analysis was performed in radioresistant HCT116 cells using Gene Expression Omnibus, and then miR-1226-5p, which had the highest expression in resistant cells compared to parental cells, was selected. To confirm the effect of miR-1226-5 on tumorigenicity, Western blot, qRT-PCR, transwell migration, and invasion assays were performed to confirm the expression of EMT factors, cell mobility and invasiveness. Additionally, the tumorigenic ability of miR-1226-5p was confirmed in organoids derived from colorectal cancer patients. In CRC cells, IRF1, a target gene of miR-1226-5p, and circSLC43A1, which acts as a sponge for miR-1226-5p, were discovered and the mechanism was analyzed by confirming the tumorigenic phenotype. To analyze the effect of tumor-derived miR-1226-5p on macrophages, the expression of M2 marker in co-cultured cells and CRC patient tissues were confirmed by qRT-PCR and immunohistochemical (IHC) staining analyses. Results: This study found that overexpressed miR-1226-5p in radioresistant CRC dramatically promoted epithelial-mesenchymal transition (EMT), migration, invasion, and tumor growth by suppressing the expression of its target gene, IRF1. Additionally, we discovered circSLC43A1, a factor that acts as a sponge for miR-1226-5p and suppresses its expression, and verified that EMT, migration, invasion, and tumor growth are suppressed by circSLC43A1 in radioresistant CRC cells. Resistant CRC cells-derived miR-1226-5p was transferred to macrophages and contributed to tumorigenicity by inducing M2 polarization and secretion of TGF-β. Conclusions: This study showed that the circSLC43A1/miR-1226-5p/IRF1 axis is involved in radioresistance and cancer aggressiveness in CRC. It was suggested that the discovered signaling factors could be used as potential biomarkers for diagnosis and treatment of radioresistant CRC. [ABSTRACT FROM AUTHOR]

Macrophage-myofibroblast transformation (MMT) has emerged as a discovery in the field of fibrotic disease research. MMT is the process by which macrophages differentiate into myofibroblasts, leading to organ fibrosis following organ damage and playing an important role in fibrosis formation and progression. Recently, many new advances have been made in studying the mechanisms of MMT occurrence in fibrotic diseases. This article reviews some critical recent findings on MMT, including the origin of MMT in myofibroblasts, the specific mechanisms by which MMT develops, and the mechanisms and effects of MMT in the kidneys, lungs, heart, retina, and other fibrosis. By summarizing the latest research related to MMT, this paper provides a theoretical basis for elucidating the mechanisms of fibrosis in various organs and developing effective therapeutic targets for fibrotic diseases. [ABSTRACT FROM AUTHOR]

Glioblastoma Multiforme (GBM), designated as grade IV by the World Health Organization, is the most aggressive and challenging brain tumor within the central nervous system. Around 80% of GBM patients have a poor prognosis, with a median survival of 12–15 months. Approximately 90% of GBM cases originate from normal glial cells via oncogenic processes, while the remainder arise from low-grade tumors. GBM is notorious for its heterogeneity, high recurrence rates, invasiveness, and aggressive behavior. Its malignancy is driven by increased invasive migration, proliferation, angiogenesis, and reduced apoptosis. Throughout various stages of central nervous system (CNS) development, pivotal signaling pathways, including Wnt/β-catenin, Sonic hedgehog signaling (Shh), PI3K/AKT/mTOR, Ras/Raf/MAPK/ERK, STAT3, NF-КB, TGF-β, and Notch signaling, orchestrate the growth, proliferation, differentiation, and migration of neural progenitor cells in the brain. Numerous upstream and downstream regulators within these signaling pathways have been identified as significant contributors to the development of human malignancies. Disruptions or aberrant activations in these pathways are linked to gliomagenesis, enhancing the invasiveness, progression, and aggressiveness of GBM, along with epithelial to mesenchymal transition (EMT) and the presence of glioma stem cells (GSCs). Traditional GBM treatment involves surgery, radiotherapy, and chemotherapy with Temozolomide (TMZ). However, most patients experience tumor recurrence, leading to low survival rates. This review provides an overview of the major cell signaling pathways involved in gliomagenesis. Furthermore, we explore the signaling pathways leading to therapy resistance and target key molecules within these signaling pathways, paving the way for the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Benign prostatic hyperplasia (BPH) is the enlargement of the prostate gland, primarily occurring in aging men, in which transforming growth factor-beta (TGF-ß) plays a critical role in prostate cell hyperproliferation and leads to uncomfortable urinary symptoms in BPH patients. Pterocarpus indicus Willd. is well known for its ethnopharmacological applications for treating ailments such as diuresis and bladder stones. Methods: This study aimed to examine the effect of P. indicus extract (PI extract) on TGF-ß-induced WPMY-1 cell proliferation, followed by bioassay-guided fractionation to isolate the active metabolites. Angolensin (Ang) and maackiain (Mac) were isolated from bioassay-guided fractionation. Network analysis was performed to investigate the potential mechanisms. Furthermore, network analysis of the Ang-Mac combination in BPH highlighted the potential top ten pathways, including PI3K/AKT signaling pathway. Accordingly, subsequent investigation focused on evaluating the effect of PI extract, Ang, Mac, and Ang-Mac combination on the expression of PCNA, p53, and PI3K/AKT protein localization and expression. Methods: This study aimed to examine the effect of P. indicus extract (PI extract) on TGF-ß-induced WPMY-1 cell proliferation, followed by bioassay-guided fractionation to isolate the active metabolites. Angolensin (Ang) and maackiain (Mac) were isolated from bioassay-guided fractionation. Network analysis was performed to investigate the potential mechanisms. Furthermore, network analysis of the Ang-Mac combination in BPH highlighted the potential top ten pathways, including PI3K/AKT signaling pathway. Accordingly, subsequent investigation focused on evaluating the effect of PI extract, Ang, Mac, and Ang-Mac combination on the expression of PCNA, p53, and PI3K/AKT protein localization and expression. cells. This study suggests that PI extract, Ang, and Mac are promising compounds for treating BPH, as evidenced by in silico and in vitro studies. Additionally, Ang and Mac could be used to standardize PI extract in future investigations. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms (MPNs) are characterized by an increased production of blood cells due to the acquisition of mutations such as JAK2V617F. TGF‐β, whose secretion is increased in MPN patients, is known to negatively regulate haematopoietic stem cell (HSC) proliferation. Using an isogenic JAK2V617F or JAK2 wild‐type UT‐7 cell line we observed that JAK2V617F cells resist to TGF‐β antiproliferative activity. Although TGF‐β receptors and SMAD2/3 expressions are similar in both cell types, TGF‐β‐induced phosphorylation of SMAD2/3 is reduced in UT‐7 JAK2V617F cells compared with JAK2 WT cells. We confirmed that JAK2V617F mutated cells are resistant to the antiproliferative effect of TGF‐β in a competitive assay as we observed a positive selection of JAK2V617F cells when exposed to TGF‐β. Using cell lines, CD34‐positive cells from MPN patients and bone marrow cells from JAK2V617F knock‐in mice we identified a down regulation of the SHP‐1 phosphatase, which is required for the regulation of HSC quiescence by TGF‐β. The transduction of SHP‐1 cDNA (but not a phosphatase inactive cDNA) restores the antiproliferative effect of TGF‐β in JAK2V617F mutated cells. Finally, SC‐1, a known agonist of SHP‐1, antagonized the selection of JAK2V617F mutated cells in the presence of TGF‐β. In conclusion, we show a JAK2‐dependent down regulation of SHP‐1 in MPN patients' cells which is related to their resistance to the antiproliferative effect of TGF‐β. This may participate in the clonal selection of cancer cells in MPNs. [ABSTRACT FROM AUTHOR]

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-β1 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. [ABSTRACT FROM AUTHOR]

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-β 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-β 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-β levels in BD, and higher TGF-β levels in SCH patients. Using moderated mediation analysis, TGF-β 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. [ABSTRACT FROM AUTHOR]

Hypertrophy of the ligamentum flavum (HLF) is a common contributor to lumbar spinal stenosis (LSS). Fibrosis is a core pathological factor of HLF resulting in degenerative LSS and associated low back pain. Although progress has been made in HLF research, the specific molecular mechanisms that promote HLF remain to be defined. The molecular factors involved in the onset of HLF include increases in inflammatory cytokines such as transforming growth factor (TGF)-β, matrix metalloproteinases, and pro-fibrotic growth factors. In this review, we discuss the current understanding of the mechanisms involved in HLF with a particular emphasis on aging and mechanical stress. We also discuss in detail how several pathomechanisms such as fibrosis, proliferation and apoptosis, macrophage infiltration, and autophagy, in addition to several molecular pathways involving TGF-β1, mitogen-activated protein kinase (MAPKs), and nuclear factor-κB (NF-κB) signaling, PI3K/AKT signaling, Wnt signaling, micro-RNAs, extracellular matrix proteins, reactive oxygen species (ROS), etc. are involved in fibrosis leading to HLF. We also present a summary of the current advancements in preclinical animal models for HLF research. In addition, we update the current and potential therapeutic targets/agents against HLF. An improved understanding of the molecular processes behind HLF and a novel animal model are key to developing effective LSS prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) represent major primary liver cancers, affecting one of the most vital organs in the human body. T regulatory (Treg) cells play an important role in liver cancers through the immunosuppression of antitumor immune responses. The current study focuses on the characterization of circulating natural killer (NK) cells and T cell subsets, including Treg cells, in CCA and HCC patients, before and after surgical tumor resection, in order to understand the effect of tumor resection on the homeostasis of peripheral blood NK cells and T cells. Methods: Whole blood assays were performed to monitor immune alterations and the functional competence of circulating lymphocytes in a group of ten healthy individuals, eight CCA patients, and twenty HCC patients, before and one month after the surgical procedure, using flow cytometry, cell sorting, and qRT-PCR. Results: Before tumor resection, both HCC and CCA patients display increased percentages of CD8+ Treg cells and decreased frequencies of circulating CD4+ Treg cells. Notwithstanding, no functional impairment was detected on circulating CD4+ Treg cells, neither in CCA nor in HCC patients. Interestingly, the frequency of peripheral CD4+ Treg cells increased from 0.55% ± 0.49 and 0.71% ± 0.54 (in CCA and HCC, respectively) at T0 to 0.99% ± 0.91 and 1.17% ± 0.33 (in CCA and HCC, respectively) at T1, following tumor resection. Conclusions: Our results suggest mechanisms of immune modulation induced by tumor resection. [ABSTRACT FROM AUTHOR]

Abstract\nPLAIN LANGUAGE SUMMARYTGF-β 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 β (TGF-β) in cancer biology, focusing on its intricate interactions with monocytes and macrophages within the tumor microenvironment (TME). We specifically discuss how TGF-β modulates monocyte and macrophage activities, leading to immunosuppression and tumor progression. We conclude with the current translational and clinical efforts targeting TGF-β, recognizing the promising role of this strategy in immunooncology.Transforming growth factor β (TGF-β), a pivotal cytokine, plays a crucial role in maintaining homeostasis and influencing cancer development by affecting various cell types. In cancer, TGF-β initially suppresses tumor cell growth but later contributes to tumor progression and metastasis, presenting challenges in developing therapeutics targeting this cytokine. Mechanistically, TGF-β 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-β renders immune cells immunosuppressive, hindering their ability to fight tumor development. This article explores the effects of TGF-β 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-β 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-β 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-β signaling in tumor-associated monocytes and macrophages as a promising therapeutic approach in TGF-β secreting tumors. [ABSTRACT FROM AUTHOR]

Despite various clinical options, human anterior cruciate ligament (ACL) lesions do not fully heal. Biomaterial‐guided gene therapy using recombinant adeno‐associated virus (rAAV) vectors may improve the intrinsic mechanisms of ACL repair. Here, we examined whether poly(sodium styrene sulfonate)‐grafted poly(ε‐caprolactone) (pNaSS‐grafted PCL) films can deliver rAAV vectors coding for the reparative basic fibroblast growth factor (FGF‐2) and transforming growth factor beta (TGF‐β) in human mesenchymal stromal cells (hMSCs) as a source of implantable cells in ACL lesions. Efficient and sustained rAAV‐mediated reporter (red fluorescent protein) and therapeutic (FGF‐2 and TGF‐β) gene overexpression was achieved in the cells for at least 21 days in particular with pNaSS‐grafted PCL films relative to all other conditions (up to 5.2‐fold difference). Expression of FGF‐2 and TGF‐β mediated by rAAV using PCL films increased the levels of cell proliferation, the DNA contents, and the deposition of proteoglycans and of type‐I and ‐III collagen (up to 2.9‐fold difference) over time in the cells with higher levels of transcription factor expression (Mohawk, Scleraxis) (up to 1.9‐fold difference), without activation of inflammatory tumor necrosis alpha especially when using pNaSS‐grafted PCL films compared with the controls. Overall, the effects mediated by TGF‐β were higher than those promoted by FGF‐2, possibly due to higher levels of gene expression achieved upon rAAV gene transfer. This study shows the potential of using functionalized PCL films to apply rAAV vectors for ACL repair. [ABSTRACT FROM AUTHOR]

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-β 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-β 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-β and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-β/TNF-α cooperativity was attenuated by selective inhibition of the TGF-βRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-β-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-β/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-β could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis. [ABSTRACT FROM AUTHOR]

Transforming Growth Factor-β (TGF-β) can have both tumour-promoting and tumour-suppressing activity in breast cancer. Elucidating the key downstream mediators of pro-tumorigenic TGF-β signalling in this context could potentially give rise to new therapeutic opportunities and/or identify biomarkers for anti-TGF-β directed therapy. Here, we identify C1orf106 (also known as innate immunity activator INAVA) as a novel TGF-β target gene which is induced in a SMAD3-dependent but SMAD2/SMAD4-independent manner in human and murine cell lines. C1orf106 expression positively correlates with tumourigenic or metastatic potential in human and murine breast cancer cell line models, respectively, and is required for enhanced migration and invasion in response to TGF-β stimulation. C1orf106 promoted self-renewal and colony formation in vitro and may promote tumour-initiating frequency in vivo. High C1orf106 mRNA expression correlates with markers of aggressiveness and poor prognosis in human breast cancer. Taken together, our findings indicate that C1orf106 may act as a tumour promoter in breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Transforming growth factor-beta (TGF-β) is considered as a regulator of cells' growth and differentiation. Ki-67 is a broadly known nuclear protein accompanied by cell growth as well as division. Colchicine is a traditional mitotic inhibitor used in treating several diseases. Objectives: To assess Colchicine administration outcome on the histology of filiform papillae with the TGF-β and Ki-67 immunohistochemical expression. Design: Forty male albino rats (200-250gm) were employed in the study. Animals were assigned equally as two groups, Control Group: received no drug and Colchicine treated group: received Colchicine (3mg/Kg/day) for 7 days. After sacrifice, processing of tongue specimens was done, then the slides were stained by Hematoxylin and Eosin, anti-TGF-β and anti-Ki-67. Area% of positive TGF-β and number of Ki-67 positive cells were statistically analyzed. Results: Histologically, Colchicine treated group showed shortened and narrowed simple conical filiform papillae with increased interpapillary areas. The epithelial covering revealed some dark hyperchromatic nuclei and vacuolations. Thickness of lamina propria and connective tissue (CT) cores were reduced with few fibroblasts, dilated and congested blood vessels. The papillae of Colchicine group showed wide distribution of strong intensity positive TGF-β immunoreactivity in both epithelial and CT cells, in addition to low intensity few positive Ki-67 basal and parabasal cells with rare positive CT cells. Statistical analysis showed highly significant increase in positive area% of TGF-β and highly significant decrease in Ki-67 positive epithelial as well as CT cells in this group when compared to the control. Conclusions: Colchicine induced degenerative histological changes in filiform papillae, in addition to a highly significant increase of TGF-β and a highly significant decrease of Ki-67 immunohistochemical expression. [ABSTRACT FROM AUTHOR]

To systematically assess the clinical efficacy of Salvia miltiorrhiza (SM) in treating pathological scars and provide a reference basis for scar pharmacotherapy, we conducted a comprehensive literature search in both English and Chinese databases from database inception to December 2022. Key search terms included Salvia miltiorhiza, cryptotanshinone, tanshinone IIA, sodium-tanshinol, compound Salvia miltiorrhiza dripping pills, cicatrix, cicatrices, and scar. The inclusion criteria encompassed all clinical randomized controlled studies on the treatment of pathological scars with SM, without regard to blinding or allocation concealment, as well as irrespective of patient nationality, race, or age. Data from the selected literature were subjected to analysis using RevMan 5.4 software, employing the standard mean difference or weighted mean difference for numerical variables and odds ratios (ORs) for dichotomous variables. Statistical significance was set at P < 0.05. Six eligible studies involving a total of 778 patients met the inclusion criteria. The analysis revealed a significant therapeutic efficacy with an OR of 3.83 (95% CI: 2.65-5.54), indicating a substantially higher therapeutic efficacy rate in SM group compared to the control group. Furthermore, the total effective rate of treatment exhibited an OR of 6.94 (95% CI: 2.53-19.06), signifying a significantly superior treatment outcome in SM group. Regarding scar scores, no significant improvement was observed in SM group compared to the control group after 3 months of treatment (mean difference [MD] = -0.96, 95% CI: -2.29-0.36). However, after 6 months of treatment, the scar score demonstrated a noteworthy improvement in SM group (MD = -1.37, 95% CI: -2.44 to -0.30) compared to the control group. In summary, this study affirmed that SM treatment markedly enhanced the therapeutic efficacy and overall treatment efficiency for clinical scar patients, underscoring its positive clinical therapeutic impact on scar patients. [ABSTRACT FROM AUTHOR]

Background: The aim of this paper was to investigate the protein concentrations of high-temperature requirement A 1 (HTRA1) and transforming growth factor- β (TGF- β) in the vitreous humor of patients with chorioretinal vascular diseases. Methods: This study measured protein concentrations of HTRA1, TGF- β 1 − 3 , and vascular endothelial growth factor A (hereinafter called VEGF) in the vitreous humor from seven eyes of patients with chorioretinal vascular diseases (age-related macular degeneration, diabetic macular edema, and retinal vein occlusion) and six control eyes (idiopathic epiretinal membrane and macular hole). We analyzed the mutual relationship among the protein levels. Results: The protein levels of HTRA1 and VEGF were significantly increased in the chorioretinal vascular disease group compared with the control group (1.57 ± 0.79 × 10 − 9 mol/mL vs. 0.68 ± 0.79 × 10 − 9 mol/mL, p = 0.039; 3447.00 ± 3423.47 pg/mL vs. 35.33 ± 79.01 pg/mL, p = 0.046, respectively). TGF- β 2 levels were not significantly different between groups (2222.71 ± 1151.25 pg/mL for the chorioretinal vascular disease group vs. 1918.83 ± 744.01 pg/mL for the control group, p = 0.62). The concentration of HTRA1 was strongly associated with TGF- β 2 levels in the vitreous humor, independent of VEGF (r = 0.80, p = 0.0010). Conclusions: We revealed that vitreous HTRA1 was increased in patients with chorioretinal vascular diseases and strongly correlated with TGF- β 2 . [ABSTRACT FROM AUTHOR]

Simple Summary: TGF-β is an important cytokine shown to drive oncogenesis in head and neck squamous cell carcinoma (HNSCC) through its diverse influences on the tumor microenvironment. While this cytokine is vital in maintaining tissue homeostasis in normal head and neck epithelia, in cancer, it paradoxically drives metastasis, angiogenesis, immune evasion, and therapy resistance. Despite promising preclinical data, the outcome of clinical trials of TGF-β inhibitors for HNSCC has been suboptimal. Patient stratification is warranted to improve this targeted therapy. Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy. [ABSTRACT FROM AUTHOR]

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications. [ABSTRACT FROM AUTHOR]

In clinical settings, addressing large bone defects remains a significant challenge for orthopedic surgeons. The use of genetically modified bone marrow mesenchymal stem cells (BMSCs) has emerged as a highly promising approach for these treatments. Signal peptide‐CUB‐EGF domain‐containing protein 3 (SCUBE3) is a multifunctional secreted glycoprotein, the role of which remains unclear in human hBMSCs. This study used various experimental methods to elucidate the potential mechanism by which SCUBE3 influences osteogenic differentiation of hBMSCs in vitro. Additionally, the therapeutic efficacy of SCUBE3, in conjunction with porous GeLMA microspheres, was evaluated in vivo using a mouse bone defect model. Our findings indicate that SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs, and that reducing SCUBE3 levels can hinder this differentiation. Overexpressing SCUBE3 elevated osteogenesis gene and protein levels and enhanced calcium deposition. Furthermore, treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF‐β expression, activated mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation. In vivo, GELMA/OE treatment effectively accelerated bone healing in mice. In conclusion, SCUBE3 fosters osteogenic differentiation and mitophagy in hBMSCs by activating the BMP2/TGF‐β signaling pathway. When combined with engineered hydrogel cell therapy, it could offer valuable guidance for the clinical management of extensive bone defects. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-β pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were measured. DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-β1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1β, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-β1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-β/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy. [ABSTRACT FROM AUTHOR]

Epithelial‐to‐mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti‐cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor‐β (TGF‐β)‐induced EMT in non‐small‐cell lung cancer. Our study revealed that TGF‐β plays a role in EMT functions by upregulation of cytidine 5′‐triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF‐β‐induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF‐β‐mediated downregulation of UDP‐glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non‐small‐cell lung cancer. [ABSTRACT FROM AUTHOR]

The menopausal period causes vagina atrophy due to a decrease in estrogen. This condition is associated with symptoms such as dryness, burning, irritation, discomfort, pain during sex, and impaired sexual function. The use of natural ingredients as therapy in menopause is currently being widely developed. Flavonoids can bind to estrogen receptors because they have a similar structure and activity to endogenous estrogens. Banana Ambones blossom (Musa acuminata Colla) contains flavonoid compounds that have phytoestrogenic activity. This study evaluated the improvement of vaginal atrophy with the use of natural ingredients in menopausal rats. This study used female Wistar rats aged 10-12 weeks, weighing 200-250 g, 25 rats were divided into 5 groups, and the rats were subjected to ovariectomy. The normal group (KN), and negative control group (K-) were given standard food and drinking water; the positive control group (K+) received 0.01125 mg/day of conjugated estrogen. The P1 group was given banana blossom extract 200 mg/kg b.w, and the P2 group was given banana blossom extract 400 mg/kg b.w. After 21 days, vaginal tissues were collected and examined immunohistochemically. The results showed that banana flowers (Musa acuminata Colla) increased the expression of actin (p=0.036), Claudin-1 (p=0.029), TGF-β (p = 0.018), and collagen (p=0.001). The use of natural ingredients as an alternative therapy to correct vaginal atrophy should be further developed because phytoestrogens can reduce the negative effects of synthetic estrogen use which adversely affects health during menopause. [ABSTRACT FROM AUTHOR]

Purpose: Physalis angulata Linn. (Ciplukan) is a plant widely used in traditional medicine in subtropical and tropical regions. Most studies focus on its antioxidant and anti-inflammatory activity. Many studies also reported its therapeutic potential for treating cancer, malaria, hepatitis, rheumatism, liver problems, and tumors, but few studies have reported its anti-fibrosis activity. Here, we aimed to investigate the potential of P. angulata as an antioxidant and anti-inflammatory that may be correlated with its anti-fibrosis action. Methods: In our study, we treated 3T3-L1 and TGF-β-induced 3T3-L1 cells with an ethanol extract of P. angulata. We then monitored the cell's response, evaluated the antioxidant activity using an MTT assay, and observed the cells' migration using the cell scratch assay. We used RT-PCR to determine the expression of HIF-1α and IL-6 on TGF-β-induced 3T3-L1 cells. Results: The ethanol extract of P. angulata showed antioxidant activity and promoted cell proliferation on 3T3-L1 cells. Interestingly, the extract inhibited the migration of TGF-β-induced 3T3-L1 cells. Further analysis revealed that the extract could inhibit HIF-1α expression and suppress IL-6 expression on TGF-β-induced 3T3-L1 cells. Conclusion: The ethanol extract of P. angulata showed antioxidant and anti-inflammation activities in 3T3-L1 cells. Both activities are associated with the antifibrotic activity of P. angulata's ethanol extract. [ABSTRACT FROM AUTHOR]

The human kallikrein-related peptidase (KLK) family which consists of 15 members is associated with prostate cancer and other cancers. It has been reported that overexpression of KLK4 in prostate cancer correlates with bone metastasis or advanced stage. Hypoxia occurs in the early stages of prostate cancer due to the accumulation of acidic metabolites or reactive oxygen species (ROS). In our study, KLK4 gene expression in hypoxic conditions in PC-3 and LNCaP cells which are treated with TGF-β was evaluated with mRNA, protein, and promoter activity levels. A chemical hypoxia model was created and confirmed at mRNA and protein level. No statistically significant cytotoxic effect of CoCl2 and TGF-β was observed in PC-3 and LNCaP cells with the MTT test. Four different truncated KLK4 gene promoter constructs were cloned in pmetLuc expression vector and basal activities of all promoter fragments were analyzed. The activities of P1 (−447/ + 657), P2 (−103/ + 657), and P3 (−267/ + 657) promoter fragments increased in hypoxic conditions except P4 (+555/ + 657), which does not contain the SMAD and HRE region. KLK4 mRNA levels in both PC-3 and LNCaP cells increased in the hypoxia and hypoxia/TGF groups compared to the non-treated groups. The stimulating effect of TGF-β is correlated with the increase in SMAD2/3 mRNA levels. KLK4 expression is up-regulated by TGF-β, especially under hypoxic conditions, and its interaction with the SMAD pathway is determined with different inhibitor experiments. HIF-1α and SMAD transcription factors bind to the KLK4 promoter showing the direct interaction of HIF-1α (−80/−52) and SMAD (+163/+194) regions with EMSA. [ABSTRACT FROM AUTHOR]

Background: Aberrant TGF‐β signaling pathway can lead to invasive phenotype of colorectal cancer (CRC), resulting in poor prognosis. It is pivotal to develop an effective prognostic factor on the basis of TGF‐β‐related genes to accurately identify risk of CRC patients. Methods: We performed differential analysis of TGF‐β‐related genes in CRC patients from databases and previous literature to obtain TGF‐β‐related differentially expressed genes (TRDEGs). LASSO‐Cox regression was utilized to build a CRC prognostic feature model based on TRDEGs. The model was validated using two GEO validation sets. Wilcoxon rank‐sum test was utilized to test correlation of model with clinical factors. ESTIMATE algorithm and ssGSEA and tumor mutation burden (TMB) analysis were used to analyze immune landscape and mutation burden of high‐risk (HR) and low‐risk (LR) groups. CellMiner database was utilized to identify therapeutic drugs with high sensitivity to the feature genes. Results: We established a six‐gene risk prognostic model with good predictive accuracy, which independently predicted CRC patients' prognoses. The HR group was more likely to experience immunotherapy benefits due to higher immune infiltration and TMB. The feature gene TGFB2 could inhibit the efficacy of drugs such as XAV‐939, Staurosporine, and Dasatinib, but promote the efficacy of drugs such as CUDC‐305 and by‐product of CUDC‐305. Similarly, RBL1 could inhibit the drug action of Fluphenazine and Imiquimod but promote that of Irofulven. Conclusion: A CRC risk prognostic signature was developed on basis of TGF‐β‐related genes, which provides a reference for risk and further therapeutic selection of CRC patients. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME) has been demonstrated to play a significant role in tumor initiation, progression, and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of TME and exhibit heterogeneous properties in their communication with tumor cells. This heterogeneity of CAFs can be attributed to various origins, including quiescent fibroblasts, mesenchymal stem cells (MSCs), adipocytes, pericytes, endothelial cells, and mesothelial cells. Moreover, single-cell RNA sequencing has identified diverse phenotypes of CAFs, with myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) being the most acknowledged, alongside newly discovered subtypes like antigen-presenting CAFs (apCAFs). Due to these heterogeneities, CAFs exert multiple functions in tumorigenesis, cancer stemness, angiogenesis, immunosuppression, metabolism, and metastasis. As a result, targeted therapies aimed at the TME, particularly focusing on CAFs, are rapidly developing, fueling the promising future of advanced tumor-targeted therapy. [ABSTRACT FROM AUTHOR]

Abstract Background NAD(P)-dependent steroid dehydrogenase-like protein (NSDHL), which is involved in breast tumor growth and metastasis, has been implicated in the maintenance of cancer stem cells. However, its role in regulating breast cancer stem-like cells (BCSCs) remains unclear. We have previously reported the clinical significance of NSDHL in patients with estrogen receptor-positive (ER +) breast cancer. This study aimed to elucidate the molecular mechanisms by which NSDHL regulates the capacity of BCSCs in the ER + human breast cancer cell line, MCF-7. Methods NSDHL knockdown suppressed tumor spheroid formation in MCF-7 human breast cancer cells grown on ultralow-attachment plates. RNA sequencing revealed that NSDHL knockdown induced widespread transcriptional changes in the MCF-7 spheroids. TGF-β signaling pathway was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway (fold change ≥ 2, P ≤ 0.05) identified in NSDHL-knockdown MCF-7 spheroids compared with the control. In orthotopic tumor models injected with NSDHL-knockdown MCF-7 spheroids, tumor initiation and growth were strongly suppressed compared with those in the control. Results BCSC populations with CD44+/CD24- and CD49f+/EpCAM + phenotypes and high ALDH activity were decreased in NSDHL-knockdown MCF-7 spheroids and xenograft tumors relative to controls, along with decreased secretion of TGF-β1 and 3, phosphorylation of Smad2/3, and expression of SOX2. In RNA-sequencing data from The (TCGA) database, a positive correlation between the expression of NSDHL and SOX2 was found in luminal-type breast cancer specimens (n = 998). Our findings revealed that NSDHL plays an important role in maintaining the BCSC population and tumor-initiating capacity of ER-positive MCF-7 spheroids, suggesting that NSDHL is an attractive therapeutic target for eliminating BCSCs, thus preventing breast cancer initiation and progression. Conclusions Our findings suggest that NSDHL regulates the BCSC/tumor-initiating cell population in MCF-7 spheroids and xenograft tumors.

Abstract In the last forty years, the number of people over 60 years of age has increased significantly owing to better nutrition and lower rates of infectious diseases in developing countries. Aging significantly impacts adipose tissue, which plays crucial role in hormone regulation and energy storage. This can lead to imbalances in glucose, and overall energy homeostasis within the body. Aging is irreversible phenomena and potentially causing lipid infiltration in other organs, leading to systemic inflammation, metabolic disorders. This review investigates various pathways contributing to aging-related defects in adipogenesis, such as changes in adipose tissue function and distribution. Polyphenols, a diverse group of natural compounds, can mitigate aging effects via free radicals, oxidative stress, inflammation, senescence, and age-related diseases. Polyphenols like resveratrol, quercetin and EGCG exhibit distinct mechanisms and regulate crucial pathways, such as the TGF-β, AMPK, Wnt, PPAR-γ, and C/EBP transcription factors, and influence epigenetic modifications, such as DNA methylation and histone modification. This review highlights the critical importance of understanding the intricate relationship between aging and adipogenesis for optimizing well-being with increasing age. These findings highlight the therapeutic potential of polyphenols like quercetin and resveratrol in enhancing adipose tissue function and promoting healthy aging.

Abstract 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-β1 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.

Abstract 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-β 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-β 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-β levels in BD, and higher TGF-β levels in SCH patients. Using moderated mediation analysis, TGF-β 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.

Epithelial‐to‐mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti‐cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor‐β (TGF‐β)‐induced EMT in non‐small‐cell lung cancer. Our study revealed that TGF‐β plays a role in EMT functions by upregulation of cytidine 5′‐triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF‐β‐induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF‐β‐mediated downregulation of UDP‐glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non‐small‐cell lung cancer.

Sporadic thoracic aortic aneurysm and dissection (sTAAD) is a complicated vascular disease with a high mortality rate. And its genetic basis has not been fully explored.

Abstract Background Aberrant TGF‐β signaling pathway can lead to invasive phenotype of colorectal cancer (CRC), resulting in poor prognosis. It is pivotal to develop an effective prognostic factor on the basis of TGF‐β‐related genes to accurately identify risk of CRC patients. Methods We performed differential analysis of TGF‐β‐related genes in CRC patients from databases and previous literature to obtain TGF‐β‐related differentially expressed genes (TRDEGs). LASSO‐Cox regression was utilized to build a CRC prognostic feature model based on TRDEGs. The model was validated using two GEO validation sets. Wilcoxon rank‐sum test was utilized to test correlation of model with clinical factors. ESTIMATE algorithm and ssGSEA and tumor mutation burden (TMB) analysis were used to analyze immune landscape and mutation burden of high‐risk (HR) and low‐risk (LR) groups. CellMiner database was utilized to identify therapeutic drugs with high sensitivity to the feature genes. Results We established a six‐gene risk prognostic model with good predictive accuracy, which independently predicted CRC patients' prognoses. The HR group was more likely to experience immunotherapy benefits due to higher immune infiltration and TMB. The feature gene TGFB2 could inhibit the efficacy of drugs such as XAV‐939, Staurosporine, and Dasatinib, but promote the efficacy of drugs such as CUDC‐305 and by‐product of CUDC‐305. Similarly, RBL1 could inhibit the drug action of Fluphenazine and Imiquimod but promote that of Irofulven. Conclusion A CRC risk prognostic signature was developed on basis of TGF‐β‐related genes, which provides a reference for risk and further therapeutic selection of CRC patients.

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-β, secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.

MicroRNAs (miRNAs) have been demonstrated to control chicken skeletal muscle growth, however, the potential function of the miR-181-5p family in chicken myogenesis remains largely unknown. Here, our study identified the two chicken (Gallus gallus; Gga) miR-181-5p family members widely expressed in various tissues, specifically miR-181a-5p and miR-181b-5p. Besides, the breast muscles of fast-growing broilers expressed higher levels of miR-181a-5p and miR-181b-5p than those of slow-growing layers. Functionally, miR-181a-5p and miR-181b-5p both promote the expression level of myogenic factors including myogenin (MyoG), myogenic differentiation 1 (MyoD1), and myosin heavy chain (MyHC), meanwhile accelerating the myotube formation of skeletal muscle satellite cells (SMSCs). Mechanistically, miR-181a-5p and miR-181b-5p directly bind to the 3´ untranslated region (UTR) of the transforming growth factor beta receptor 1 (TGFBR1) mRNA, further reducing the expression of TGFBR1. TGFBR1 is a key Transforming growth factor beta (TGF-β) signaling transduction receptor and had a negative function in muscle cell differentiation. Furthermore, knockdown of TGFBR1 facilitated the expression of chicken myogenic factors, boosted myotube formation, and decreased the SMAD family member 2/3 (SMAD2/3) phosphorylation in chicken SMSCs. SMAD2/3 are downstream of TGF-β signaling, and miR-181a-5p and miR-181b-5p could reduce the expression of TGFBR1 to further diminish the SMAD2/3 phosphorylation. Our findings revealed that the miR-181-5p family targets TGFBR1 to break the TGF-β signaling transduction, which resulted in promoting chicken skeletal muscle development.

Introduction. Today, prevalence of neurodegenerative diseases increases. In recent years, more studies have revealed a new knowledge about the role of microglia in the development of these diseases. Animal experiments showed that peripheral inflammation causes activation of microglia in brain. All this points to the essential role of the cells in the development of neurodegeneration. Under the influence of various factors, microglia can change the phenotype and participate in both repair and damage to brain cells. Chronic herpesvirus infection caused by HSV-1 is another known factor in the development of neurodegenerative pathology. However, the exact pathogenetic mechanisms are still unknown, nevertheless, studying the virus effect on microglia has great potential. The goal of our study in this connection was to assess the effect of HSV-1 on microglia polarization in mouse strain with normal susceptibility to this virus and in strain which is more resistant to the action of HSV-1. For this purpose, changes in the cytokine profile were detected. A comparison of interstrain differences in the expression of cytokine genes was also compared in control groups. Materials and methods. The study involved infecting C57BL/6 and BALB/c mice with herpes simplex virus type 1, an isolation of microglia was based on separation steps using a discontinuous gradient density, the cytokine profile was assessed by gene expression levels using a real-time reverse transcription PCR. To calculate the relative fold gene expression of samples the 2–ΔΔCt method was used. Statistical significance was determined using the Mann–Whitney U-test. Results. There were found no interstrain differences in cytokine gene expression in control groups of different mouse strains. At the same time, gene expression differed in the experimental groups: in BALB/c mice, the expression of genes for both pro-inflammatory and anti-inflammatory cytokines increased; in C57BL/6 mice, a slight increase in the expression of IL-1β genes was observed. Conclusion. The data indicate the formation of different microglial phenotypes after HSV-1 infection in different mouse strains. Apparently, in BALB/c mice there is a switch from the pro-inflammatory M1 phenotype of microglia to the anti-inflammatory M2 phenotype, while in C57BL/6 mice the attenuation of the infectious process occurs through a return to the original M0 phenotype.

Rong Huang,1,&ast; Jun Zeng,1,&ast; Xiaoze Yu,1 Yunke Shi,2 Na Song,1 Jie Zhang,1 Peng Wang,1 Min Luo,1 Yiming Ma,2 Chuang Xiao,1 Lueli Wang,1 Guanhua Du,3 Hongyan Cai,4 Weimin Yang1 1School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2The First Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 4The Second Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weimin Yang, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, People’s Republic of China, Email ywmbessie@yeah.net Hongyan Cai, The Second Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China, Email caihy@ydyy.cnPurpose: Luteolin is a promising candidate for diabetic nephropathy due to its potential anti-inflammatory and anti-fibrotic properties. This study explored the molecular mechanisms through which luteolin combats fibrosis in DN.Methods: Potential targets affected by luteolin and genes associated with DN were collected from databases. Overlapping targets between luteolin and diabetic nephropathy were identified through Venn analysis. A protein-protein interaction network was constructed using these common targets, and critical pathways and targets were elucidated through GO and KEGG analysis. These pathways and targets were confirmed using a streptozotocin-induced mouse model. Luteolin was administered at 45 mg/kg and 90 mg/kg. Various parameters were evaluated, including body weight, blood glucose levels, and histopathological examinations. Protein levels related to energy metabolism, inflammation, and fibrosis were quantified.Results: Fifty-three targets associated with luteolin and 36 genes related to diabetic nephropathy were extracted. The AGE-RAGE signaling pathway was the key pathway impacted by luteolin in diabetic nephropathy. Key molecular targets include TGF-β, IL-1β, and PPARG. Luteolin reduced body weight and blood glucose levels, lowered the left kidney index, and improved insulin and glucose tolerance. Furthermore, luteolin mitigated inflammatory cell infiltration, basement membrane thickening, and collagen deposition in the kidney. Luteolin up-regulated the protein expression of p-AMPKα (Th172) while simultaneously down-regulated the protein expression of p-NF-&kgreen;B (p65), NLRP3, TGF-β 1, α-SMA, and Collagen I.Conclusion: Luteolin mitigated renal fibrosis by alleviating energy metabolism disruptions and inflammation by modulating the AMPK/NLRP3/TGF-β signaling pathway.Keywords: diabetic nephropathy, network pharmacology, inflammation, TGF-β, fibrosis

B cells play a crucial role in the pathogenesis of various diseases, such as autoimmune disorders, cancers, and infections. Unlike regulatory T cells, the anti-inflammatory capabilities of B cells have only recently garnered attention. Cytokines IL-10 and TGF-β are among the key secreted immunosuppressive factors, therefore studying the characteristics of their transcriptional regulation in B cells appears to be a relevant task. This study focuses on characterizing the promoter regions of IL10 and TGFB1 genes in immortalized B cell lines representing different developmental stages – Reh and Raji. To achieve this, we identified potential promoter regions guided by the epigenetic features of functional regulatory regions determined by bioinformatics methods of ChIP-Seq data analysis of chromatin marks in CD19+ lymphocytes. We examined the activity of selected promoters using reporter analysis in B cells. Additionally, we studied the impact of a single nucleotide polymorphism rs1800469 in the TGFB1 promoter, which is associated with the development of colorectal cancer, chronic obstructive pulmonary disease, and the risk of radiation fibrosis. Our results showed increased promoter activity of IL10 and TGFB1 in the Reh pro-B cells compared to the Raji mature B cells upon stimulation. Interestingly, the presence of the minor allele of rs1800469 led to enhanced TGFB1 promoter activity in the Reh cells. Higher activity of IL10 and TGFB1 promoters in acute lymphoblastic leukemia Reh cells may be associated with the increased immunosuppression, which is characteristic of this pathology. It is also possible that activation of pro-B cells Reh induces their differentiation into monocyte-like cells, which can be polarized into alternatively activated (M2) macrophages by autocrine TGF-β and IL-10. M2 macrophages can function as tumor-associated macrophages and contribute to the development of colorectal cancer. Moreover, increased levels of TGF-β in tissues increase the risks of fibrosis and decrease inflammation levels in chronic obstructive pulmonary disease.

Abstract The clinical impact of soluble molecules in pleural effusion (PE) is unclear in patients with malignant pleural mesothelioma (MPM). In this single-center, retrospective, observational study, we assessed soluble forms of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1) using enzyme-linked immunosorbent assays; three TGF-β isoforms were measured via multiplex assay in PE of patients with fibrinous pleuritis (FP) or MPM, to assess relationships between the levels of six molecules, clinicopathological characteristics, and efficacy of immune checkpoint inhibitors. Soluble forms of CTLA-4, PD-L1, PD-1, TGF-β1, TGF-β2, and TGF-β3 were variably produced in PE of FP (n = 34) and MPM (n = 79); we found significant relationships between the six molecules and clinicopathological features. Although none of the three soluble immune checkpoint molecules showed diagnostic or prognostic effects in patients with MPM, TGF-β2 level in PE is a useful differential diagnostic marker between FP and MPM. Both TGF-β1 and TGF-β3 levels are promising prognostic markers for MPM. Moreover, we found that higher baseline levels of PD-1 soluble forms predicted the response to anti-PD1 monotherapy. Our findings identify novel diagnostic, prognostic, and predictive biomarkers for anti-PD1 therapy in patients with MPM.