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Objectives: This randomized, double-blind, placebo-controlled clinical trial aimed to prospectively examine the effect of pentoxifylline (PTX) on hypoxia-inducible factor-2 alpha (HIF-2α) and its role in controlling anemia in hemodialysis (HD) patients. Methods: Eighty patients on HD were randomized to receive 400 mg of PTX or placebo twice daily for 6 months. The hemoglobin (Hb) and other hematologic parameters, the weekly erythropoiesis-stimulating agents (ESAs), and the ESA resistance index (ERI) were assessed monthly during the study. The HIF-2α, transforming growth factor-β1 (TGF-β1), and high-sensitivity C-reactive protein (hs.CRP) were measured before and after the intervention. Results: In the pentoxifylline group, an appreciable increase in Hb from 9.7 (9.3, 10.3) g/dl to 10.5 (9.3, 11.4) g/dl and hematocrit (Hct) from 31.3 (29.6, 32.4)% to 33.2 (29.4, 35.9)% was observed after one month of PTX administration, and this effect was maintained over the study time (p < 0.001). This was along with a decrease in the ESA doses required from 8000 (8000, 11500) IU/wk to 4000 (2000, 8000) IU/wk (p < 0.001), and an improvement in the ERI from 11.6 (8.07, 16.97) IU/kg/wk/g/dl to 5.79 (2.01, 10.09) IU/kg/wk/g/dl (p < 0.001). Additionally, the HIF-2α increased significantly at the end of the intervention in patients who received PTX from 3245.35 (2886.8, 4691.56) pg/ml to 7208.75 (5382, 9182.7) pg/ml, while TGF-β1 and hs.CRP decreased significantly from 657.78 (539.78, 1146.62) pg/ml and 88.08 (39.93, 100.4) mg/l to 329.94 (228.67, 793.18) pg/ml and 48.65 (34.44, 84.61) mg/l, respectively. The percent changes in HIF-2α, TGF-β1, and hs.CRP levels in the pentoxifylline group were also statistically significant in comparison with the placebo group. Conclusions: PTX could be a promising agent for correcting anemia in HD patients via increasing HIF-2α levels. Clinical trial registration: Clinicaltrials.gov, February 2023, registry number: NCT05708248. [ABSTRACT FROM AUTHOR]

TGF-β1 (Transforming growth factor-β1) plays an important role in the regeneration and repair of pulp-dentin complex. However, the biological function of TGF-β1 on odontoblastic differentiation remains unclear, mainly due to the processes of differentiation were controlled by complex signaling pathways. This study aimed to investigate the signaling pathways involved in regulating the early differentiation of dental pulp stem cells (DPSCs) by TGF-β1 and their functional role. DPSCs were treated with 1 ng/mL TGF-β1 and Western blotting was conducted to examine the activation of protein kinase B (AKT), small mothers against decapentaplegic 3 (Smad3), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2). DPSCs were exposed to mineralization medium contained TGF-β1 with/without the specific signaling pathway inhibitors, and early odontogenic differentiation was evaluated by assessing the expression of alkaline phosphatase (ALP), collagen type 1 alpha 1 (COL1A), dentin matrix protein 1 (DMP-1) and runt-related transcription factor 2 (Runx2). TGF-β1 stimulated AKT, Smad3, p38 MAPK, Erk1/2 and JNK phosphorylation in DPSCs within 120 min. TGF-β1 enhanced ALP activity and elevated levels of COL1A, DMP-1 and Runx2. LY294002, U0126 and SB203580 attenuated the effect of TGF-β1 on DPSCs, however, the SIS3 and SP600125 treated groups had no significant effect. TGF-β1 promotes the early stage of odontoblastic differentiation in DPSCs by activating AKT, Erk1/2 and p38 MAPK signaling pathways, but not by Smad3 and JNK. [ABSTRACT FROM AUTHOR]

Astragaloside IV (AS#IV) has previously demonstrated antitumoractivity. We investigated the effect and mechanisms of AS#IV in relation to epithelial–mesenchymal transition (EMT), viainterference with the Wnt/β-catenin signaling pathway in gliomaU251 cells. Induction of glioma U251 cells by transforming growthfactor (TGF)#β1 activated EMT, including switching E#cadherin toN-cadherin and altering the expression of Wnt/β-catenin signalingpathway components such as vimentin, β-catenin, and cyclin-D1.AS-IV inhibited the viability, invasion, and migration of TGF-β1-induced glioma U251 cells. AS-IV also interfered with the TGF#β1-induced Wnt/β-catenin signaling pathway in glioma U251 cells.These findings indicate that AS#IV prohibits TGF#β1-induced EMTby disrupting the Wnt/β-catenin pathway in glioma U251 cells. AS#IV may thus be a potential candidate agent for treating glioma andother central nervous system tumors. Astragaloside IV interfered with the TGF-β1-induced Wnt/β-catenin signaling pathway in glioma cells. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aimed to investigate the effects of prostaglandin E2 receptor subtypes 1 (EP1) and 2 (EP2) on endoplasmic reticulum (ER) stress induced by TGF-β1 in mouse mesangial cells (MCs) and to explore its potential mechanisms. MATERIALS AND METHODS: M ouse m esangial cells were isolated and cultured. EP-siRNAs were transfected into mesangial cells for silencing EP1 and EP2. Mesangial cell proliferation was assessed by the CCK-8 method. Expression of PGE2 was measured by enzyme-linked immunosorbent assay (ELISA). GRP78, TRPC1, ERK1/2, and phospho-ERK1/2 levels were examined by Western blot. RESULTS: TGF-β1 induced mesangial cell proliferation and increased PGE2 secretion. Besides, TGF-β1 significantly upregulated GRP78 and TRPC1 expression at the protein level. Phospho- ERK1/2 protein amounts were also increased (p<0.05). Compared with the TGF-β1 group, cell proliferation in the EP1-siRNA+TGF-β1 group was reduced, while GRP78, TRPC1, and ERK1/2 protein amounts were downregulated (p<0.05). EP1 agonist significantly enhanced above changes and their activities (p<0.05). EP1 antagonist significantly attenuated the above changes (p<0.05). Compared with TGF-β1 group, cell proliferation in EP2-siRNA+TGF-β1 group was increased, while GRP78, TRPC1, and ERK1/2 protein amounts were increased (p<0.05). EP2 agonist significantly attenuated the above changes (p<0.05). CONCLUSIONS: EP1 receptor may increase TGF-β1-induced cell damage by increasing the activities of GRP78, TRPC1, and ERK1/2 via ER stress. Meanwhile, the EP2 receptor may reduce TGF-β1-induced cell damage by suppressing GRP78, TRPC1, and ERK1/2 activities, also via ER stress. EP1 inhibition and EP2 stimulation may be a therapeutic option for delaying renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Treating colorectal cancer (CRC) continues to be a clinical challenge. Studies have shown that epithelial-mesenchymal transition (EMT) is a critical step in tumor progression and transforming growth factor-β1 (TGF-β1) signaling has been shown to play a crucial role in EMT. Here, we investigate the inhibition effect of Ginsenoside Rb2, main bioactive component of ginseng, in human colorectal cancer cells via TGF-β1.Purpose: The current study aims to study the inhibitory effect of Ginsenoside Rb2 on HCT116 and SW620 cells and its anti-tumor mechanism.Methods: Histomorphological analysis and western blot analysis were performed to evaluate expression of TGF-β1 in human cancerous colon samples and the adjacent normal samples. The docking simulation assay were performed to explore the potential mode of binding of Ginsenoside Rb2 to the TGF-β1 protein. CCK8, adhesion and invasion assay were used to assess the effects of Ginsenoside Rb2 in HCT116 and SW620 cells. RT-PCR, Western blot and Immunohistochemical staining were employed to detect the TGF-β1-related signaling pathways in the colon cancer cells and/or xenograft mice.Results: The expression of TGF-β1 in human cancerous colon samples was significantly increased compared with the adjacent normal samples. Ginsenoside Rb2 inhibit the growth, adhesion, EMT and metastasis of human colorectal cancer cells. The docking simulation assay confirmed that Ginsenoside Rb2 bound to the hydrophobic pocket of TGF-β1, which partially overlaps with the binding sites on TGF-β1, and thus disrupted TGF-β1 dimerization. Western Blot analysis further confirmed that Ginsenoside Rb2 could inhibit the expression of TGF-β1 in vitro and in vivo. Furthermore, Ginsenoside Rb2 could inhibit the expression of Smad4 and phosphorylated Smad2/3.Conclusion: Ginsenoside Rb2 could inhibit EMT of colorectal cancer cells through the TGF-β1/Smad signaling, and might be a potential candidate for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background/purpose: Many fibrotic processes are associated with an increased level of transforming growth factor-β1 (TGF-β1). TGF-β1 can increase synthesis of matrix proteins and enhance secretion of protease inhibitors, resulting in matrix accumulation. Connective tissue growth factor (CTGF) is a downstream profibrotic effector of TGF-β1 and is associated with the fibrosis in several human organs. Curcumin has been applied to reduce matrix accumulation in fibrotic diseases. This study was aimed to evaluate whether curcumin could suppress TGF-β1-induced CTGF expression and its related signaling pathway involving in this inhibitory action in primary human gingival fibroblasts.Methods: The differences in CTGF expression among three types of gingival overgrowth and normal gingival tissues were assessed by immunohistochemistry. Gingival fibroblast viability in cultured media with different concentrations of curcumin was studied by MTT assay. The effect of curcumin on TGF-β1-induced CTGF expression in primary human gingival fibroblasts was examined by immunoblotting. Moreover, the proteins involved in TGF-β1 signaling pathways including TGF-β1 receptors and Smad2 were also analyzed by immunoblotting.Results: CTGF was highly expressed in fibroblasts, epithelial cells and some of endothelial cells, smooth muscle cells, and inflammatory cells in phenytoin-induced gingival overgrowth tissues rather than in those of hereditary and inflammatory gingival overgrowth tissues. Moreover, CTGF expression in the epithelial and connective tissue layers was higher in phenytoin-induced gingival overgrowth tissues than in normal gingival tissues. Curcumin was nontoxic and could reduce TGF-β1-induced CTGF expression by attenuating the phosphorylation and nuclear translocation of Smad2.Conclusion: Curcumin can suppress TGF-β1-induced CTGF expression through the interruption of Smad2 signaling. [ABSTRACT FROM AUTHOR]

An in vitro human blood–brain barrier (BBB) model was developed using human brain microvascular endothelial cells (HBMECs) co-cultured with human brain vascular pericytes (HBVPs) and human astrocytes (HAs) at various ratios (HBVPs:HAs = 1:1, 1:2, 1:6), associated with pericyte-conditioned medium (PCM) and astrocyte-conditioned medium (ACM). After 7 days of co-culturing of HBMECs with HBVPs and HAs at a ratio of 1:2, and a 1:1 ratio of PCM and ACM, the transendothelial electrical resistance was enhanced to 319 ± 16.67 Ω × cm 2 (225% increase) and the permeability coefficient of propidium iodide was reduced to 2.09 ± 0.5 × 10 −6  cm/s (61% decrease). Analysis of three major barrier integrity modulators: transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), revealed a higher TGF-β1 expression and lower VEGF and MMP-9 expressions in a co-culture of HBMECs with HBVPs and HAs at a ratio of 1:2. Calcein-AM analysis showed higher P-glycoprotein (P-gp) activity in the model using PCM and ACM with HBVPs:HAs = 1:2 (100%) than that with HBVPs:HAs = 1:1 (55%) and HBVPs:HAs = 1:6 (49%). The effect of TGF-β1 receptor inhibitor SB431542, VEGF inhibitor asterric acid, and MMP-9 inhibitor CTT (H-Cys-Thr-Thr-His-Trp-Gly-Phe-Thr-Leu-Cys-OH) on the BBB model suggested that TGF-β1 up-regulates P-gp activity and VEGF down-regulates P-gp activity. In the presence of PCM and ACM, co-culturing of HBMECs with HBVPs and HAs at a ratio of 1:2 could approach the in vivo BBB in a well representative manner. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore a new approach for treating renal insufficiency with gene therapy by implanting decorin (DCN)-expressing fibroblasts within the renal tissue of rats with renal failure to neutralize TGF-β1 activity. MATERIALS AND METHODS: The 5/6 kidney of the selected male SD rats were removed under aseptic conditions. The rats were grouped randomly after the establishment of the model. There were 10 rats in the sham-operated group (Group A), 10 in the operation control group (without treatment, Group B), 10 in the blank control group [treated with empty vector-transfected fibroblasts (FB (LXSN) cells), Group C], and 10 in the treatment group [treated with FB (LDCNSN) cells, Group D]. The pathological changes of rats including body weight, blood lipids, renal function, and renal histology, were observed. The expression of TGF-β1 and DCN in renal tissue was detected by immunohistochemistry. RESULTS: There were no significant differences in body weight and blood lipids between the groups at 4 weeks after treatment. The levels of blood urea nitrogen and serum creatinine in rats in Group D were significantly decreased compared with those in Group C (p < 0.05). Although the differences were not statistically significant, the levels of those pathological indicators are higher than baseline values. The expression of DCN in renal tissue increased significantly after 4 weeks in rats of Group D and the differences were significant compared with the other groups. There were no significant differences in TGF-β1 expression between any two groups of Group D, B, and C. Furthermore, pathological damage to the renal interstitium of rats in Group D was significantly decreased compared with that of Group B and C. CONCLUSIONS: DCN can alleviate fibrosis and delay the progression of renal failure. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of this study was to observe the expression of transforming growth factor-β1 (TGF-β1) in myocardial tissue and the concentration of serum B-type natriuretic peptide (BNP) in myocardial remodeling of Sprague-Dawley rats induced by isoproterenol (ISO) and the effects of carvedilol intervention. MATERIALS AND METHODS: Thirty rats were divided randomly into three groups: (1) Control group: rats were injected with 5 mL/(kg·d) of saline for 10 days, followed by 10 mL/(kg·d) of saline by gavage for 4 weeks. (2) Model group: rats were injected with 5 mg/(kg·d) ISO for 10 days, followed by 10 mL/(kg·d) of saline by gavage for 4 weeks. (3) Treatment group: rats were injected with 5 mg/(kg·d) ISO for 10 days, followed by 10 mg/(kg·d) carvedilol by gavage for 4 weeks. Following treatments, the Cardiac Weight Index (CWI) was measured. The pathological changes to myocardial tissue were observed by HE staining and Masson's trichrome staining. The mRNA expression of TGF-β1 was determined by RT-PCR. The protein expression of TGF-β1 was detected by immunohistochemistry and Western blot. The concentration of serum BNP was measured by ELISA. RESULTS: According to our results, no significant pathological changes were observed in myocardial tissue of the control group. The denaturation, hypertrophy, edema and necrosis of myocardial cells as well as increased collagen fibers in myocardial tissue of the model group, were more pronounced compared to the treatment group. The CWI, level of TGF-β1 in myocardial tissue, and the concentration of serum BNP of the model group, were significantly higher than that of the treatment group, and those of the treatment group were significantly higher than in the control group. There were significant differences among the three groups. There were also significant differences between any two groups. CONCLUSIONS: The expression of TGF-β1 in myocardial tissue was upregulated and the concentration of serum BNP was increased in myocardial remodeling of SD rats induced by ISO. Carvedilol intervention can downregulate the expression of TGF-β1 and decrease the concentration of BNP, inhibiting myocardial remodeling, and improve cardiac function. [ABSTRACT FROM AUTHOR]

Background: Chronic diabetic foot wounds are a leading cause of amputation, morbidity, and hospitalization for patients with diabetes. Negative-pressure wound therapy (NPWT) can putatively facilitate wound healing, but the underlying mechanisms remain unclear. Cellular fibronectin (cFN) and transforming growth factor-β1 (TGF-β1) play an important role in wound healing. This prospective randomized controlled trial evaluated the effects of NPWT on the production of cFN and the expression of TGF-β1 in diabetic foot wounds of patients. Methods: From January 2012 to January 2015, 40 patients with diabetic foot wounds were randomly and equally apportioned to receive either NPWT or advanced moist wound therapy (control) for 7 days. Granulation tissue was harvested before and after treatment. Immunohistochemistry and Western blot were performed to evaluate protein levels of cFN and TGF-β1, and real-time polymerase chain reaction (PCR) to measure corresponding mRNA expressions. Results: NPWT facilitated the expression of cFN and TGF-β1 in diabetic foot wounds. Immunohistochemical analysis revealed higher levels of cFN and TGF-β1 in the NPWT group than in the control group. Western blot and real-time PCR analysis further showed that protein and mRNA levels of cFN or TGF-β1 were higher in the NPWT group than that in the control group (P < .01, both). Conclusion: Our results showed that NPWT facilitated the production of cFN and the expression of TGF-β1 in granulation tissue in diabetic foot ulcers. Level of Evidence: Level I, randomized controlled study. [ABSTRACT FROM AUTHOR]

Fucoidan from sea cucumber exerts anti-hyperglycemia and anti-inflammatory effects. However, its renoprotective activities are unclear. In the current study, renoprotective effects of fucoidan from Acaudina molpadioides ( Am -FUC) were investigated in type 2 diabetic mice induced by intraperitoneal administration of streptozotocin and high fat diet feeding. Results showed that Am -FUC attenuated renal dysfunction through the decreases in urinary urea nitrogen, albumin, β-N-Acetyl-D-glucosaminidase, and albumin-to-creatinine ratio. In Am -FUC-treated mice, significant reductions in tubular atrophy and glomerular basement membrane thickness were observed. Immunohistological examination revealed that Am -FUC attenuated renal fibrosis. Am -FUC decreased the expression of transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor 1, and phosphorylated Smad3. Renal oxidative stress and inflammation were also alleviated by Am -FUC treatment. Our data demonstrate that Am -FUC has significantly renoprotective effects through attenuating TGF-β1 signal, which associated with the improvement against hyperglycemia, obesity, oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Calcific aortic valve disease (CAVD) is an active and cellular-driven fibrocalcific process characterised by differentiation of valve interstitial cells (VICs) towards an osteogenic-like phenotype. A recently identified lncRNA, lncTSI , has been reported to inhibit fibrogenesis through transforming growth factor (TGF)-β/Smad3 pathway. Here, the present study aimed to investigate the role of lncTSI in CAVD. The effect of TGF-β1 on lncTSI of VICs was measured. TGF-β1, RUNX2 and collagen I expression between calcified aortic valve tissue and normal samples by immunohistochemistry and western blotting. Human VICs were cultured and treated with TGF-β1. SiRNA and pcDNA3.1-lncTSI plasmid transfection were used to silence and overexpress lncTSI in VICs for 48 h, Smads phosphorylation, RUNX2 and collagen I expression were then verified by western blotting. In ApoE−/− mice fed with 0.25 % high-cholesterol diet, AAV2- lncTSI were injected intravenously to observe their effect on the formation of aortic valve calcification. lncTSI was highly expressed in VICs treated with TGF-β1. lncTSI was transcriptionally regulated by Smad3 and reversely inhibited TGF-β1-induced Smad3 phosphorylation and downregulated profibrotic gene expression. Silencing lncTSI increased TGF-β1–induced Smad3 phosphorylation, and subsequently, upregulated RUNX2 and collagen I expressions in VICs. While overexpression of lncTSI reversed the production of RUNX2 and collagen I in VICs. In a mouse CAVD model of 24 week 0.25 % high-cholesterol diet feeding, overexpression of lncTSI significantly reduced calcium deposition, RUNX2, pSmad3, and collagen I expression in aortic valve leaflets, with less aortic valve stenosis. The novel findings of present study suggested that lncTSI alleviated aortic valve calcification through negative regulation of the TGF-β/Smad3 pathway. The results may help elucidate new diagnostic and therapeutic targets to prevent CAVD progression. • Calcific aortic valve disease is an important and common cardiovascular disease. • long noncoding TSI expression was upregulated in calcified aortic valves. • lncTSI alleviated aortic valve calcification through negative regulation of the TGF-β/Smad3 pathway. • These data suggest that long noncoding TSI is a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background The exact pathogenesis of pterygium is still not fully understood. Growth factors are considered to play an important role in the formation of pterygium. Transforming growth factor (TGF)-β1 is considered to be one of the main mediators of fibroblast stimulation and tissue remodeling in allergic conditions. The objective of the present study was to investigate the association between TGF-β1 gene expression and pterygium in atopic and nonatopic participants. Methods We used questionnaires to record demographic and clinical information from patients who underwent pterygium excision surgery. Skin prick examination was done to confirm or rule out atopy in 30 patients with atopy (Case Group) and 30 individuals without atopy (Control Group). Additionally, measurement of serum immunoglobulin E, cytokines, including interleukin-4 and interferon-γ, and peripheral blood eosinophil count was performed to confirm atopy in 30 consecutive patients (Case Group). A semiquantitative reverse transcription polymerase chain reaction was performed to determine TGF-β1 gene expression in all individuals. Results TGF-β1 mRNA gene expression was significantly higher ( p = 0.0001) in atopic patients 2.50 ± 1.11 compared to nonatopic individuals 1.40 ± 0.46. Eosinophil count and serum immunoglobulin E were significantly higher ( p = 0.031 and p = 0.001, respectively) in atopic patients compared to the Control Group. Serum interleukin-4 was also significantly higher ( p = 0.01) in atopic patients compared with nonatopic individuals. Conclusion Excess expression of TGF-β1 gene in pterygium tissue of atopic individuals suggests that growth factors play a role in the pathogenesis of pterygium. [ABSTRACT FROM AUTHOR]

Introduction This 2-part study hypothesized that a bioactive scaffold containing a sustained transforming growth factor (TGF)-β1–releasing nanoparticle system will promote migration and enhance differentiation of stem cells from the apical papilla (SCAP). The study aimed to develop and characterize a novel modified chitosan-based scaffold containing TGF-β1–releasing chitosan nanoparticles (TGF-β1-CSnp) to enhance migration and differentiation of SCAP. Methods Part I concerns the synthesis and characterization of a carboxymethyl chitosan–based scaffold and TGF-β1-CSnp. Part II examines the effect of sustained TGF-β1 release from scaffold containing TGF-β1-CSnp on odontogenic differentiation of SCAP. Results The scaffold demonstrated properties conducive to cellular activities. The incorporation of TGF-β1 in CSnp allowed sustained release of TGF-β1, facilitating delivery of a critical concentration of TGF-β1 at the opportune time. TGF-β1 bioactivity was maintained for up to 4 weeks. SCAP showed greater viability, migration, and biomineralization in the presence of TGF-β1-CSnp than in the presence of free TGF-β1. SCAP cultured in TGF-β1-CSnp + scaffold showed significantly higher dentin matrix protein-1 and dentin sialophosphoprotein signals compared with free TGF-β1 + scaffold or CSnp + scaffold. Conclusions These experiments highlighted the potential of a carboxymethyl chitosan–based scaffold with growth factor releasing nanoparticles to promote migration and differentiation of SCAP. The results of this study may have direct application to improve current endodontic regenerative protocols. [ABSTRACT FROM AUTHOR]

Introduction The purpose of this study was to evaluate the influence of pH that is due to setting reaction of Biodentine, glass ionomer cement (GIC), and intermediate restorative material (IRM) on transforming growth factor-β1 (TGF-β1) release and on the fibrin architecture of platelet-rich fibrin (PRF). Methods PRF was obtained from 8 volunteers and layered over the freshly prepared GIC, IRM, and Biodentine mixtures. TGF-β1 release was estimated by using enzyme-linked immunosorbent assay (ELISA), and fibrin structure of PRF was analyzed by using scanning electron microscope at 1 and 5 hours. Results Biodentine, GIC, and IRM increased the TGF-β1 release in comparison with that of control group (PRF alone) at both 1 and 5 hours. Biodentine released significantly more TGF-β1 than GIC and IRM at 1 hour. At 5 hours both GIC and Biodentine released significantly more TGF-β1 than IRM. The fibrin architecture of the Biodentine group was similar to that of control group at both 1 and 5 hours. In GIC and IRM groups the fibrillar structure of fibrin was collapsed, ill-defined, and cloudy with very thick fibers and irregularly reduced porosities. Conclusions Biodentine induces larger amount of TGF-β1 release and also maintains the integrity of fibrin structure when compared with GIC and IRM when layered over PRF. [ABSTRACT FROM AUTHOR]

The long-term success of intra-arterial stenting remains limited by in-stent restenosis (ISR). Transforming growth factor–β1 (TGF–β1) can inhibit smooth muscle cell (SMC) proliferation and migration and convert SMCs into extracellular matrix (ECM)–synthesizing cells. Here, we evaluate the effects of stent-based delivery of TGF-β1 on ISR in a rabbit model. Channeled stents loaded with TGF-β1 or control microspheres were deployed in rabbit aortas. Stented aortas were harvested at 7 and 28 d and evaluated for Ki-67–positive cells, collagenous ECM production, and intima-to-media (I/M) ratio. At 7 d, the TGF-β1 group exhibited fewer Ki-67–positive cells were found for the TGF-β1 group (17.87 ± 2.18 cells per mm2) relative to control (25.07 ± 2.65 cells per mm2, p = 0.04), but increased collagen content (31.4 ± 2.5 percentage area) compared with control (29.3 ± 1.2 percentage area, p = 0.019). The I/M ratio in the TGF-β1 group was reduced by 50% and 9.1% versus control at 7 d (0.13 ± 0.02 vs. 0.26 ± 0.02, p = 0.0001) and 28 d (1.80 ± 0.05 vs. 1.98 ± 0.08, p = 0.0038), respectively. Stent-based controlled release of TGF-β1 limits ISR and is associated with inhibition of SMC proliferation but an increase in ECM production. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Heart ischemia/reperfusion (I/R) injury is a common cause of heart failure. However, there is no effective method to treat the disease presently. The present research was to investigate the effects of transforming growth factor-β1 (TGF-β1) on homing of bone marrow mesenchymal stem cells (MSC) in heart I/R injury. MATERIALS AND METHODS: Effects of TGF- β1 on the expression of CXCR4 [Chemokine (CX- C Motif) Receptor 4] and che motactic effect to SDF-1 (stromal cell-derived factor 1) in MSCs were investigated by in vitro transmembrane chemotaxis. Anti-TGF-β1 was incu bated with I/R injury's heart tissue of mice. In addition, effects of TGF-β1 and anti-CXCR4 treatment using MSCs on the expression of SDF-1/CXCR4 in heart tissue and on I/R injury repair were further explored. RESULTS: CXCR4 and TGF-β1 expression were significantly increased after TGF-β1 treatment in MSCs; TGF-β1 treatment increased MSCs cell migration, and anti-CXCR4 and anti- TGF-β1 treatment blocked MSCs/TGF-β1cell migration. Expression of TGF-β1 in the I/R injury's myocardial tissue of mice was increased, and MSCs transplantation could enhance the protein expression of CXCR4 in the I/R injury's myocardial tissue of mice, and the expression of CXCR4 was decreased by the anti-TGF-β1 and the anti-CXCR4 treatment. TGF-β1 induced homing of MSCs in the repair of myocardial injury by regulating expression of CXCR4 on the cell membranes. Blue fluorescence of DAPI-positive MSCs cells of myocardial in the I/R+MSC group was enhanced significantly, which was significantly inhibited by anti-TGF-β1 and anti-CXCR4 antibody, and the inhibitory effect of anti-CXCR4 antibody was more evident than that of anti- TGF-β1 antibody. CONCLUSIONS: TGF-β1 promotes homing of bone marrow (BM) MSCs in I/R injury's myocardial. The study provided useful data on the role of TGF-β1 in regulating SDF-1/CXCR4 axis-induced MSCs homing. [ABSTRACT FROM AUTHOR]

Injury to the recurrent laryngeal nerve often leads to permanent vocal cord paralysis, which has a significant negative impact on the quality of life. Long-term denervation can induce laryngeal muscle fibrosis, which obstructs the muscle recovery after laryngeal reinnervation. However, the mechanisms of fibrosis remain unclear. In this study, we aimed to analyze the changes in the expression of fibrosis-related factors, including transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) in denervated skeletal muscles using a mouse model of accessory nerve transection. Because of the small size, we used sternocleidomastoid muscles instead of laryngeal muscles for denervation experiments. Masson's trichrome staining showed that the grade of atrophy and fibrosis of muscles became more severe with time, but showed a plateau at 4 weeks after denervation, followed by a slow decrease. Quantitative assessment and immunohistochemistry showed that TGF-β 1 expression peaked at 1 week after denervation (p < 0.05) and was maintained at its high level until 4 weeks. CTGFand α -SMA-positive muscle cells were detected at 1 week after denervation, peaked at 2 weeks (p < 0.05), and remained at high levels with a subsequent slight decrease for 3-4 weeks. These results suggest that TGF-β 1 and CTGF may be involved in the process of denervated skeletal muscle fibrosis. They may induce the differentiation of myoblasts into myofibroblasts, as characterized by the activation of α -SMA. These findings may provide insights on key pathological processes in denervated skeletal muscle fibrosis and develop novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine the effects of all-trans retinoic acid (ATRA) on diabetic nephropathy. Materials and Methods: We measured amounts of urinary albumin excretion (UAE) after administrating ATRA to Otsuka Long- Evans Tokushima Fatty (OLETF) rats. In order to understand the mechanism of action for ATRA, we administrated ATRA to examine its inhibitory action on the production of transforming growth factor-β1 (TGF-β1), protein kinase C (PKC), and reactive oxidative stress (ROS) in cultured rat mesangial cells (RMCs). Results: After 16 weeks of treatment, UAE was lower in the ATRA-treated OLETF rats than in the non-treated OLETF rats (0.07± 0.03 mg/mgCr vs. 0.17±0.15 mg/mgCr, p<0.01). After incubation of RMCs in media containing 30 or 5 mM of glucose, treatment with ATRA showed time- and dose-dependent decreases in TGF-β1 levels and ROS. Moreover, ATRA treatment showed a dosedependent decrease in PKC expression. Conclusion: ATRA treatment suppressed UAE and TGF-β1 synthesis, which was mediated by significant reductions in PKC activity and ROS production. Our results suggest that ATRA has a potential therapeutic role for diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Purpose: The degradation of the extracellular matrix has been shown to play an important role in the treatment of hepatic cirrhosis. In this study, the effect of thalidomide on the degradation of extracellular matrix was evaluated in a rat model of hepatic cirrhosis. Materials and Methods: Cirrhosis was induced in Wistar rats by intraperitoneal injection of carbon tetrachloride (CCl4) three times weekly for 8 weeks. Then CCl4 was discontinued and thalidomide (100 mg/kg) or its vehicle was administered daily by gavage for 6 weeks. Serum hyaluronic acid, laminin, procollagen type III, and collagen type IV were examined by using a radioimmunoassay. Matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and α-smooth muscle actin (α-SMA) protein in the liver, transforming growth factor β1 (TGF-β1) protein in cytoplasm by using immunohistochemistry and Western blot analysis, and MMP-13, TIMP-1, and TGF-β1 mRNA levels in the liver were studied using reverse transcriptase polymerase chain reaction. Results: Liver histopathology was significantly better in rats given thalidomide than in the untreated model group. The levels of TIMP-1 and TGF-β1 mRNA and protein expressions were decreased significantly and MMP-13 mRNA and protein in the liver were significantly elevated in the thalidomide-treated group. Conclusion: Thalidomide may exert its effects on the regulation of MMP-13 and TIMP-1 via inhibition of the TGF-β1 signaling pathway, which enhances the degradation of extracellular matrix and accelerates the regression of hepatic cirrhosis in rats. [ABSTRACT FROM AUTHOR]

Sex difference is a risk factor for abdominal aortic aneurysm (AAA) formation yet the reason for male predominance remains unclear. Androgen and the androgen receptor (AR) influence the male sex difference, indicating that AR signaling may affect AAA development. Using angiotensin II–induced AAA in apolipoprotein E null mouse models (82.4% AAA incidence), we found that mice lacking AR failed to develop AAA and aorta had dramatically reduced macrophages infiltration and intact elastic fibers. These findings suggested that AR expression in endothelial cells, macrophages, or smooth muscle cells might play a role in AAA development. Selective knockout of AR in each of these cell types further demonstrated that mice lacking AR in macrophages (20% AAA incidence) or smooth muscle cells (12.5% AAA incidence) but not in endothelial cells (71.4% AAA incidence) had suppressed AAA development. Mechanism dissection showed that AR functioned through modulation of interleukin-1α (IL-1α) and transforming growth factor-β1 signals and by targeting AR with the AR degradation enhancer ASC-J9 led to significant suppression of AAA development. These results demonstrate the underlying mechanism by which AR influences AAA development is through IL-1α and transforming growth factor-β1, and provides a potential new therapy to suppress/prevent AAA by targeting AR with ASC-J9. [ABSTRACT FROM AUTHOR]

A chronic inflammatory condition may underlie neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). For example, both PD and AD patients show an increase in transforming growth factor-β1 (TGF-β1) levels in their cerebrospinal fluid (CSF). TGF-β1 is a cytokine that inhibits inflammation. In the present study, using an enzyme-linked immunosorbent assay, we tested the hypothesis that the level of TGF-β1 in the CSF of patients with amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD), or multiple system atrophy-cerebellar subtype (MSA-C) would be elevated compared with that of normal controls. We found that TGF-β1 levels in the CSF were not significantly different between these patients and normal controls. Our data suggest that the level of TGF-β1 in the CSF is an unreliable biomarker of ALS, SCD, and MSA-C. [ABSTRACT FROM AUTHOR]

Background and aims: The objective of this study is to observe the effect of alpha-lipoic acid (ALA) on Pod injury by anti-inflammation and explore its possible renal protective mechanism. Methods: A total of 36 cases with type 2 diabetes with microalbuminuria and fasting plasma glucose (FPG) levels less than 9 mmol/L and glycated hemoglobin A1c (HbA1c) ≤9.0 % were recruited to be treated with ALA (600 mg, daily) for 6 months (group DA). Another 30 healthy individuals were chosen as normal controls (group NC). The levels of serum creatinine (Cr), FPG, and HbA1c were detected; blood pressure was recorded; and early morning urine samples (corrected for urinary Cr) were collected for the examination of urinary monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-β1 (TGF-β1), podocalyxin (PCX), nephrin, albumin and Cr in group NC and group DA at the baseline and the sixth month. Results: The excretions of urinary MCP-1, TGF-β1, PCX, nephrin and albumin to Cr ratio (abbreviated as UMCR, UTCR, UPCR, UNCR and UACR respectively) were significantly increased in group DA compared with group NC (all P < 0.01), and after 6-month treatment, all indexes mentioned above decreased markedly ( P < 0.05), while FPG and HbA1c had no obvious changes. Additionally, there was a positive correlation between UMCR, UTCR with UPCR, UNCR and UACR, respectively (all P < 0.01). Conclusions: Anti-inflammation of ALA in vivo and local kidney is implicated in the protection of glomerular Pod injury in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background and study aims The transforming growth factor (TGF)-β signalling pathway plays a dual role in hepatocarcinogenesis. It has been recognised for its role as a tumour suppressor as well as a tumour promoter depending on the cellular context. The aim of this study was to investigate the clinical significance of serum TGF-β1 level and TGF-β1 messenger RNA (mRNA) in the peripheral blood of liver cirrhosis and hepatocellular carcinoma (HCC) patients as noninvasive biomarkers in diagnosing HCC. Patients and methods Twenty patients were allocated to each of the liver cirrhosis and HCC groups, in addition to 20 healthy volunteers. TGF-β1 gene expression in peripheral blood was quantitated using real-time polymerase chain reaction (PCR), while serum TGF-β1 was analysed using enzyme-linked immunosorbent assay (ELISA). Results TGF-β1 gene expression was significantly lower in HCC patients (median 0.401 (0.241–0.699) fold change) than in liver cirrhosis patients (median 0.595 (0.464–0.816)) ( p = 0.042) and normal controls (median 1.00 (0.706–1.426) fold change) ( p = 0.001). TGF-β1 gene expression showed significant positive correlation with serum TGF-β1 ( r = 0.272, p = 0.036) and significant negative correlation with alpha-fetoprotein (AFP) ( r = −0.528, p = 0.001). Receiver operating characteristic (ROC) analysis was conducted for TGF-β1 gene expression in comparison with AFP. The area under the curve for TGF-β1 gene expression was 0.688 (95% CI = 0.517–0.858) ( p = 0.042) and AFP was 0.869 (95% CI = 0.761–0.976) ( p = 0.001). The sensitivity and specificity of TGF-β1 gene expression were 65% and 75%, respectively, at a cutoff value of 0.462 fold change. Conclusion TGF-β1 gene expression in the peripheral blood may be used as a molecular marker for the diagnosis of HCC. Additional studies on a large-scale population are necessary to gain greater insight into the impact of TGF-β1 gene expression in the pathogenesis of HCC. [ABSTRACT FROM AUTHOR]

PURPOSE: To examine and compare the expression of transforming growth factor-β1 (TGF-β1) in rat dental pulp after direct pulp capping with calcium hydroxide (CH)and mineral trioxide aggregate (MTA). METHODS: The model of direct dental pulp capping after first molars was established in 28 female Wistar rats with CH and MTA. The rats were sacrificed 1, 3, 5, 7, 14,21 and 28 days after direct pulp capping. TGF-β1 expression in pulp tissues were measured with immunohistochemical staining. The data was analyzed by Dunnett t test and paired t test with SPSS 13.0 software package. RESULTS: The results showed that no TGF-β1 expression was detected in the control group. After direct pulp capping with MTA, TGF-β1 expression gradually increased and reached peak expression on 5 day. TGF-β1 expression gradually decreased afterwards and reached normal on 21 day after direct pulp. TGF-β1 was mainly expressed in neutrophils, odontoblasts cells, vascular endothelial cells and fibroblasts. The expression of TGF-β1 was significantly different between 2 capping agents 1, 3, 5, 7, 14 days after direct pulp capping (P<0.05). CONCLUSIONS: The results suggest that TGF-β1 expression increases at first and then decreases after direct pulp capping. The type of capping agents has an impact on the expression of TGF-β1 after direct pulp capping. MTA enhances more TGFβ-1 expression than CH 1, 3, 5, 7 and 14 days after direct pulp capping. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved homoeostatic mechanism for cell survival under conditions of stress, and is widely implicated as an important pathway in many biological processes and diseases. In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. A recently emerging body of evidence from studies in renal cells in culture and experimental animal models suggests that TGF-β1 regulates autophagy and that autophagy regulates many critical aspects of normal and disease conditions associated with kidney fibrosis, such as tubulointerstitial fibrosis, glomerulosclerosis, and diabetic nephropathy. Here, we review the recent advances exploring the process of autophagy, its regulation by TGF-β1, and the implication in the pathogenesis of progressive kidney fibrosis and injury responses. Understanding the cellular and molecular bases of this process is crucial for identifying potential new diagnostic and therapeutic targets of kidney fibrosis. [ABSTRACT FROM AUTHOR]

Summary: Autophagy is a highly conserved homoeostatic mechanism for cell survival under conditions of stress, and is widely implicated as an important pathway in many biological processes and diseases. In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. A recently emerging body of evidence from studies in renal cells in culture and experimental animal models suggests that TGF-β1 regulates autophagy and that autophagy regulates many critical aspects of normal and disease conditions associated with kidney fibrosis, such as tubulointerstitial fibrosis, glomerulosclerosis, and diabetic nephropathy. Here, we review the recent advances exploring the process of autophagy, its regulation by TGF-β1, and the implication in the pathogenesis of progressive kidney fibrosis and injury responses. Understanding the cellular and molecular bases of this process is crucial for identifying potential new diagnostic and therapeutic targets of kidney fibrosis. [Copyright &y& Elsevier]

• Equine platelet lysate enhanced cell activity and muscle tissue regeneration. • PL upregulated expression of genes associated with skeletal muscle regeneration. • PL promoted morphological muscle regeneration 6 days after treatment. • This occurred despite decreased PL-related growth factor levels in the tissue. This study aimed to verify the effects of platelet lysate (PL) administration on the repair of injured horse tissue. Skeletal muscle injuries were induced in 26 Thoroughbreds by bupivacaine administration. PL or saline was administered 1 day (1D) after injury. Muscle samples from 22 horses injected with PL or saline were obtained by needle biopsy at 2, 3, 4, or 7 days (2D, 3D, 4D, or 7D, respectively) after injury, and growth-factor concentrations and muscle regeneration-associated gene expression levels were determined. Intact samples were similarly collected before injury, and samples of injured muscle not treated with PL or saline (sham samples) were also obtained at 1D, 2D, 3D, 4D, and 7D as references for comparison. Samples from the remaining 4 horses were obtained by surgical incision following euthanasia at 5 days (5D) and 7D after injury, followed by histological analysis. Although increased growth factor levels caused by PL administration were observed for up to 1-day post-administration (2D), gene expressions were enhanced for up to 6 days post-administration (7D). Moreover, the number of embryonic myosin heavy chain (MHC-e)-positive myofibrils at 5D was higher in the PL-treated group than in the saline-treated group, whereas no significant between-group difference in the number of myofibrils was recorded at 7D. Thus, PL administration in muscle injury upregulated the expression of various genes associated with muscle regeneration and promoted morphological regeneration within 6 days of treatment, although growth factor levels from PL decreased at the injected site by approximately 2 days post-administration. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have reported that the intrathecal (i.t.) administration of transforming growth factor β1 (TGF-β1) prevents and reverses neuropathic pain. However, only limited information is available regarding the possible role and effects of spinal TGF-β1 in neuropathic pain. We aimed to investigate the antinociceptive effects of exogenous TGF-β1 on chronic constriction injury (CCI)-induced neuropathic pain in rats. We demonstrated that sciatic nerve injury caused a downregulation of endogenous TGF-β1 levels on the ipsilateral side of the lumbar spinal dorsal gray matter, and that the i.t. administration of TGF-β1 (.01–10 ng) significantly attenuated CCI-induced thermal hyperalgesia in neuropathic rats. TGF-β1 significantly inhibited CCI-induced spinal neuroinflammation, microglial and astrocytic activation, and upregulation of tumor necrosis factor-α. Moreover, i.t. TGF-β1 significantly attenuated the CCI-induced downregulation of glutamate transporter 1, the glutamate aspartate transporter, and the excitatory amino acid carrier 1 on the ipsilateral side. Furthermore, i.t. TGF-β1 significantly decreased the concentrations of 2 excitatory amino acids, aspartate and glutamate, in the spinal dialysates in CCI rats. In summary, we conclude that the mechanisms of the antinociceptive effects of i.t. TGF-β1 in neuropathy may include attenuation of spinal neuroinflammation, attenuation, or upregulation of glutamate transporter downregulation, and a decrease of spinal extracellular excitatory amino acids. Perspective: Clinically, medical treatment is usually initiated after the onset of intractable pain. Therefore, in the present study, i.t. TGF-β1 was designed to be administered 2 weeks after the establishment of CCI pain. Compared to the continuous TGF-β1 infusion mode, single-dose administration seems more convenient and practical to use. [Copyright &y& Elsevier]

OBJECTIVES: KL-6 is a pulmonary epithelial-derived mucin which is secreted mainly by type II alveolar epithelial cells. The level of KL-6 in serum is closely correlated to the clinical activity of various interstitial lung diseases (ILD) and acts as a prognostic factor for ILD patients. Previous studies have showed that KL-6 promoted chemotaxis, proliferation and inhibited the apoptosis of human lung fibroblasts. However, the underlying mechanism remains unknown. In this study, we investigated the function of KL-6 on the expression of hepatocyte growth factor (HGF), transforming growth factor-β1 (TGF-β1), collagen and α-smooth muscle actin(α-SMA) in human embryonic lung fibroblasts cell line MRC-5. METHODS: Human embryonic lung fibroblasts were cultured in Eagle's minimum essential medium. The cells plated in 6-well plates was cultured in serum-free medium at 37°C in 5% CO2 and challenged with recombinant KL-6 at a final concentration of 0, 10, 20, 40 ng/mL. Five micrograms of total RNA template were transcripted to cDNA by using AMV (Avian Myeloblastosis Virus) reverse transcriptase and random 9 mers as the first-strand primer. Synthesized cDNA was used in PCR experiments. The expression of TGF-â1 and HGF in cell culture supernatants was measured using ELISA kit. Cells incubated with KL-6 for 72h were collected for flow-cytometry analysis. The analysis was done using a Beckman counter device. RESULTS: It was found that KL-6 up-regulated the expression of collagen type I and III in a dose-dependent manner. However, the addition of KL-6 significantly inhibited the production of HGF. As regard to the biological function, KL-6 induced myofibroblast differentiation confirmed by the elevated expression of a-SMA. CONCLUSIONS: KL-6 is one of the key molecules involved in epithelial-mesenchymal interactions and might contribute to the fibrosis in ILD. [ABSTRACT FROM AUTHOR]

Background/Purpose: MicroRNA-208a (miR208a) and mechanical stress play a key role in cardiac hypertrophy. The relationship between miR208a and mechanical stress in cultured cardiomyocytes has not been investigated. The molecular mechanisms underlying miR208a-induced hypertrophy of cardiomyocytes by mechanical stress is poorly understood. This study investigated whether miR208a is a critical regulator in cardiomyocyte hypertrophy under mechanical stretch. Methods: Neonatal rat cardiomyocytes grown on a flexible membrane base were stretched at 60 cycles/minute. MiR real-time quantitative assays were used to quantify miRs. A quantitative sandwich enzyme immunoassay technique was used to measure transforming growth factor-β1 (TGF-β1). A 3H-proline incorporation assay was used to measure protein synthesis. Results: Mechanical stretch significantly enhanced miR208a expression. Stretch significantly induced cardiomyocyte hypertrophic protein expression such as β-myosin heavy chain (MHCβ), thyroid hormone receptor-associated protein 100, myostatin, connexin 40, GATA4, and brain natriuretic peptide. MHCα was not induced by stretch. Overexpression of miR208a significantly increased MHCβ protein expression while pretreatment with antagomir208a significantly attenuated MHCβ protein expression induced by stretch and overexpression of miR208a. Mechanical stretch significantly increased the secretion of TGF-β1 from cultured cardiomyocytes. Exogenous addition of TGF-β1 recombinant protein significantly increased miR208a expression and pretreatment with TGF-β1 antibody attenuated miR208a expression induced by stretch. Mechanical stretch and overexpression of miR208a increased protein synthesis while antagomir208a attenuated protein synthesis induced by stretch and overexpression of miR208a. Conclusion: Cyclic stretch enhances miR208a expression in cultured rat cardiomyocytes. MiR208a plays a role in stretch-induced cardiac hypertrophy. The stretch-induced miR208a is mediated by TGF-β1. [ABSTRACT FROM AUTHOR]

Abstract: Implants that serve simultaneously as an osteoconductive matrix and as a device for local growth factor delivery may be required for optimal bone regeneration in some applications. In the present study, hollow hydroxyapatite (HA) microspheres (106–150μm) in the form of three-dimensional (3-D) scaffolds or individual (loose) microspheres were created using a glass conversion process. The capacity of the implants, with or without transforming growth factor β1 (TGF-β1), to regenerate bone in a rat calvarial defect model was compared. The 3-D scaffolds supported the proliferation and alkaline phosphatase activity of osteogenic MLO-A5 cells in vitro, showing their cytocompatibility. Release of TGF-β1 from the 3-D scaffolds into phosphate-buffered saline ceased after 2–3days when ∼30% of the growth factor was released. Bone regeneration in the 3-D scaffolds and the individual microspheres increased with time from 6 to 12weeks, but it was significantly higher (23%) in the individual microspheres than in the 3-D scaffolds (15%) after 12weeks. Loading with TGF-β1 (5μg per defect) enhanced bone regeneration in the 3-D scaffolds and individual microspheres after 6weeks, but had little effect after 12weeks. 3-D scaffolds and individual microspheres with larger HA diameter (150–250μm) showed better ability to regenerate bone. Based on these results, implants composed of hollow HA microspheres show promising potential as an osteoconductive matrix for local growth factor delivery in bone regeneration. [Copyright &y& Elsevier]

Abstract: It has been recently shown that dysregulation of transforming growth factor-β1 (TGF-β1), IL-23 and IL-17 has been identified as a major factor involved in autoimmune disorders. Based on the increasing evidence of immune dysfunction in autism the aim of this study was to measure serum levels of TGF-β 1, IL-23 and IL-17 in relation to the degree of the severity of autism. Serum TGF-β1, IL-23 and IL-17 were measured by Enzyme-linked Immunosorbent Assay technique in 50 autistic children aged 6–12 years, in comparison to 50 developmental disabilities and 50 typically developing-matched children. The severity of autism was assessed by using the Childhood Autism Rating Scale. We found that TGF-β1 and IL-23 levels were significantly decreased in the plasma of children with ASD in comparison to control groups (P <0.0001 for both) with no significant difference in IL-17 levels. There was no correlation between IL-23 and TGF-β1 with IL-17 in children with ASD. There was a negative correlation between TGF-β1, IL-23 and IL-17 with the severity of autism (P <0.0001, 0.0001, 0.005 respectively). Our results support the findings that immune dysfunction may occur in some children with autism. [Copyright &y& Elsevier]

Background: Atrial fibrosis plays a role in the development of a vulnerable substrate for atrial fibrillation (AF). Transforming growth factor (TGF)-β1 is related to the degree of atrial fibrosis and the recurrence of AF after surgical maze procedures. Whether TGF-β1 is associated with the outcome after catheter ablation for AF remains unclear. Objective: The purpose of this study was to investigate whether plasma TGF-β1 was an independent predictor of AF recurrence after catheter ablation. Methods: Two hundred consecutive AF patients (154 with paroxysmal AF and 46 with nonparoxysmal AF) underwent catheter ablation. Their TGF-β1 levels and clinical and echocardiographic data were collected before ablation. Results: Thirty patients (65%) with nonparoxysmal AF and 57 (37%) with paroxysmal AF had AF recurrence after catheter ablation. Among patients with nonparoxysmal AF, those experiencing recurrence had higher TGF-β1 levels than did those who did not experience recurrence (34.63±11.98 ng/mL vs 27.33±9.81 ng/mL; P = .026). In patients with paroxysmal AF, recurrence was not associated with different TGF-β1 levels. In patients with nonparoxysmal AF, TGF-β1 levels and left atrial diameter (LAD) were independent predictors of AF recurrence after catheter ablation. Moreover, TGF-β1 levels had an incremental value over LAD in predicting AF recurrence after catheter ablation (global χ2 of LAD alone: 6.3; LAD and TGF-β1 levels: 11.9; increment in global χ2 = 5.6; P = .013). Patients with small LAD and low TGF-β1 levels had the lowest AF recurrence rate at 11%. Conclusion: TGF-β1 level is an independent predictor of AF recurrence in patients with nonparoxysmal AF and might be useful for identifying those patients likely to have better outcomes after catheter ablation. [Copyright &y& Elsevier]

The article explores the impact of inhibition of extracellular matrix metalloproteinases activation in decelerating age-associated arterial proinflammation and increase in arterial pressure. The authors disclosed that based on their study, increased arterial pressure comes with inhibition of age-associated increases in aortic gelatinase and inhibition of proendothelin 1 activation. They conclude that matrix metalloproteinases reduces age-associated arterial proinflammatory signaling.

Summary: In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. Emerging evidence shows a complex scheme of signaling networks that enable multifunctionality of TGF-β1 actions. Specific targeting of the TGF-β signaling pathway is seemingly critical and an attractive molecular therapeutic strategy. TGF-β1 signals through the interaction of type I and type II receptors to activate distinct intracellular pathways involving the Smad and the non-Smad. The Smad signaling axis is known as the canonical pathway induced by TGF-β1. Importantly, recent investigations have shown that TGF-β1 also induces various non-Smad signaling pathways. In this review, we focus on current insights into the mechanism and function of the Smad-independent signaling pathway via TGF-β–activated kinase 1 and its role in mediating the profibrotic effects of TGF-β1. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To explore the Intervention effect of Rosiglitozone in ovarian fibrosis of PCOS rats. Methods: 60 female SD rats were randomly divided into 3 groups: control group, model group and treatment group. The model and treatment groups were established by subcutaneous injection of DHEA, while the treatment group was given RGZ. The serum hormone values, pathohistology of ovarian structure of rats, ovarian ultrastructure and the expressions of TGF-β1 and CTGF were detected. Results: The PCOS model was established successfully. The expression intensity of TGF-β1 and CTGF in Oocytes of the PCOS groups was 9.545±2.954 and 9.665±2.400, respectively and was significantly higher than that of the control group 6.636±2.264 and 7.036±2.133; after treatment with rosiglitazone, the expression was significantly decreased 6.980±2.421 and 6.642±2.721 as compared with that of the model group (P<0.05, P<0.001). The values in serum of the PCOS groups were 3.749±2.054 and 0.265±0.129, and 1.914±1.801 and 0.096±0.088 in the control group which had statistically significant difference (P<0.05, P<0.001). After treatment with rosiglitazone, the values were 2.3100±1.825 and 0.112±0.187 and were significantly different with those of the model group (P<0.05, P<0.001). Conclusion: TGF-β1 and CTGF play an important role in the development of ovary fibrosis in PCOS. However, RGZ may postpone the development of fibrosis by decreasing the levels of TGF-β1 and CTGF. [Copyright &y& Elsevier]

The matricellular protein thrombospondin (TSP) 1 is induced after tissue injury and may regulate reparative responses by activating transforming growth factor-β, by suppressing angiogenesis and by modulating inflammation and matrix metabolism. We hypothesized that endogenous TSP-1 may be involved in the pathogenesis of cardiac remodeling in the pressure-overloaded heart. Myocardial TSP-1 expression was increased in a mouse model of pressure overload because of transverse aortic constriction. TSP-1(-/-) mice exhibited increased early hypertrophy and enhanced late dilation in response to pressure overload. Pressure-overloaded TSP-1 null mice had intense degenerative cardiomyocyte changes, exhibiting more extensive sarcomeric loss and sarcolemmal disruption when compared with wild-type hearts. Accentuated hypertrophy and cardiomyocyte injury in TSP-1(-/-) hearts was accompanied by increased myofibroblast density. However, despite a 2-fold higher infiltration of the cardiac interstitium with myofibroblasts, pressure-overloaded TSP-1 null hearts did not exhibit significantly increased collagen content when compared with wild-type hearts. The disproportionately low collagen content in TSP-1 null hearts was attributed to infiltration with abundant, but functionally defective, fibroblasts that exhibited impaired myofibroblast differentiation and reduced collagen expression in comparison with wild-type fibroblasts. Impaired myofibroblast activation in TSP-1 null hearts was associated with reduced Smad2 phosphorylation reflecting defective transforming growth factor-β signaling. Moreover, TSP-1 null hearts had increased myocardial matrix metalloproteinase 3 expression and enhanced matrix metalloproteinase 9 activation after pressure overload. TSP-1 upregulation in the pressure-overloaded heart critically regulates fibroblast phenotype and matrix remodeling by activating transforming growth factor-β signaling and by promoting matrix preservation, thus preventing chamber dilation. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor-β1 (TGF-β1), its downstream signaling mediators (Smad proteins), and specific targets, including connective tissue growth factor (CTGF), play important roles in tissue remodeling and fibrosis via myofibroblast activation. We investigated the effect of overexpression of Smad7, a TGF-β1 signaling inhibitor, on transition of gingival fibroblast to myofibroblast. Moreover, we analyzed the participation of CTGF on TGF-β1-mediated myofibroblast transformation. Methods: To study the inhibitory effect of Smad7 on TGF-β1/CTGF-mediating gingival fibroblast transition into myofibroblasts, we stably overexpressed Smad7 in normal gingival fibroblasts and in myofibroblasts from hereditary gingival fibromatosis (HGF). Myofibroblasts were characterized by the expression of the specific marker isoform α of the smooth muscle actin (α-SMA) by Western blot, flow cytometry, and immunofluorescence. Enzyme-linked immunosorbent assay for type I collagen was performed to measure myofibroblast activity. CTGF's role on myofibroblast transformation was examined by enzyme-linked immunosorbent assay and small interference RNA. Results: TGF-β1 induced the expression of α-SMA and CTGF, and small interference RNA-mediating CTGF silencing prevented fibroblast-myofibroblast switch induced by TGF-β1. In Smad7-overexpressing fibroblasts, ablation of TGF-β1-induced Smad2 phosphorylation marked decreased α-SMA, CTGF, and type I collagen expression. Similarly, HGF transfectants overexpressing Smad7 demonstrated low levels of α-SMA and phospho-Smad2 and significant reduction on CTGF and type I collagen production. Conclusions: CTGF is critical for TGF-β1-induced gingival fibroblast-myofibroblast transition, and Smad7 overexpression is effective in the blockage of myofibroblast transformation and activation, suggesting that treatments targeting myofibroblasts by Smad7 overexpression may be clinically effective in gingival fibrotic diseases, such as HGF. [ABSTRACT FROM AUTHOR]

Summary: Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists are increasingly used in patients with diabetes, and some studies have suggested a beneficial effect on organ fibrosis, but their effects on dermal cell growth and extracellular matrix (ECM) turnover are unknown. To investigate the effect of the PPAR-γ agonist troglitazone on cell growth and matrix production in human dermal fibroblasts (HDF), HDF were cultured and grown in a different concentration of troglitazone. PPAR-γ expression and matrix production were measured in HDF in the presence of troglitazone. The mRNA expressions of TGF-β1, collagen I (Col I) and fibronectin (FN) were determined by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). The protein of transforming growth factor-β1 (TGF-β1) was determined by enzyme-linked immunosorbent assay (ELISA) and proteins of Col I and FN were determined by Western blotting. The mRNA expression of TGF-β1, Col I and FN were significantly decreased in HDF in 15–30μmoll−1 troglitazone compared to the control group with Dulbecco''s modified Eagle''s medium (P <0.01). An obvious decrease of TGF-β1 protein was found in troglitazone-treated groups as compared to the control group (P <0.05). Exposure of HDF to troglitazone reduced col I secretion (P <0.05), and fibronectin secretion (P <0.05). This study suggests that PPAR-γ agonist will provide a novel approach with therapeutic potential in dermal fibrosis, such as hypertrophic scar, keloid and so on. [Copyright &y& Elsevier]

Abstract: This study was carried out to investigate whether rosmarinic acid (RA) has antifibrotic effect on experimental liver fibrosis in vitro and in vivo and its possible mechanism. Culture of hepatic stellate cells (HSCs) determine proliferation and expression of transforming growth factor-β1 (TGF-β1), connective transforming growth factor (CTGF) and α-smooth muscle actin (α-SMA). In carbon tetrachloride (CCL4)-induced rat liver fibrosis model, determined biochemical indicator, liver fibrosis grade and histopathological changes, immunohistochemical detected liver TGF-β1 and CTGF expression. The results indicated that RA could inhibit HSCs proliferation, inhibit TGF-β1, CTGF and α-SMA expression in cultured HSCs. It has marked evident in reducing fibrosis grade, ameliorating biochemical indicator and histopathological morphology, reducing liver TGF-β1 and CTGF expression in CCL4-induced liver fibrosis. These findings suggest that RA has potentially conferring antifibrogenic effects. [Copyright &y& Elsevier]

Abstract: Elastin breakdown in vascular aneurysms is mediated by cytokines such as tumor necrosis factor α (TNF-α, which induces vascular smooth muscle cell (SMC) activation and regulates their deposition of matrix. We previously demonstrated that exogenous supplementation with TGF-β1 (1ngml−1) and hyaluronan oligomers (0.786kDa, 0.2μgml−1) cues the upregulation of elastin matrix synthesis by healthy cultured SMCs. Here, we determine whether these cues likewise enhance elastin matrix synthesis and assembly by TNF-α-stimulated SMCs, while restoring their healthy phenotype. Adult rat aortic SMCs were treated with TNF-α alone or together with TGF-β1/hyaluronan oligomeric cues and the release of inflammatory markers were monitored during over a 21day culture. Biochemical analysis was used to quantify cell proliferation, matrix protein synthesis and cross-linking efficiency, while immunofluorescence and electron microscopy were used to analyze the elastin matrix quality. It was observed that SMC activation with TNF-α (10ngml−1) induced matrix calcification and promoted production of elastolytic MMP-2 and MMP-9. However, these effects were attenuated by the addition of TGF-β1 and HA oligomer cues to TNF-α-stimulated cultures, which also enhanced tropoelastin and collagen production, improved elastin matrix yield and cross-linking, promoted elastin fiber formation and suppressed elastase activity, although the release of MMP-2 and MMP-9 was not affected. Overall, the results suggest that TGF-β1 and HA oligomers are potentially useful in suppressing SMC activation and inducing regenerative elastin repair within aneurysms. [Copyright &y& Elsevier]

In this study, we investigated the effect of TGF-β1 on cholesterol synthesis in human keratinocytes. TGF-β1 increased the level of cholesterol and the mRNA level of3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)reductasein human keratinocytes. These results show that TGF-β1 induces cholesterol synthesis by increasingHMG-CoA reductasemRNA expression in human keratinocytes. [ABSTRACT FROM AUTHOR]

Objective To study the association of CT perfusion imaging parameters with plasma level of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth (VEGF) in patients with non small cell lung cancer (NSCLC). Methods A total of 67 patients with NSCLC (NSCLC group) and 64 patients with benign lesion (control group) were given with CT perfusion imaging to obtain blood flow, blood volume, mean transit time, time to peal and permeability surface through CT perfusion software. The plasma levels of TGF-β1 and VEGF were tested by ELISA. The relationship between plasma levels of TGF-β1, VEGF and CT perfusion imaging parameters were analyzed. Results CT perfusion imaging parameters and the plasma levels of TGF-β1 and VEGF of NSCLC group were significantly higher than the control group ( P < 0.05), while CT perfusion parameters and the levels of TGF-β1 and VEGF in NSCLC group showed significant difference in different tumor node metastasis stages ( P < 0.05). Correlation analysis showed that the level of plasma TGF-β1 and VEGF were positively correlated with blood flow, blood volume, and mean transit time ( P < 0.05), and negatively correlated with time to peal ( P < 0.05). There was no significant correlation between TGF-β1 and VEGF with the permeability surface. Conclusions CT perfusion imaging parameters in patients with NSCLC is closely associated with plasma TGF-β1, VEGF and its biological characteristics. CT perfusion imaging is a convenient method to detect tumor blood perfusion. [ABSTRACT FROM AUTHOR]

The article analyzes the impact of peroxisome proliferator-activated receptor (PPAR) on the extracellular matrix synthesis and degradation. Results of clinical analysis show that PPAR regulates the extracellular matrix synthesis and degradation by transforming growth factor β1 and its reflector SMad3. Moreover, investigations also prove its significant role in the proper function of the heart.

Summary: Background: Transforming growth factor-β1 (TGF-β1), a multifunctional cytokine, has been implicated to be responsible for the increased deposition of extracellular matrix in the airways, and increased submucosal collagen expression in chronic obstructive pulmonary disease (COPD). We determined plasma TGF-β1 levels in patients with COPD and explored its association with common functional polymorphisms of TGF-β1 gene at C-509T and T869C in the development of COPD in a case–control study. Methods: Stable COPD patients who were ever smokers, and age and pack-years smoked matched healthy controls (n = 205 in each group) were recruited for measurement of plasma TGF-β1 levels using commercially available ELISA kit, and genotyped at C-509T and T869C functional polymorphisms of TGF-β1 gene using polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP). Results: COPD patients had significantly elevated plasma TGF-β1 levels in comparison to healthy controls irrespective of the genotypes. Allele frequencies and genotype distributions at both polymorphic sites were not different among COPD patients or controls. TGF-β1 levels were inversely correlated (Pearson''s correlation analysis) with FEV1 (% predicted) (p < 0.001) and FVC (% predicted) (p < 0.001). Conclusion: The findings of elevated plasma TGF-β1 levels in patients with COPD suggest that TGF-β1 may play a role in COPD pathogenesis. The C-509T and T869C functional polymorphisms of TGF-β1 gene do not represent a genetic predisposition to COPD susceptibility in Hong Kong Chinese patients. [Copyright &y& Elsevier]

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[Display omitted] • Cranberry and cinnamonaldehyde enhance pioglitazone treatment of NAFLD. • HIF-1α/TGF-β1/Smad/β-catenin signaling underlies the pioglitazone action. • Cranberry and Cinnamaldehyde boost biochemical and molecular gains of pioglitazone. The involvement of hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β1 (TGF-β1), Smad and β-catenin signaling pathway in non-alcoholic fatty liver disease (NAFLD) is not fully elucidated. Pioglitazone improves NAFLD, whereas the underlying molecular mechanisms are not extensively clarified. In addition, cranberry and cinnamon have received increasing attention as potential therapeutic agents in metabolic disorders. Hence, this study aimed to test the hypothesis that the downregulation of HIF-1α/TGF-β1/Smad/β-catenin signaling might underlie the pioglitazone effect in HFD-induced liver steatosis in rats. In addition, the study aimed to determine whether the concurrent use of cranberry and/or cinnamaldehyde would boost biochemical and molecular gains of pioglitazone while limiting its significant side effect; weight gain. Rats were kept on a high-fat diet for 14 weeks, and HFD rats were orally treated with pioglitazone, cranberry, or their combinations for 8 weeks. Pioglitazone, cranberry, and to a lesser extent cinnamaldehyde significantly ameliorated the pathological lesions, improved the hepatic histological structure of cinnamaldehyde, and successfully rectified liver index, AST, ALT, lipid profile, hepatic triglycerides, and HOMA-IR. They also inhibited HIF-1α, β-catenin, TGF-β1 and subsequently inhibited phosphorylated/total Smad2/3 and their ratios. In conclusion, the beneficial effects of this combination in HFD-induced hepatic steatosis might be attributed to the modulation of hypoxia/HIF-1α, TGF-β1/Smads, and Wnt/β-catenin pathways in the liver. Thus, cranberry and cinnamon might be potential add-on agents to other pharmacotherapies in liver steatosis. [ABSTRACT FROM AUTHOR]