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• Suspended particulate matter induces the accumulation of ROS, which plays an essential role in oxidative stress. • Suspended particulate matter produces IL-8 and TGF-β1, which develops inflammation and fibrosis. • ROS, IL-8 and TGF-β1 interact together to induces SMAD3-dependent pathway. • Exposure to suspended particulate matter promotes epithelial-to-mesenchymal transition via TGF-β1-mediated ROS/IL-8/SMAD3 axis in A549 cells. Epidemiological evidence presents that dust storms are related to respiratory diseases, such as pulmonary fibrosis (PF). However, the precise underlying mechanisms of SPM-elicited adverse effects still need to be investigated. Epithelial-mesenchymal transition (EMT) process is a characteristic of PF. We discussed whether suspended particulate matter (SPM) is involved in EMT induction via transforming growth factor-β1 (TGF-β1). In this study, a detailed elemental analysis (55 elements), particle size, and morphology were determined. To investigate the toxicity of SPM, an MTT test was performed to detect cell viability. Next, A549 cells were exposed to selected concentrations of SPM (20 and 40 µg/mL) for single and repeated exposures. The DCFH-DA assay showed that exposure to SPM could produce reactive oxygen species (ROS). The ELISA assay demonstrated increased levels of interleukin-8 (IL-8) and TGF-β1 in the supernatant. Western blot was used to detect the expression of proteins associated with EMT and the SMAD3-dependent pathway. Results of western blot demonstrated that E-cadherin was reduced, whereas p-SMAD3, vimentin, and α-smooth muscle actin were elevated. Our findings indicated that SPM triggered EMT by induction of oxidative stress, inflammation, and the TGF-β1/SMAD3 pathway activation. [ABSTRACT FROM AUTHOR]

This study investigates the correlation between serum levels of YKL-40, LXRs, PPM1A, and TGF-β1 and airway remodeling and lung function in bronchial asthma patients. The study involved 80 bronchial asthma patients and 92 healthy individuals. Serum cytokines, airway remodeling, and lung function markers were compared across mild, moderate, and severe asthma cases using high-resolution CT, t-tests, ANOVA, and Pearson correlation analysis. Asthmatic patients exhibited higher levels of serum YKL-40, LXRα, LXRβ, TGF-β1, airway wall thickness (T)/outer diameter (D), and WA% of total cross-sectional area compared to controls. Conversely, their serum PPM1A, Peak Expiratory Flow (PEF), and Forced Expiratory Volume in 1 s (FEV1) were lower. Serum YKL-40 and TGF-β1 levels were positively correlated with T/D and WA%, and negatively correlated with PEF and FEV1. PPM1A levels were strongly associated with T/D, WA%, PEF, and FEV1. The severity of bronchial asthma is associated with increased serum levels of YKL-40, LXRα, LXRβ, and TGF-β1 and decreased PPM1A. The levels of YKL-40, PPM1A, and TGF-β1 have a significant correlation with airway remodeling and lung function. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects. Methods: First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-β1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD. Results: The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-β1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-β1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis. Conclusions: MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-β1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients. [ABSTRACT FROM AUTHOR]

Breast milk contains numerous factors that are involved in the maturation of the immune system and development of the gut microbiota in infants. These factors include transforming growth factor-β1 and 2, immunoglobin A, and lactoferrin. Breast milk factors may also affect epidermal differentiation and the stratum corneum (SC) barrier in infants, but no studies examining these associations over time during infancy have been reported. In this single-center exploratory study, we measured the molecular components of the SC using confocal Raman spectroscopy at 0, 1, 2, 6, and 12 months of age in 39 infants born at our hospital. Breast milk factor concentrations from their mothers' breast milk were determined. Correlation coefficients for the two datasets were estimated for each molecular component of the SC and breast milk factor at each age and SC depth. The results showed that breast milk factors and molecular components of the SC during infancy were partly correlated with infant age in months and SC depth, suggesting that breast milk factors influence the maturation of the SC components. These findings may improve understanding of the pathogenesis of skin diseases associated with skin barrier abnormalities. [ABSTRACT FROM AUTHOR]

转化生长因子 β1 (transforming growth factor-beta 1, TGF-β1) 是 TGF-β 超家族的一员, 也是 TGF-β 在人体内的主 要存在形式。TGF-β1 由多种细胞产生, 参与调控了细胞的生长、分化、增殖、凋亡, 一方面在维持机体正常生理功能, 如维持胚 胎正常发育、促进皮肤创面修复、协调骨稳态、促进软骨生成等发挥至关重要的作用; 另一方面又与瘢痕形成、器官纤维化、肿瘤 发生发展等病理进程密切相关。现从 TGF-β1 的基因定位、分子结构、受体、信号通路及其生物学作用等方面, 以整形外科视角 对其作一综述。 [ABSTRACT FROM AUTHOR]

Keloid is a benign hyperplastic dermatosis with high recurrence rate and complex pathogenesis. There is no universally effective treatment yet. New therapies and elucidation of pathogenesis are urgently required. To explore the function of IRE1α/XBP1 in keloid fibroblasts and to investigate the potential mechanism of artesunate in inhibiting keloid hyperplasia. Human keloid fibroblasts (KFs) were cultured, and the expressions of XBP1 and TGF-β1 were detected by immunohistochemistry. The expression of IRE1 was interfered with through cell transfection and the effects of IRE1 interference on cell proliferation and the cell cycle were assessed using MTS, colony formation assays, and flow cytometry. Detection of the expressions of XBP1 and TGF-β1 by qRT-PCR and Western blot. Then artesunate was applied to a subset of the cells, and its effects on cell viability and the expression of related proteins using the same methods. The IRE1α/XBP1 pathway was activated in KFs. Knocking out the gene IRE1α can inhibit the expression of TGF-β1, in addition, the cell viability and cell cycle progression of KFs were also significantly affected. After artesunate treatment, there was a remarkable reduction in cell proliferation. Meanwhile, the cell cycle of KFs treated with artesunate was blocked in G1 phase.After upregulating the expression of IRE1α and treating KFs with artesunate, both cell cycle and proliferation showed inhibitory effects, and related proteins also exhibited suppressed expression. The IRE1α/XBP1 pathway is activated in keloid, and inhibiting the expression of this pathway can affect the cell proliferation activity. In addition, artesunate also has a significant effect on fibroblast proliferation, and the IRE1α/XBP1 pathway may participate in this process. These findings suggest that IRE1α/XBP1 signal pathway may be a potential target for scar treatment, and artesunate could also be a powerful candidate for keloid treatment. • The IRE1α/XBP1 pathway was activated in KFs. Knock out of the gene IRE1α can inhibit the cell proliferation of KFs. • The proliferation and cell cycle of KFs treated with artesunate was significantly inhibited. • The IRE1α/XBP1 pathway is involved in the inhibition of artesunate on the proliferation of KFs. [ABSTRACT FROM AUTHOR]

Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. Epithelial-mesenchymal transition (EMT) is an essential player in these alterations. Scutellarin is isolated from Erigeron breviscapus. Its vascular relaxative, myocardial protective, and anti-inflammatory effects have been well established. This study was designed to detect the biological roles of scutellarin in asthma and its related mechanisms. The asthma-like conditions were induced by ovalbumin challenges. The airway resistance and dynamic compliance were recorded as the results of AHR. Bronchoalveolar lavage fluid (BALF) was collected and processed for differential cell counting. Hematoxylin and eosin staining, periodic acid-Schiff staining, and Masson staining were conducted to examine histopathological changes. The levels of asthma-related cytokines were measured by enzyme-linked immunosorbent assay. For in vitro analysis, the 16HBE cells were stimulated with 10 ng/mL transforming growth beta-1 (TGF-β1). Cell migration was estimated by Transwell assays and wound healing assays. E-cadherin, N-cadherin, and α-smooth muscle actin (α-SMA) were analyzed by western blotting, real-time quantitative polymerase chain reaction, immunofluorescence staining, and immunohistochemistry staining. The underlying mechanisms of the mitogen-activated protein kinase (MAPK) and Smad pathways were investigated by western blotting. In an ovalbumin-induced asthmatic mouse model, scutellarin suppressed inflammation and inflammatory cell infiltration into the lungs and attenuated AHR and airway remodeling. Additionally, scutellarin inhibited airway EMT (upregulated E-cadherin level and downregulated N-cadherin and α-SMA) in ovalbumin-challenged asthmatic mice. For in vitro analysis, scutellarin prevented the TGF-β1-induced migration and EMT in 16HBE cells. Mechanistically, scutellarin inhibits the phosphorylation of Smad2, Smad3, ERK, JNK, and p38 in vitro and in vivo. In conclusion, scutellarin can inactivate the Smad/MAPK pathways to suppress the TGF-β1-stimulated epithelial fibrosis and EMT and relieve airway inflammation and remodeling in asthma. This study provides a potential therapeutic strategy for asthma. [ABSTRACT FROM AUTHOR]

To investigate the predictive value of preoperative serum transforming growth factor-β1 (TGF-β1), high mobility group protein B1 (HMGB1) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) on the prognosis of patients with spinal fracture combine with spinal cord injury (SCI). 134 patients with spinal fracture combine with SCI who underwent surgical treatment in Guizhou Orthopaedic Hospital from May 2021 to June 2022 were selected, patients were divided into good prognosis group (83 cases) and poor prognosis group (51 cases) according to the 12 months prognosis after surgery. The preoperative serum levels of TGF-β1, HMGB1 and NLRP3 were detected by enzyme-linked immunosorbent assay. Multifactorial logistic regression was used to analyze the factors of poor prognosis in patients with spinal fracture combine with SCI, and the predictive value of preoperative serum TGF-β1, HMGB1, and NLRP3 levels in patients with spinal fracture combine with SCI was analyzed by receiver operating characteristics (ROC) curves. The incidence of poor prognosis in 134 patients with spinal fracture combine with SCI was 38.06% (51/134) at 12 months after surgery. Compared with good prognosis group, HMGB1 and NLRP3 were higher and TGF-β1 was lower in poor prognosis group (P<0.05). Multivariate logistic regression analysis showed that diabetes, injury to treatment time≥ 8 h, spinal canal encroachment rate ≥ 50%, elevated HMGB1 and elevated NLRP3 were independent risk factors for poor prognosis in patients with spinal fracture combine with SCI, increased ASIA grade and elevated TGF-β1 were independent protective factors (P<0.05). The area under the curve (AUC) of preoperative serum TGF-β1, HMGB1, and NLRP3 combined to predict poor prognosis in patients with spinal fracture combine with SCI was 0.924, which was greater than that predicted by each of the indicators alone (P<0.05). The decrease of preoperative serum TGF-β1 level and the increase of HMGB1 and NLRP3 levels are closely relate to the poor prognosis of patients with spinal fracture combine with SCI, the combination of preoperative serum TGF-β1, HMGB1 and NLRP3 levels has a high predictive value for the poor prognosis of patients with spinal fracture combine with SCI. [ABSTRACT FROM AUTHOR]

To determine their involvement in the onset of the disease, we investigated the changing levels of liver fibrosis-related proteins, namely, type-I collagen, α-smooth muscle actin (α-SMA), and transforming growth factor β1 and β3 (TGF-β1, β3). The four groups of Sprague-Dawley (SD) rats were involved in the study, namely, (i) normal control group, (ii) high-fat diet group (HFD), (iii) carbon tetrachloride (CCl4) group, and (iv) NAFLD group (animal model) which were chosen at random. The NAFLD model received HFD combined with subcutaneous injection of small doses of CCl4. Histopathological examination confirmed extent of liver fibrosis, while other immunological and molecular methods were used to evaluate expression and distribution of α-SMA, type I collagen TGF-β1 and TGF-β3, at both m-RNA and protein levels. In contrast to the normal control group, the NAFLD group showed moderately elevated expressions of TGF-β1, α-SMA, and type I collagen, which was proportional on temporal scale of NAFLD persistence in the model (P < 0.05). In the early phage of NAFLD, enhancement in the mRNA transcripts and, henceforth, protein expression of TGF-β3 was observed. However, these were found to be downregulated in case of liver fibrosis (P < 0.05). This NAFLD rat model shows the histopathologic changes of human NAFLD and is suitable for the study of NAFLD pathogenesis. These findings suggest that type I collagen and the liver fibrosis-related factors TGF- β1, TGF- β3, and α-SMA may be significant contributors to NAFLD. Although NAFLD model is previously demonstrated by other researchers, our study is novel in terms of exploration of involvement of fibrosis-related factors and in particular aforementioned proteins at the early stage of NAFLD vis-à-vis dynamics of type-I collagen distribution. [ABSTRACT FROM AUTHOR]

Effective root canal disinfection and the subsequent release of natural growth factors from dentin are crucial to the success of regenerative endodontic procedures. This study evaluated the effect of newly introduced calcium silicate-based temporary intracanal medicament Bio-C Temp and calcium hydroxide-based material UltraCal XS on the release of transforming growth factor β1 (TGF-β1) from root canal dentin. Twenty-two intact and fully developed human premolars from patients aged 15–18 were shaped and irrigated according to the current clinical recommendations. The teeth were then gently split in half, and the root canal dentin of paired samples was covered with Bio-C Temp or UltraCal XS. After 3 weeks of incubation, the specimens were conditioned with 17% EDTA and the collected solution was subjected to the quantification of the released TGF-β1 by performing an ELISA. One-way analysis of variance (ANOVA), followed by Tukey's test, was selected to determine the statistically significant differences between the groups at the 0.95 confidence level. The highest mean value of released TGF-β1 (1993.1 pg/mL) was detected in the control group, where the root canal dentin was conditioned with 17% EDTA alone. Regarding the experimental groups, Bio-C Temp released a statistically significantly higher amount of TGF-β1 (282.14 pg/mL) compared to UltraCal XS (114.28 pg/mL; p = 0.0158). Bio-C Temp affected the release of growth factors from root canal dentin less than UltraCal XS and may therefore serve as an intracanal medicament for regenerative endodontic procedures. [ABSTRACT FROM AUTHOR]

Nickel (Ni) is recognized as a carcinogenic metal, and its widespread use has led to severe environmental and health problems. Although the lung is among the main organs affected by Ni, the precise mechanisms behind this effect remain poorly understood. This study aimed to elucidate the physiological mechanisms underlying Ni‐induced pulmonary fibrosis (PF), using various techniques including histopathological detection, biochemical analysis, immunohistochemistry, western blotting, and quantitative real‐time PCR. Mice were treated with nickel chloride (NiCl2), which induced PF (detected by Masson staining), up‐regulation of α‐smooth muscle actin (α‐SMA), and collagen‐1 mRNA and protein expression. NiCl2 was found to induce PF by: activation of the epithelial‐mesenchymal transition (EMT) and the transforming growth factor‐β1 (TGF‐β1)/Smad signaling pathway; up‐regulation of protein and mRNA expression of TGF‐β1, p‐Smad2, p‐Smad3, vimentin, and N‐cadherin; and down‐regulation of protein and mRNA expression of E‐cadherin. In addition, NiCl2 treatment increased malondialdehyde content while inhibiting antioxidant activity, as indicated by decreased catalase, total antioxidant capacity, and superoxide dismutase activities, and glutathione content. Co‐treatment with the effective antioxidant and free radical scavenger N‐acetyl cysteine (NAC) plus NiCl2 was used to study the effects of oxidative stress in NiCl2‐induced PF. The addition of NAC significantly mitigated NiCl2‐induced PF, and reversed activation of the TGF‐β1/Smad signaling pathway and EMT. NiCl2‐induced PF was therefore shown to be due to EMT activation via the TGF‐β1/Smad signaling pathway, mediated by oxidative stress. [ABSTRACT FROM AUTHOR]

Environmental arsenic exposure is one of the major global public health problems. Studies have shown that arsenic exposure can cause renal fibrosis, but the underlying mechanism is still unclear. Integrating the in vivo and in vitro models, this study investigated the potential molecular pathways for arsenic‐induced renal fibrosis. In this study, SD rats were treated with 0, 5, 25, 50, and 100 mg/L NaAsO2 for 8 weeks via drinking water, and HK2 cells were treated with different doses of NaAsO2 for 48 h. The in vivo results showed that arsenic content in the rats' kidneys increased as the dose increased. Body weight decreased and kidney coefficient increased at 100 mg/L. As a response to the elevated NaAsO2 dose, inflammatory cell infiltration, renal tubular injury, glomerular atrophy, tubulointerstitial hemorrhage, and fibrosis became more obvious indicated by HE and Masson staining. The kidney transcriptome profiles further supported the protein–protein interactions involved in NaAsO2‐induced renal fibrosis. The in vivo results, in together with the in vitro experiments, have revealed that exposure to NaAsO2 disturbed mitochondrial dynamics, promoted mitophagy, activated inflammation and the TGF‐β1/SMAD signaling pathway, and finally resulted in fibrosis. In summary, arsenic exposure contributed to renal fibrosis via regulating the mitochondrial dynamics and the NLRP3‐TGF‐β1/SMAD signaling axis. This study presented an adverse outcome pathway for the development of renal fibrosis due to arsenic exposure through drinking water. [ABSTRACT FROM AUTHOR]

Introduction. Tendon and ligament injuries affect people of all ages, including professional athletes. Tumor Growth Factor β (TGF- β) isoforms play a significant role in the regeneration of tendons and ligaments, such as through the recruitment of macrophages and fibroblasts or the regulation of the formation of extracellular matrix (ECM). Although the TGF- β family regulates signalling pathways related to the healing process, excessive TGF- β activation can lead to fibrosis and the formation of scars and adhesions. This article recapped the significance of TGF- β isoforms TGF- β1, TGF- β2, and TGF- β3 in the physiological healing of injured tendons and ligaments. Material and Methods. A total of 1434 articles were identified using the PubMed search string (TGF-β isoforms or TGF-β1 or tgfb1 or TGF-β2 or tgfb2 or TGF-β3 or tgfb3) and (tendon or ligament). Human studies, animal models and in vitro cultures were included in the search. Forty-nine published articles were included. Results. Histologic evidence demonstrated greater ligament and tendon regeneration and collagen type I expression when using TGF-β1, often leading to fibrosis. TGF-β3 inhibits the TGF-β1 and TGF-β2 by switching Smad2/3 signaling to Smad7 and CREB-1 transcription factor. There was a delay in TGF-β3 level peak compared to other isoforms. Conclusions. All 3 TGF-β isoforms seem to play a significant role in the subsequent stages of healing. We state a hypothesis that during the initial phase of tendon and ligament healing, TGF-β1 levels need to be elevated. Further, TGF-β3 may inhibit the action of TGF-β1 and TGF-β2, which leads to the inhibition of inflammation and changes in ECM production, and consequently to a reduction in the level of scarring. [ABSTRACT FROM AUTHOR]

Theileria equi (T. equi) is an apicomplexan parasite that causes severe hemolytic anemia in equids. Presently, there is inadequate knowledge of the immune responses induced by T. equi in equid hosts impeding understanding of the host parasite relationship and development of potent vaccines for control of T. equi infections. The objective of this study was to evaluate the host-parasite dynamics between T. equi merozoites and infected horses by assessing cytokine expression during primary and secondary parasite exposure, and to determine whether the pattern of expression correlated with clinical indicators of disease. Our findings showed that the expression of pro-inflammatory cytokines was very low and inconsistent during both primary and secondary infection. There was also no correlation between the symptoms observed during primary infection and expression of the cytokines. This suggests that the symptoms might have occurred primarily due to hemolysis and likely not the undesirable effects of pro-inflammatory responses. However, IL-10 and TGF-β1 were highly expressed in both phases of infection, and their expression was linked to antibody production but not moderation of pro-inflammatory cytokine responses. [ABSTRACT FROM AUTHOR]

Physiochemical tissue inducers and mechanical stimulation are both efficient variables in cartilage tissue fabrication and regeneration. In the presence of biomolecules, decellularized extracellular matrix (ECM) may trigger and enhance stem cell proliferation and differentiation. Here, we investigated the controlled release of transforming growth factor beta (TGF-β1) as an active mediator of mesenchymal stromal cells (MSCs) in a biocompatible scaffold and mechanical stimulation for cartilage tissue engineering. ECM-derived hydrogel with TGF-β1-loaded alginate-based microspheres (MSs) was created to promote human MSC chondrogenic development. Ex vivo explants and a complicated multiaxial loading bioreactor replicated the physiological conditions. Hydrogels with/without MSs and TGF-β1 were highly cytocompatible. MSCs in ECM-derived hydrogel containing TGF-β1/MSs showed comparable chondrogenic gene expression levels as those hydrogels with TGF-β1 added in culture media or those without TGF-β1. However, constructs with TGF-β1 directly added within the hydrogel had inferior properties under unloaded conditions. The ECM-derived hydrogel group including TGF-β1/MSs under loading circumstances formed better cartilage matrix in an ex vivo osteochondral defect than control settings. This study demonstrates that controlled local delivery of TGF-β1 using MSs and mechanical loading is essential for neocartilage formation by MSCs and that further optimization is needed to prevent MSC differentiation towards hypertrophy. [ABSTRACT FROM AUTHOR]

Introduction: Transforming Growth Factor-Beta 1 (TGF-β1) plays a crucial role in the success of Regenerative Endodontic Procedures (REPs) as they directly impact the proliferation and differentiation of stem cells. TGF-β1 is released by conditioning of the dentin matrix using 17% EDTA. EDTA was found to have deleterious effects on dentin especially in immature teeth with fragile dentin walls. Decreasing the irrigation time was reported to decrease these effects. Accordingly, enhancement and activation of the EDTA solution to maintain its efficiency in TGF-β1 release from dentin and thus compensating the reduction in irrigation time was employed. EDTA solution was enhanced by adding Nanobubble (NB) water which contains oxygen filled cavities less than 200 nm in diameter. Additionally, EDTA was activated with XP-endo Finisher rotary file. The aim of this study was to assess the impact of NB enhancement and/or XP-endo Finisher activation of the EDTA solution on the TGF-β1 release from dentin. Methods: Fifty standardized root segments with open apex were allocated to two main groups according to whether EDTA was enhanced with NB water or not, and within each group whether XP-endo Finisher activation was used or not in addition to a Negative Control group. The concentration of the released TGF-β1 in the root canal was measured using enzyme-linked immunosorbent assay (ELISA). The statistical analysis was done using the Shapiro- Wilk, Kolmogorov Smirnov, ANOVA and Post-hoc Tukey tests. Results: All groups released a considerable amount of TGF-β1 with the highest values in the EDTA/NB/XP group, followed by EDTA/NB, EDTA/DW/XP, EDTA/DW and Negative Control groups respectively. Conclusions: The results of this study suggest that NBs can promote the success of REPs since it revealed a significant increase in the TGF-β1 release following its use in the enhancement of the EDTA solution. A comparable effect was obtained by XP-endo finisher activation of the EDTA solution. The combined use of NBs and XP-endo Finisher can be a promising addition in REPs. Accordingly, Enhancement and activation of the EDTA solution may compensate decreasing the EDTA irrigation time attempted to avoid the deleterious effect of EDTA on dentin. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) progression involves diminished tumor antigen presentation and an immunosuppressive microenvironment, characterized by diminished expression of major histocompatibility complexes (MHC) class I molecule and elevated programmed death ligand 1 (PDL1) in MM cells, along with an enriched population of regulatory T cells (Tregs). To investigate Treg's influence on MM cells, we established a co-culture system using Tregs from MM patients and the MM cell lines (MM.1S and SK-MM-1) in vitro and assessed the effects of intervening in the relevant pathways connecting Tregs and MM cells in vivo. In vitro, Tregs induced transforming growth factor beta-1 (TGF-β1) production, downregulated MHC I members, and increased PDL1 expression in MM cells. Treg-derived TGF-β1 suppressed the cGAS-STING pathway, contributing to the loss of MHC I molecule expression and PDL1 upregulation. Correspondingly, neutralizing TGF-β1 or activating the cGAS-STING pathway restored MHC I and PDL1 expression, effectively countering the pro-tumorigenic effect of Tregs on MM cells in vivo. These data elucidated how Tregs influence tumor antigen presentation and immunosuppressive signal in MM cells, potentially providing therapeutic strategies, such as neutralizing TGF-β1 or activating the cGAS-STING pathway, to address the immune escape and immunosuppressive dynamics in MM. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is a disease characterised by diffuse nonspecific alveolar inflammation with interstitial fibrosis, which clinically manifests as dyspnoea and a significant decline in lung function. Many studies have shown that the epithelial–mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of pulmonary fibrosis. Based on our previous findings, hypericin (Hyp) can effectively inhibit the process of the EMT to attenuate lung fibrosis. Therefore, a series of hyperoside derivatives were synthesised via modifying the structure of hyperoside, and subsequently evaluated for A549 cytotoxicity. Among these, the pre-screening of eight derivatives inhibits the EMT. In this study, we evaluated the efficacy of Z6, the most promising hyperoside derivative, in reversing TGF-β1-induced EMTs and inhibiting the EMT-associated migration of A549 cells. After the treatment of A549 cells with Z6 for 48 h, RT-qPCR and Western blot results showed that Z6 inhibited TGF-β1-induced EMTs in epithelial cells by supressing morphological changes in A549 cells, up-regulating E-cadherin (p < 0.01, p < 0.001), and down-regulating Vimentin (p < 0.01, p < 0.001). This treatment significantly reduced the mobility of transforming growth factor β1 (TGF-β1)-stimulated cells (p < 0.001) as assessed by wound closure, while increasing the adhesion rate of A549 cells (p < 0.001). In conclusion, our results suggest that hyperoside derivatives, especially compound Z6, are promising as potential lead compounds for treating pulmonary fibrosis, and therefore deserve further investigation. [ABSTRACT FROM AUTHOR]

Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood pressure, the pH of blood, and the water–electrolyte balance and by eliminating unnecessary metabolic waste products from blood. What is more, this disease does not show any specific symptoms at the beginning. The development of CKD is predisposed by certain conditions, such as diabetes mellitus or hypertension. However, these disorders are not the only factors promoting the onset and progression of CKD. The primary purpose of this review is to examine renin–angiotensin–aldosterone system (RAAS) activity, transforming growth factor-β1 (TGF-β1), vascular calcification (VC), uremic toxins, and hypertension in the context of their impact on the occurrence and the course of CKD. We firmly believe that a deeper comprehension of the cellular and molecular mechanisms underlying CKD can lead to an enhanced understanding of the disease. In the future, this may result in the development of medications targeting specific mechanisms involved in the decline of kidney function. Our paper unveils the selected processes responsible for the deterioration of renal filtration abilities. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression and clinical significance of tear interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ẞ1 (TGF-β1) of patients with type 2 diabetes mellitus (T2DM) complicated with dry eye(DE). Methods: A total of 97 patients with T2DM admitted to our hospital from May 2021 to October 2023 were selected and divided into T2DM group and T2DM combined with DE group according to whether DE was combined. In addition, 45 healthy subjects who underwent physical examination during the same period were selected as the control group. The expression levels of tear IL-6, MMP-9 and TGF-B1 of the three groups were detected by enzyme-linked immunosorbent assay (ELISA). The expression levels of tear IL-6, MMP-9 and TGF-β1 of DE patients with different disease severity were compared. The influencing factors of T2DM complicated with DE were analyzed by univariate and multivariate Logistics regression analysis. The receiver operating characteristic curve (ROC) was used to analyze the predictive value of tear IL-6, MMP-9 and TGF-β1 for T2DM complicated with DE. Results: The expression levels of IL-6, MMP-9 and TGF-B1 in tears of T2DM combined with DE group were higher than those of T2DM group, and those of T2DM group were higher than those of control group(P<0.05). The expression levels of tear IL-6, MMP-9, TGF-β1 and ocular surface disease index (OSDI) score in the severe group were higher than those in the moderate group, and those in the moderate group were higher than those in the mild group (P<0.05). The tear film rupture time (BUT) and tear secretion test (SIT) in the severe group were lower than those in the moderate group, and those in the moderate group were lower than those in the mild group (P<0.05). The results of univariate analysis showed that age, fasting blood glucose (FBG), fasting insulin (FINS), high-sensitivity C-reactive protein (hs-CRP), BUT, SIT and OSDI scores were all influencing factors of T2DM complicated with DE (P<0.05), the results of multivariate analysis showed that OSDI score and the increase of tear IL-6, MMP-9 and TGF-β1 were independent risk factors for T2DM complicated with DE (P<0.05), and the in- crease of BUT and SIT were protective factors(P<0.05). Conclusion: The expression of tear IL-6, MMP-9 and TGF-B1 of T2DM patients with DE is increased, which can aggravate the condition of DE. The combined detection of the three indicators has a high predictive value for the risk of T2DM complicated with DE. [ABSTRACT FROM AUTHOR]

Background/Aims: Diabetic nephropathy (DN) is one of the complications of diabetes mellitus (DM). This study aimed to investigate the association between genetic polymorphisms, specifically AGTR1 (rs5186) and TGF-β1 (rs1800470), and the risk of developing Diabetic nephropathy (DN) in type 2 diabetes mellitus patients, compared to those without DN and healthy controls. Methods: A case-control study was conducted on 165 diabetic patients (59 with diabetic nephropathy (DN) and 54 without DN (DM)), and 52 healthy controls (HC). The genotyping was done using amplification refractory mutation system method (ARMS-PCR). Age, gender, and duration of diabetes were matched across groups. Clinical parameters including FBS, RBS, HbA1C, creatinine, urea, SBP, DBP, total cholesterol, triglycerides, LDL, and BMI were assessed. Results: Diabetic patients with nephropathy exhibited significantly higher levels of clinical parameters compared to those without nephropathy and healthy controls. The risk allele of AGTR1, C (p <0.0001), and risk allele containing genotypes AC (p <0.0001) and CC (p-0.0010) were significantly higher in DN patients compared to DM and HC groups. Similarly, the TGF-β1 risk allele C (p- 0.0001), and corresponding genotypes TC (p- 0.0038) and CC (p- 0.0027) were significantly associated with increased risk of diabetic nephropathy compared to DM and HC groups. Conclusion: The data showed significant association of AGTR1 (rs5186) and TGF-β1 (rs1800470) polymorphism with an increased risk of diabetic nephropathy in type 2 diabetes mellitus patients. More investigation will be required to disseminate the results, while increasing the samples size and using whole genome sequencing. [ABSTRACT FROM AUTHOR]

Glioma stem cells (GSCs) exhibit diverse molecular subtypes with the mesenchymal (MES) population representing the most malignant variant. The oncogenic potential of Salmonella pathogenicity island 1 (SPI1), an oncogenic transcription factor, has been established across various human malignancies. In this study, we explored the association between the SPI1 pathway and the MES GSC phenotype. Through comprehensive analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas glioma databases, along with patient‐derived GSC cultures, we analyzed SPI1 expression. Using genetic knockdown and overexpression techniques, we assessed the functional impact of SPI1 on GSC MES marker expression, invasion, proliferation, self‐renewal, and sensitivity to radiation in vitro, as well as its influence on tumor formation in vivo. Additionally, we investigated the downstream signaling cascades activated by SPI1. Our findings revealed a positive correlation between elevated SPI1 expression and the MES phenotype, which in turn, correlated with poor survival. SPI1 enhanced GSC MES differentiation, self‐renewal, and radioresistance in vitro, promoting tumorigenicity in vivo. Mechanistically, SPI1 augmented the transcriptional activity of both TGF‐β1 and FKBP12 while activating the non‐canonical PI3K/Akt pathway. Notably, inhibition of TGF‐β1/PI3K/Akt signaling partially attenuated SPI1‐induced GSC MES differentiation and its associated malignant phenotype. Collectively, our results underscore SPI1's role in activating TGF‐β1/PI3K/Akt signaling through transcriptional upregulation of FKBP12, thereby supporting the aggressive MES phenotype of GSCs. Therefore, SPI1 emerges as a potential therapeutic target in glioma treatment. [ABSTRACT FROM AUTHOR]

Esophageal restenosis is a serious complication after esophageal stent placement, which influences the clinical prognosis of stent implantation and the patient's quality of life. TGF-β1/Smads signaling pathway plays an important role in the development of the eosinophilic esophagitis and scar repair after skin trauma. However, the role of TGF-β1/Smads in the development of esophageal restenosis after esophageal stent placement remains unknown. Our study aimed to investigate whether TGF-β1/Smads plays an important role in the development of esophageal restenosis after esophageal stent, and whether the exogenous TGF-β1 inhibitor supplement could ameliorate the esophageal restenosis after esophageal stent. We established the model of esophageal restenosis after esophageal stenting in rats, and determined the expression levels of TGF-β1/Smads signaling pathway and the relevant markers of fibroblast activation by immunochemistry (IHC), Western Blot and real time qPCR. Those all the indicators were also determined in esophageal fibroblast when exposed to rhTGF-β1 with or without TGF-β1 inhibitor P144. The serum level of IL-1β and TNFα were significantly increased in stent implantation group compared to blank control group, and obviously ameliorated when treated with P144. The TGF-β1/Smads signaling pathway and the relevant markers of fibroblast activation were significantly increased in stent implantation group compared to blank control group, and obviously ameliorated when treated with P144. Those all the indicators were significantly increased when exposed to rhTGF-β1, and obviously decreased when treated with P144. TGF-β1 Inhibitor P144 could protect against benign restenosis after esophageal stenting by down-regulating the expression levels of relevant markers of fibroblast activation through TGF-β1/Smads signaling pathway inhibition, and may be used as a novel therapy for benign restenosis after esophageal stenting. [ABSTRACT FROM AUTHOR]

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway. [ABSTRACT FROM AUTHOR]

Since December 2019, coronavirus disease 2019 (COVID-19) has been spreading worldwide with devastating immediate or long-term effects on people’s health. Although the lungs are the primary organ affected by COVID-19, individuals infected with SARS-CoV-2 also develop systemic lesions involving multiple organs throughout the body, such as the cardiovascular system. Emerging evidence reveals that COVID-19 could generate myocardial fibrosis, termed “COVID-19-associated myocardial fibrosis.” It can result from the activation of fibroblasts via the renin-angiotensin-aldosterone system (RAAS), transforming growth factor-β1 (TGF-β1), microRNAs, and other pathways, and can also occur in other cellular interactions with SARS-CoV-2, such as immunocytes, endothelial cells. Nonetheless, to gain a more profound insight into the natural progression of COVID-19-related myocardial fibrosis, additional investigations are necessary. This review delves into the underlying mechanisms contributing to COVID-19-associated myocardial fibrosis while also examining the antifibrotic potential of current COVID-19 treatments, thereby offering guidance for future clinical trials of these medications. Ultimately, we propose future research directions for COVID-19-associated myocardial fibrosis in the post-COVID-19 era, such as artificial intelligence (AI) telemedicine. We also recommend that relevant tests be added to the follow-up of COVID-19 patients to detect myocardial fibrosis promptly.

The accumulation of SIRT4 in the nuclei of kidney cells drives kidney fibrosis, so blocking the movement of this protein could be a potential therapeutic strategy against fibrosis.

Abstract Pre-injured lungs are prone to injury progression in response to mechanical ventilation. Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-β1 (AdTGF-β1) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH2O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH2O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-β1 compared to AdCl across PEEP levels. H was minimized at PEEP = 5–8 cmH2O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (= derecruitment) and reduced density of alveolar number and surface area (= distension), respectively. In AdTGF-β1 exposed mice, 27% of alveoli remained derecruited at Pao = 20 cmH2O. A further decrease in Pao down to 2 cmH2O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao = 2–5 cmH2O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-β1 exposed mice is high. H is optimized at PEEP 5–8 cmH2O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-β1 than in AdCl. The increased alveolar size heterogeneity at Pao = 5 cmH2O argues for the use of PEEP = 8 cmH2O for lung protective mechanical ventilation in this animal model.

Abstract Background Skin fibrosis affects the normal function of the skin. TGF-β1 is a key cytokine that affects organ fibrosis. The latency-associated peptide (LAP) is essential for TGF-β1 activation. We previously constructed and prepared truncated LAP (tLAP), and confirmed that tLAP inhibited liver fibrosis by affecting TGF-β1. SPACE peptide has both transdermal and transmembrane functions. SPACE promotes the delivery of macromolecules through the stratum corneum into the dermis. This study aimed to alleviate skin fibrosis through the delivery of tLAP by SPACE. Methods The SPACE-tLAP (SE-tLAP) recombinant plasmid was constructed. SE-tLAP was purified by nickel affinity chromatography. The effects of SE-tLAP on the proliferation, migration, and expression of fibrosis-related and inflammatory factors were evaluated in TGF-β1-induced NIH-3T3 cells. F127-SE-tLAP hydrogel was constructed by using F127 as a carrier to load SE-tLAP polypeptide. The degradation, drug release, and biocompatibility of F127-SE-tLAP were evaluated. Bleomycin was used to induce skin fibrosis in mice. HE, Masson, and immunohistochemistry were used to observe the skin histological characteristics. Results SE-tLAP inhibited the proliferation, migration, and expression of fibrosis-related and inflammatory factors in NIH-3T3 cells. F127-SE-tLAP significantly reduced ECM production, collagen deposition, and fibrotic pathological changes, thereby alleviating skin fibrosis. Conclusion F127-SE-tLAP could increase the transdermal delivery of LAP, reduce the production and deposition of ECM, inhibit the formation of dermal collagen fibers, and alleviate the progression of skin fibrosis. It may provide a new idea for the therapy of skin fibrosis.

مقاله پژوهشی مقدمه: بیماری فیبروز کبدی اغلب به فعال شدن سلول‌های ستاره‌ای کبد (Hepatic stellate cells) HSC و تشکیل بیش از حد زخم در کبد نسبت داده می‌شود. ایزورامنتین با مهار بیان ژن‌های فیبروژنیک ناشی از (Transforming growth factor beta) TGF-β1، در برابر فیبروز کبدی اثر محافظتی دارد. در این مطالعه، نقش ایزورامنتین بر میزان بیان فاکتورهای فیبروز کبدی و سطح (Reactive oxygen species) ROS در سلول‌های ستاره‌ای کبد مورد بررسی قرار گرفت. روش‌ها: ابتدا سلول‌ها تا رسیدن به تراکم مناسب در محیط کشت DMEM همراه با 10 درصد از (Fetal Bovine Serum) FBS کشت داده شدند و با غلظت‌های 75 و 100 میکرومولار از ایزورامنتین به مدت 24 ساعت تیمار شدند، سپس میزان بیان ژن‌هایα-SMA ، Collagen1α ، NOX1، NOX2 و نیز سطح ROS برای ارزیابی فیبروز کبدی مورد سنجش قرار گرفت. یافته‌ها: نتایج نشان داد که میزان بیان ژن‌هایα-SMA ، Collagen1α، NOX1، NOX2 و نیز سطح ROS در غلظت ng/m2 از TGF-β1 نسبت به گروه شاهد، افزایش معنی‌داری پیدا کرد. همچنین در حضور غلظت‌های 75 و 100 میکرومولار ایزورامنتین بیان این ژن‌ها و نیز سطح ROS نسبت به گروه فیبروز به صورت معنی‌داری کاهش یافت. نتیجه‌گیری: TGF-β با افزایش بیان ژن‌های درگیر در پیشرفت بیماری فیبروز کبدی و نیز افزایش سطح ROS یافت افزایش تولید ماتریکس خارج سلولی از جمله Collagen1α می‌شود. ایزورامنتین باعث کاهش بیان ژن‌های درگیر در پیشرفت فیبروز کبدی می‌شود. در نتیجه می‌تواند از پیشرفت فیبروز کبدی جلوگیری کند.

The issues of recurrencies in chronic rhinosinusitis with nasal polyps (CRSwNP) still remain unresolved. Therefore, detection patients with uncontrolled clinical course of CRSwNP is required.The aim of the present study was to assess cytokine profile in nasal polyps as well as clinical characteristics of patients with CRSwNP at varying levels of therapeutic control.The study included 99 patients with chronic rhinosinusitis. The contents of interferon IFNγ, interleukin IL- 1β, IL-4, IL-5, IL-13, tumor necrosis factor TNFα, transforming growth factors TGF-β1, TGF-β2, TGF-β3 were measured in polyp tissue samples by means of multiplex analysis. The patients were treated according to a stepwise СRSwNP therapeutic algorithm [9]. Following observation for 5 years, all patients were divided into groups, as based on medical control degree. Group 1 included patients with mild CRSwNP, who mainly received stage I and II treatment for the entire observation period. Group 2 was presented by moderate- severity CRSwNP, with stage II or III therapy according to the referred algorithm. Group 3 included the patients with severe CRSwNP who received one or more stage IV courses. The patients underwent repeated SNOT-22 questionnaire, endoscopic examination, clinical assessment. In case of bronchial asthma (BA), ACQ-7 was repeated. Initial cytokine profile of nasal polyps was analyzed by the mentioned clinical groups.Results:After 5 years of observations in group 1 (mild CRSwNP), we found a minimal decrease in quality of life (SNOT-22), severity of nasal congestion, or smell impairment. Bronchial asthma duration in these patients was significantly lower compared to group 3, the patients had better asthma control level. Cytokine profile of nasal polyps was characterized by the highest IL-4 concentration, average values IL-1β, TNFα, IFNγ and minimal TGF-β1 values.In group 2 (moderate CRSwNP), we noted more pronouced impairment of smell, nasal congestion and quality of life. Bronchial asthma was less controlled than in group 1. The maximal concentrations of IFNγ, IL-1β, TNFα, IL-5, TGF-β1, TGF-β2 were registered.In group 3 with poor CRSwNP control, the highest SNOT-22 scores, severity of difficulty in nasal breathing, impaired sense of smell were revealed. Duration of bronchial asthma was longer, with lowest levels of medical control. In nasal polyps, minimal levels of IFNγ, IL-1β, TNFα, IL-4, IL-5, TGF-β2, TGF-β3 were noted.Treatment of patients depending on the clinical phenotypes of CRSwNP in the presence/absence of allergic rhinitis or bronchial asthma may improve control and reduce incidence of relapses in CRSwNP.

Abstract Background The gene cell division cycle associated 5 (CDCA5), also called sororin, has oncogenic characteristics and is upregulated in various carcinomas. Nevertheless, the involvement of CDCA5 in ovarian cancer (OC), a highly aggressive form of cancer, and the underlying mechanism of metastasis remain inadequately investigated. Results The bioinformatics data revealed a negative correlation between the patient’s survival and CDCA5 expression, which was overexpressed in OC. Functional assays also confirmed high expression levels of CDCA5 in OC tissues and cells. This suggests that CDCA5 may potentially enhance the motility, migration, and proliferation of OC cells invitro. It impedes DNA damage and apoptosis in OC cells, inhibiting xenograft development in nude mice. The RNA sequencing results suggest CDCA5 is majorly associated with biological functions related to the extracellular matrix (ECM) and influences the transforming growth factor (TGF) signaling pathway. Moreover, subsequent functional investigations elucidated that CDCA5 facilitated the migration and invasion of OC cells viathe TGF-β1/Smad2/3 signaling pathway activation. Conclusions CDCA5 may be a strong potential therapeutic target for the treatment and management of OC.

Yueying Niu,1 Mengqing Cao,1 Shumin Li,1 Juanfen Mo,2 Ziyi Zhu,1 Haiqin Wang1 1Department of Respiratory Medicine, The Second Hospital of Jiaxing, Jiaxing, Zhejiang, People’s Republic of China; 2The Key Laboratory, The Second Hospital of Jiaxing, Jiaxing, Zhejiang, People’s Republic of ChinaCorrespondence: Haiqin Wang; Ziyi Zhu, Department of Respiratory Medicine, The Second Hospital of Jiaxing, 1518 Huanchen North Road, Jiaxing, Zhejiang, 314000, People’s Republic of China, Email w_haiqin@163.com; zhuziyi1986@163.comObjective: To retrospectively study the effects of budesonide inhalation combined with conventional symptomatic treatment on serum inflammatory factor expression levels and pulmonary function in patients with cough variant asthma (CVA) and to evaluate treatment efficacy.Methods: This retrospective cohort study included 200 patients diagnosed with CVA at the Second Hospital of Jiaxing between January 2022 and June 2023 and given conventional symptomatic treatment plus budesonide inhalation were included in this study. Patients were divided into a no remission group, a partial remission group and a complete remission group based on treatment effect. The expression levels of serum inflammatory factors, cough symptom scores, and small airway function indicators in the three groups of patients at different time points were compared.Results: In the three groups of CVA patients, after receiving budesonide inhalation combined with conventional symptomatic treatment, the expression levels of serum IL-5, IL-6, IL-8, TNF-α, TGF-β 1, and IgE and number of eosinophils significantly decreased (P < 0.05). There were statistically significant differences in the IL-6 and TGF-β 1 levels among the three groups of CVA patients at T1, T2 and T3. There were statistically significant differences in IgE levels, number of eosinophils, cough symptom scores, and small airway function indicators between T2 and T3 (P< 0.05). The receiver operating characteristic (ROC) curve prediction analysis revealed significant differences in the expression of IL-6 and TGF-β 1 at T1, T2, and T3.Conclusion: Budesonide inhalation combined with conventional symptomatic treatment can significantly reduce the levels of serum inflammatory factors in patients with CVA to reduce inflammation and the allergic response, thereby reducing the cough symptom score, improving pulmonary function, and improving therapeutic efficacy. In addition, IL-6 and TGF-β 1 can be used as early predictors of budesonide inhalation efficacy.Keywords: budesonide, cough variant asthma, cytokines, IL-6, TGF-β 1

Transforming growth factor-beta1 (TGF-β1) stimulates matrix metalloproteinase-13 (MMP-13, a bone-remodeling gene) expression, and this effect requires p300-mediated Runx2 (Runt-related transcription factor 2) acetylation in osteoblasts. p300 and Runx2 are transcriptional coactivator and bone transcription factor, respectively, which play key roles in the regulation of bone-remodeling genes. Non-coding ribonucleic acids (ncRNAs), such as long ncRNAs (lncRNAs) and microRNAs (miRNAs), have been linked to both physiological and pathological bone states. In this study, we proposed that TGF-β1-mediated stimulation of MMP-13 expression is due to the downregulation of p300 targeting miRNAs in osteoblasts. We identified miR-130b-5p as one of the miRNAs downregulated by TGF-β1 in osteoblasts. Forced expression of miR-130b-5p decreased p300 expression, Runx2 acetylation, and MMP-13 expression in these cells. Furthermore, TGF-β1 upregulated circ_ST6GAL1, (a circular lncRNA) in osteoblasts; circRNA directly targeted miR-130b-5p. Antisense-mediated knockdown of circ_ST6GAL1 restored the function of miR-130b-5p, resulting in downregulation of p300, Runx2, and MMP-13 in these cells. Hence, our results suggest that TGF-β1 influences circ_ST6GAL1 to sponge and degrade miR-130b-5p, thereby promoting p300-mediated Runx2 acetylation for MMP-13 expression in osteoblasts. Thus, the circ_ST6GAL1/miR-130b-5p/p300 axis has potential significance in the treatment of bone and bone-related disorders.

Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and kidneys. Recently, advanced extraction and synthesis techniques have made it possible to develop derivatives of rhein, which have better pharmacological properties and lower toxicity. This article comprehensively summarizes the biological activity and action mechanism of rhein. Notably, we found that TGF-β1 is the target of rhein improving tissue fibrosis, while NF-κB is the main target of its anti-inflammatory effect. Additionally, we reviewed the current research status of the pharmacokinetics, toxicology, structural optimization, and potential drug applications of rhein and found that the coupling and combination therapy of rhein and other active ingredients exhibit a synergistic effect, significantly enhancing therapeutic efficacy. Finally, we emphasize the necessity of further studying rhein’s pharmacological mechanisms, toxicology, and development of analogs, aiming to lay the foundation for its widespread clinical application as a natural product and elucidate its prospects in modern medicine.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood. We analyzed the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interaction. We found that TIMP-1 is aberrantly overexpressed in tumor-associated fibroblasts (TAFs) in ADC compared to SCC. Mechanistically, TIMP-1 overexpression was mediated by the selective hyperactivity of the pro-fibrotic TGF-β1/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-β1-activated ADC-TAFs is both necessary and sufficient to enhance growth and invasion of ADC cancer cells in culture, and that tumor cell expression of CD63 was required for these effects. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced SMAD3 or TIMP-1 expression into immunocompromised mice attenuated tumor aggressiveness compared to tumors bearing parental fibroblasts. We also found that high TIMP1 and CD63 mRNA levels combined define a stronger prognostic biomarker than TIMP1 alone. Our results identify an excessive stromal TIMP-1 within the tumor microenvironment selectively in lung ADC, and implicate it in a novel tumor-promoting TAF-carcinoma crosstalk, thereby pointing to TIMP-1/CD63 interaction as a novel therapeutic target in lung cancer.

There is an urgent need for alternative therapies targeting human dendritic cells (DCs) that could reverse inflammatory syndromes in many autoimmune and inflammatory diseases and organ transplantations. Here, we describe a bispecific antibody (bsAb) strategy tethering two pathogen-recognition receptors at the surface of human DCs. This cross-linking switches DCs into a tolerant profile able to induce regulatory T-cell differentiation. The bsAbs, not parental Abs, induced interleukin 10 and transforming growth factor β1 secretion in monocyte-derived DCs and human peripheral blood mononuclear cells. In addition, they induced interleukin 10 secretion by synovial fluid cells in rheumatoid arthritis and gout patients. This concept of bsAb-induced tethering of surface pathogenrecognition receptors switching cell properties opens a new therapeutic avenue for controlling inflammation and restoring immune tolerance. [ABSTRACT FROM AUTHOR]

Pre-injured lungs are prone to injury progression in response to mechanical ventilation. Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-β1 (AdTGF-β1) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH2O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH2O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-β1 compared to AdCl across PEEP levels. H was minimized at PEEP = 5–8 cmH2O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (= derecruitment) and reduced density of alveolar number and surface area (= distension), respectively. In AdTGF-β1 exposed mice, 27% of alveoli remained derecruited at Pao = 20 cmH2O. A further decrease in Pao down to 2 cmH2O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao = 2–5 cmH2O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-β1 exposed mice is high. H is optimized at PEEP 5–8 cmH2O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-β1 than in AdCl. The increased alveolar size heterogeneity at Pao = 5 cmH2O argues for the use of PEEP = 8 cmH2O for lung protective mechanical ventilation in this animal model. [ABSTRACT FROM AUTHOR]

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-β1 (TGF-β1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-β1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-β1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-β1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-β1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-β1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-β1 concentrations in DS subjects at higher risk to develop cognitive decline. [ABSTRACT FROM AUTHOR]

Spinal tuberculosis is a common extrapulmonary type that is often secondary to pulmonary or systemic infections. Mycobacterium tuberculosis infection often leads to the balance of immune control and bacterial persistence. In this study, 64 patients were enrolled and the clinicopathological and immunological characteristics of different age groups were analyzed. Anatomically, spinal tuberculosis in each group mostly occurred in the thoracic and lumbar vertebrae. Imaging before preoperative anti-tuberculosis therapy showed that the proportion of abscesses in the older group was significantly lower than that in the younger and middle-aged groups. However, pathological examination of surgical specimens showed that the proportion of abscesses in the older group was significantly higher than that in the other groups, and there was no difference in the granulomatous inflammation, caseous necrosis, inflammatory necrosis, acute inflammation, exudation, granulation tissue formation, and fibrous tissue hyperplasia. B cell number was significantly lower in the middle-aged and older groups compared to the younger group, while the number of T cells, CD4+ T cells, CD8+ T cells, macrophages, lymphocytes, plasma cells, and NK cells did not differ. Meaningfully, we found that the proportion of IL-10 high expression and TGF-β1 positive in the older group was significantly higher than that in the younger group. TNF-α, CD66β, IFN-γ, and IL-6 expressions were not different among the three groups. In conclusion, there are some differences in imaging, pathological, and immune features of spinal tuberculosis in different age groups. The high expression of IL-10 and TGF-β1 in older patients may weaken their anti-tuberculosis immunity and treatment effectiveness. [ABSTRACT FROM AUTHOR]

Introduction: Transforming growth factor (TGF)-β1 is crucial in developing liver fibrosis. Curcumin has been shown to effectively halt the advancement of liver fibrosis by inhibiting the TGF-β1/Smad signaling pathway. Nevertheless, curcumin's impact on liver fibrosis regression remains unclear. This study explored the involvement of curcumin and TGF-β1 in the regression of liver fibrosis. Methods: An experimental male C57BL/6 mice model included 6 treatment groups. The treatment groups were injected with carbon tetrachloride (CCl4) for 4 and 6 weeks to induce liver fibrosis, negative controls were injected with olive oil. After cessation of injection, 2 of the treatment groups were given curcumin for 2 weeks. TGF-β1 expression in liver cells was analyzed by real-time PCR assay. ELISA analyzed hydroxyproline liver tissue levels. Values of p<0.05 were regarded as statistically significant. Results: CCl4 injection induced liver fibrosis and significantly increased TGF-β1 expression and hydroxyproline levels in tissues. Curcumin administration decreased the expression of TGF-β1 and hydroxyproline levels in the liver and accelerated the regression of liver fibrosis. Conclusion: Curcumin accelerates regression of liver fibrosis, likely through decreasing TGF-β1 expression in the liver. [ABSTRACT FROM AUTHOR]

• Secretome from M1 and M2 macrophages were generated to treat keloid fibroblasts. • M2 secretome enhances the fibrogenic profile of keloid fibroblasts. • M1 secretome attenuates the fibrogenic profile of keloid fibroblasts. • M1 secretome prevents from profibrotic effect of TGF-β1 in keloid fibroblasts. • First demonstration that M1/M2 macrophages differentially impact fibrogenesis in keloid. Keloid refers to a fibroproliferative disorder characterized by an accumulation of extracellular matrix (ECM) components at the dermis level, overgrowth beyond initial wound, and formation of tumor-like nodule areas. Treating keloid is still an unmet clinical need and the lack of an efficient therapy is clearly related to limited knowledge about keloid etiology, despite the growing interest of the scientific community in this pathology. In past decades, keloids were often studied in vitro through the sole prism of fibroblasts considered as the major effector of ECM deposition. Nevertheless, development of keloids results from cross-interactions of keloid fibroblasts (KFs) and their surrounding microenvironment, including immune cells such as macrophages. Our study aimed to evaluate the effect of M1 and M2 monocyte-derived macrophages on KFs in vitro. We focused on the effects of the macrophage secretome on fibrosis-related criteria in KFs, including proliferation, migration, differentiation, and ECM synthesis. First, we demonstrated that M2-like macrophages enhanced the fibrogenic profile of KFs in culture. Then, we surprisingly founded that M1-like macrophages can have an anti-fibrogenic effect on KFs, even in a pro-fibrotic environment. These results demonstrate, for the first time, that M1 and M2 macrophage subsets differentially impact the fibrotic fate of KFs in vitro , and suggest that restoring the M1/M2 balance to favor M1 in keloids could be an efficient therapeutic lever to prevent or treat keloid fibrosis. [ABSTRACT FROM AUTHOR]

Platelets are actively involved in tissue injury site regeneration by producing a wide spectrum of platelet-derived growth factors such as PDGF (platelet-derived growth factor), IGF-1 (insulin-like growth factor), TGF-β1 (transforming growth factor β), FGF (fibroblast growth factor), etc. A rotating magnetic field (RMF) can regulate biological functions, including reduction or induction regarding inflammatory processes, cell differentiation, and gene expression, to determine the effect of an RMF on the regenerative potential of platelets. The study group consisted of 30 healthy female and male volunteers (n = 15), from which plasma was collected. A portion of the plasma was extracted and treated as an internal control group. Subsequent doses of plasma were exposed to RMF at different frequencies (25 and 50 Hz) for 1 and 3 h. Then, the concentrations of growth factors (IGF-1, PDGF-BB, TGF-β1, and FGF-1) were determined in the obtained material by the ELISA method. There were statistically significant differences in the PDGF-BB, TGF-β1, IGF-1, and FGF-1 concentrations between the analyzed groups. The highest concentration of PDGF-BB was observed in the samples placed in RMF for 1 h at 25 Hz. For TGF-β1, the highest concentrations were obtained in the samples exposed to RMF for 3 h at 25 Hz and 1 h at 50 Hz. The highest concentrations of IGF-1 and FGF-1 were shown in plasma placed in RMF for 3 h at 25 Hz. An RMF may increase the regenerative potential of platelets. It was noted that female platelets may respond more strongly to RMF than male platelets. [ABSTRACT FROM AUTHOR]

Vitiligo is a T cell-mediated depigment skin disease caused by the complex interplay between melanocyte dysfunction, environmental stimulation, and dysregulated immune signals. Transforming growth factor-β1 (TGF-β1), which typically derives from regulatory T cells, has long been identified at low levels in the peripheral system of vitiligo patients. Here, through RNA-sequencing and transcription factor enrichment, we revealed that in response to CD8+ T cell-secreted interferon-gamma (IFN-γ), stromal fibroblast downregulates early growth response 1 (EGR1) activity, leading to TGF-β1 deficiency. The defective immune regulation loop further exacerbated local CD8+ T cell inflammation and promoted inflammatory cell migration in vitiligo. Thus, fibroblast-derived TGF-β1 plays an important stromal signal in vitiligo pathogenesis. [ABSTRACT FROM AUTHOR]

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