Plasma Transforming Growth Factor-β1 Research Articles

Acrylamide exposure increases cardiovascular risk of general adult population probably by inducing oxidative stress, inflammation, and TGF-β1: A prospective cohort study.

Acrylamide (ACR) exposure and consequent health hazards are alarming public health issues that attract worldwide concern. The World Health Organization urges more researches into health hazards from ACR exposure. However, whether and how ACR exposure increases cardiovascular risk remain unclear, and we sought to address these issues in this prospective cohort study conducted on 3024 general adults with 3-year follow-up (N=871 at follow-up). Individual urinary ACR metabolites (N-Acetyl-S-(2-carbamoylethyl)-L-cysteine [AAMA] and N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine [GAMA]) as credible biomarkers of ACR exposure were detected to assess their cross-sectional and longitudinal relationships with 10-year cardiovascular disease (CVD) risk, a well measure of overall cardiovascular risk. Besides, biomarkers of oxidative stress (urinary 8-hydroxy-deoxyguanosine [8-OHdG] and 8-iso-prostaglandin-F2α [8-iso-PGF2α]) and inflammation (circulating mean platelet volume [MPV] and plasma C-reactive protein [CRP]) as well as plasma transforming growth factor-β1 (TGF-β1) were measured to assess their mediating/mechanistic roles in the relationships of ACR metabolites with 10-year CVD risk. We found AAMA, GAMA, and ΣUAAM (AAMA+GAMA) were cross-sectionally and longitudinally related to increased 10-year CVD risk with odds ratios (95% confidence intervals [CIs]) of 1.32 (1.04, 1.70), 1.81 (1.36, 2.40), and 1.40 (1.07, 1.82), respectively, and risk ratios (95% CIs) of 1.99 (1.10, 3.60), 2.48 (1.27, 4.86), and 2.13 (1.15, 3.94), respectively. Furthermore, 8-OHdG, 8-iso-PGF2α, MPV, CRP, and TGF-β1 were found to significantly mediate 8.06-48.92% of the ACR metabolites-associated 10-year CVD risk increment. In summary, daily ACR exposure of general adults was cross-sectionally and longitudinally associated with increased cardiovascular risk, which was partly mediated by oxidative stress, inflammation, and TGF-β1, suggesting for the first time that ACR exposure may well increase cardiovascular risk of general adult population partly by mechanisms of inducing oxidative stress, inflammation, and TGF-β1. Our findings have important public health implications that provide potent epidemiological evidence and vital mechanistic insight into cardiovascular risk increment from ACR exposure.

TGF-β1 is associated with deficits in cognition and cerebral cortical thickness in first-episode schizophrenia.

Background:Evidence indicates that cytokines are associated with cognitive deficits in schizophrenia; however, the underlying brain–behaviour mechanisms remain unclear. We hypothesized that aberrations in brain structural connectivity mediate the cytokine effect in schizophrenia.Methods:In this study, we recruited patients with first-episode schizophrenia (n = 75, average illness duration 12.3 months, average medication period 0.6 days) and healthy controls (n = 44) of both sexes. We first conducted whole-blood RNA sequencing to detect differentially expressed genes. We also explored transcriptomic data on the dorsal lateral prefrontal cortices (dlPFC) retrieved from the CommonMind Consortium for gene functional clustering; we measured plasma transforming growth factor β1 (TGF-β1) levels by enzyme-linked immunosorbent assay; we acquired high-resolution T1-weighted MRI data on cortical thickness MRI; and we assessed cognitive function using the validated Chinese version of the MATRICS Consensus Cognitive Battery. We compared these parameters in patients with schizophrenia and controls, and analyzed their associations.Results:Patients with schizophrenia had higher TGF-β1 at both the mRNA level (log2 fold change = 0.24; adjusted p = 0.026) and the protein level (12.85 ± 6.01 μg/mL v. 8.46 ± 5.15 μg/mL, adjusted p < 0.001) compared to controls. Genes coexpressed with TGFB1 in the dlPFC were less abundant in patients with schizophrenia compared to healthy controls. In patients with schizophrenia, TGF-β1 protein levels were inversely correlated with cortical thickness, especially of the lateral occipital cortex (r = −0.47, adjusted p = 0.001), and with the MATRICS Consensus Cognitive Battery visual learning and memory domain (r = −0.50, adjusted p < 0.001). We found a complete mediation effect of the thickness of the lateral occipital cortex on the negative relationship between TGF-β1 and visual cognition (p < 0.05).Limitations:We did not explore the effect of other blood cytokines on neurocognitive performance and cortical thickness. Participants from the CommonMind Consortium did not all have first-episode schizophrenia and they were not all antipsychotic-naive, so we could not exclude an effect of antipsychotics on TGF-β1 signalling in the dlPFC. The sample size and cross-sectional design of our study were additional limitations.Conclusion:These findings highlighted an association between upregulated blood levels of TGF-β1 and impairments in brain structure and function in schizophrenia.

Hesperidin inhibits L-NAME-induced vascular and renal alterations in rats by suppressing the renin-angiotensin system, transforming growth factor-β1, and oxidative stress.

The protective effect of hesperidin on vascular and renal alterations and possible underlying mechanisms involved in Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats were investigated in this study. Male Sprague-Dawley rats were administered L-NAME (40mg/kg/day), L-NAME plus hesperidin (30mg/kg/day), and L-NAME plus captopril (2.5mg/kg/day) for 5weeks. Hesperidin and captopril significantly prevented L-NAME-induced hypertension, vascular and renal dysfunction, intrarenal artery remodelling, glomerular extracellular matrix accumulation, and renal fibrosis. The preventive treatment with hesperidin and captopril also significantly decreased serum angiotensin-converting enzyme activity and plasma transforming growth factor-β1 (TGF-β1) levels and downregulated angiotensin II receptor type I and TGF-β1 protein expression in the kidneys. In addition, decreased malondialdehyde levels and increased superoxide dismutase activity in the plasma and kidney were observed after co-treatment with hesperidin or captopril. These findings suggest that hesperidin inhibits L-NAME-induced vascular and renal alterations in rats. The possible mechanism may be related to the suppression of the activation of the renin-angiotensin system and expression of TGF-β1, and reduction of oxidative stress.

Comparison of rapamycin and methylprednisolone for treating inflammatory muscle disease in a murine model of experimental autoimmune myositis.

Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune inflammatory muscle diseases. Rapamycin has been shown to ameliorate inflammation and improve muscle function in a mouse model of experimental autoimmune myositis (EAM). In the present study, the therapeutic effect of rapamycin was compared with methylprednisolone (MP) on EAM. Mice were injected with myosin for 10 days to induce EAM and were subsequently treated with rapamycin (1.5 mg/kg), MP (40 mg/kg) or placebo (DMSO) for 14 days. The rapamycin-treated group exhibited significantly decreased severe inflammation and improved muscle strength compared with the MP-treated group. The plasma transforming growth factor-β (TGF-β) concentration in the rapamycin-treated group was significantly higher compared with the placebo group. However, both treatment groups exhibited significantly lower plasma interleukin-10 levels compared with the placebo group. Moreover, splenic regulatory T cell frequency in both the rapamycin- and MP-treated animals was significantly lower than that in the animals of the placebo group. Rapamycin showed better immune suppressive effects than MP in this model of EAM, and these effects were likely to be mediated by the TGF-β signaling pathway.

Exposure to acrylamide and reduced heart rate variability: The mediating role of transforming growth factor-β

The potential adverse health effects of acrylamide have drawn worldwide attention and the World Health Organization has urged further urgent studies on its health threat. Herein we explored the exposure-response relationship and underlying mechanism between internal acrylamide exposure and heart rate variability (HRV) alteration, a marker of cardiac autonomic dysfunction. We measured six HRV indices and two urinary acrylamide metabolites (N-Acetyl-S-(2-carbamoylethyl)-l-cysteine, AAMA; N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine, GAMA) for 2997 general Chinese adults from the Wuhan-Zhuhai cohort, of whom 2414 had data on plasma transforming growth factor-β1 (TGF-β1). The associations among urinary acrylamide metabolites, HRV and TGF-β1 were evaluated by linear mixed models and restricted cubic spline models. The mediating role of TGF-β1 was investigated by conducting mediation analysis. We found significantly negative dose-response relationships of all urinary acrylamide metabolites and TGF-β1 with all six HRV indices after adjusting for potential confounders (all P < 0.05). Urinary GAMA (β=0.074, P < 0.05) rather than AAMA (β=0.024, P > 0.05) was positively and dose-dependently associated with TGF-β1, which in turn significantly mediated 5.71–7.41 % of the GAMA-associated HRV reduction. Our findings suggest for the first time that daily exposure of general population to acrylamide is associated with cardiac autonomic dysfunction, where a mechanism involving TGF-β pathway may be involved.

Comparative study the levels of plasma transforming growth factor-β1, serum crp, fecal lactoferrin, and fecal calprotectin as biomarkers for disease activity in Egyptian patients with ulcerative colitis

Aim This study aimed to analyze the utility of transforming growth factor-β1 (TGF-β1), C-reactive protein (CRP), fecal lactoferrin (LF), fecal calprotectin, and the Mayo score for severity of ulcerative colitis (UC) in monitoring disease activity in Egyptian patients with UC. Patients and methods This study was carried out on 130 patients with UC and scored according to the Mayo score for severity of UC. Patients and controls were exposed to fecal and blood samples to assess TGF-β1, CRP, fecal LF, and fecal calprotectin. Results The values of TGF-β1, CRP, fecal LF, and fecal calprotectin in UC patients (n=130) compared with controls (n=30) were as follows: TGF-β1: 489.32±315.68 versus 5.93±1.81 pg/ml, CRP: 15.97±9.13 versus 3.17±0.95 mg/l, fecal LF: 497.06±448.95 versus 7.01±4.00 μg/g, fecal calprotectin: 809.70±554.36 versus 36.33±15.51 µg/g (for all P&lt;0.001). The parameters of Mayo Score that determine the severity of ulcerative colitis correlated significantly with TGF-β1 (Spearman's rank correlation coefficient r=0.925), CRP (r=0.957), LF (r=0.932), and calprotectin (r=0.953). TGF-β1, CRP, fecal LF, and calprotectin levels were significantly lower in UC patients with inactive disease (TGF-β1: 46.4±37.1 pg/ml; CRP: 4.8±1.3; LF: 28.6±28.3 μg/g; calprotectin: 71.7±24.2 µg/g; P&lt;0.001 for both LF and calprotectin, but P&gt;0.05 for both TGF-β1, and CRP) compared with patients with mild (TGF-β1: 343.4±110.7 pg/ml; CRP: 9.8±2.1; LF: 177.8±66.8 μg/g; calprotectin: 459.0±206.7 µg/g; P&lt;0.001), moderate (TGF-β1: 640.6±141.0 pg/ml; CRP: 18.6±3.5; LF: 561.0±181.9 μg/g; calprotectin: 1080.8±224.1 µg/g; P&lt;0.001), and high active disease (TGF-β1: 814.5±132.9 pg/ml; CRP: 27.1±3.0; LF: 1048.3±296.8 μg/g; and calprotectin: 1421.7±95.5 µg/g; P&lt;0.001). The overall accuracy for the detection of histopathologic active disease was 87.7% for TGF-β1, 89.2% for the Mayo score for severity of UC, 84.6% for CRP, 90% for fecal LF, and 91.5 for fecal calprotectin. Conclusion Fecal LF, fecal calprotectin and TGF-β1, and CRP correlated significantly with the Mayo score for UC and histopathology. Furthermore, calprotectin and LF are appropriate markers that can distinguish endoscopic and histopathologic inactive from active disease. Also, TGF-β1 and CRP were used as suitable markers to differentiate mild from moderate and the moderate from high active disease. Thus, these four biomarkers may be used for surveillance of UC activity.

Early intervention with faecal microbiota transplantation: an effective means to improve growth performance and the intestinal development of suckling piglets

Recent studies indicate that early postnatal period is a critical window for gut microbiota manipulation to optimise the immunity and body growth. This study investigated the effects of maternal faecal microbiota orally administered to neonatal piglets after birth on growth performance, selected microbial populations, intestinal permeability and the development of intestinal mucosal immune system. In total, 12 litters of crossbred newborn piglets were selected in this study. Litter size was standardised to 10 piglets. On day 1, 10 piglets in each litter were randomly allotted to the faecal microbiota transplantation (FMT) and control groups. Piglets in the FMT group were orally administrated with 2ml faecal suspension of their nursing sow per day from the age of 1 to 3 days; piglets in the control group were treated with the same dose of a placebo (0.1M potassium phosphate buffer containing 10% glycerol (vol/vol)) inoculant. The experiment lasted 21 days. On days 7, 14 and 21, plasma and faecal samples were collected for the analysis of growth-related hormones and cytokines in plasma and lipocalin-2, secretory immunoglobulin A (sIgA), selected microbiota and short-chain fatty acids (SCFAs) in faeces. Faecal microbiota transplantation increased the average daily gain of piglets during week 3 and the whole experiment period. Compared with the control group, the FMT group had increased concentrations of plasma growth hormone and IGF-1 on days 14 and 21. Faecal microbiota transplantation also reduced the incidence of diarrhoea during weeks 1 and 3 and plasma concentrations of zonulin, endotoxin and diamine oxidase activities in piglets on days 7 and 14. The populations of Lactobacillus spp. and Faecalibacterium prausnitzii and the concentrations of faecal and plasma acetate, butyrate and total SCFAs in FMT group were higher than those in the control group on day 21. Moreover, the FMT piglets have higher concentrations of plasma transforming growth factor-β and immunoglobulin G, and faecal sIgA than the control piglets on day 21. These findings indicate that early intervention with maternal faecal microbiota improves growth performance, decreases intestinal permeability, stimulates sIgA secretion, and modulates gut microbiota composition and metabolism in suckling piglets.

Carthamus Tinctorius L. extract attenuates cardiac remodeling in L-NAME-induced hypertensive rats by inhibiting the NADPH oxidase-mediated TGF-β1 and MMP-9 pathway

Carthamus tinctorius L. (CT) has been widely used in Asian countries as a beverage and a folk medicine. The current study investigates the effect of CT extract on cardiac remodeling and possible mechanisms involved in Nw-nitro-l-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were administrated with L-NAME (40mg/kg/day) for five weeks to induce hypertension. Hypertensive rats were treated with CT extract (300mg/kg/day) or captopril (5mg/kg/day) or vehicle for a further two weeks. Treatment of hypertensive rats with CT extract or captopril significantly decreased systolic blood pressure, left ventricular (LV) hypertrophy and fibrosis, small intramyocardial coronary artery remodeling, and cardiac weight index. CT extract or captopril increased plasma nitric oxide metabolite (NOx) levels and reduced plasma transforming growth factor β1 (TGF-β1) level, together with downregulation of cardiac TGF-β1 and matrix metalloproteinases-9 (MMP-9) expression. In addition, decreased plasma malondialdehyde (MDA) levels, consistent with downregulation of NADPH oxidase subunit gp91phox expression in heart tissue, was also observed after CT extract or captopril treatment. These findings suggest that CT extract alleviates cardiac remodeling in L-NAME-induced hypertensive rats, which is possibly related to inhibition of the NADPH oxidase-mediated TGF-β1-MMP-9 pathway.

Downregulation of lnRNA-NEF is involved in the postoperative cancer distant recurrence in prostate carcinoma patients.

LnRNA-NEF has characterized functionality only in liver cancer. In the present study, we observed that plasma lnRNA-NEF was downregulated, while plasma transforming growth factor-β1 (TGF-β1) was upregulated in patients with early-stage prostate carcinoma (PC) than in healthy controls. The levels of plasma lnRNA-NEF and plasma TGF-β1 were inversely correlated in patients with PC but not in healthy controls. After surgical resection, the follow-up was performed for 5 years. It was observed that lnRNA-NEF was further decreased in patients with distant recurrence (DR), but not in patients with local recurrence and nonrecurrence. lnRNA-NEF overexpression caused inhibited TGF-β1 expression in cells of PC cell lines, while TGF-β1 overexpression failed to affect lnRNA-NEF expression. LnRNA-NEF overexpression inhibited, while the TGF-β1 overexpression promoted the migration and invasion of cells of PC cell lines. TGF-β1 overexpression partially rescued the inhibited migration and invasion of cells of PC cell lines caused by thelnRNA-NEF overexpression. Therefore, the downregulation of lnRNA-NEF may contribute to the postoperative DR in patients with PC through the interactions with TGF-β1.

Elevated Plasma Transforming Growth Factor β1 Levels Predict the Development of Hypertension in Normotensives: The 14-Year Follow-Up Study.

Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine. There is growing evidence that TGF-β1 is involved in the pathogenesis of hypertension and the development of target organ damage in hypertensives. Although several studies have shown that TGF-β1 induced vascular hypertrophy and remodelling in various vascular diseases, there are no longitudinal data on hypertension in the epidemiological studies. The present study tested the hypothesis whether elevated TGF-β1 levels can predict the development of hypertension. In 2002-2004, 528 subjects received health examinations in Uku town, southwestern Japan. We examined blood pressure (BP), body mass index, and blood test. Data on fasting plasma TGF-β1 were obtained from 528 individuals. Of these, 149 normotensives (BP <140/90 mm Hg without antihypertensive medications) at baseline were followed-up for 14 years. The receiver-operating characteristic curve was used and the calculated cutoff value was 8.9 ng/ml. Of 149 normotensives at baseline, 59 subjects developed hypertension. Plasma TGF-β1 levels were significantly associated with the development of hypertension after adjustment for confounding factors. To further examine the association between them, we performed logistic regression analysis. We divided the baseline plasma TGF-β1 levels into 2 groups using a cutoff value. The significant high odds ratio [3.582 (95% confidence interval, 1.025-12.525)] for the development of hypertension was found in the highest group of TGF-β1 level vs. the lowest group after adjustment for confounders. This is the first report demonstrating the causal relationship between them. Elevated plasma TGF-β1 levels predicted the development of hypertension in normotensives in a population of community-dwelling Japanese.

Cardio-Ankle Vascular Index (CAVI) and Plasma Transforming Growth Factor-β1 (TGF-β1) Level Correlate with Aortopathy in Adults with Repaired Tetralogy of Fallot.

It is challenging to evaluate aortopathy in congenital heart disease using conventional investigations such as brachial-ankle pulse wave velocity (baPWV). Therefore, we evaluated the cardio-ankle vascular index (CAVI), a dimension of the ascending aorta and plasma transforming growth factor-β1 (TGF-β1) level, in order to find novel noninvasive parameters of aortopathy in adults with repaired tetralogy of Fallot (TOF). Prospectively, we enrolled 42 consecutive adults with TOF (28 patients with repaired TOF were not on ARB, 8 patients with repaired TOF on ARB, 6 patients with no repair or only palliative repair) and 20 age-matched healthy controls. We measured CAVI, baPWV, plasma TGF-β1 level and a diameter of the ascending aorta using echocardiography. The mean age of repaired TOF without ARB were 31.9±9.1years. An aortic diameter of the ascending aorta, CAVI, and plasma TGF-β1 level were significantly higher in repaired TOF without ARB than those in controls, whereas baPWV did not differ. On a univariate analysis, CAVI, plasma TGF-β1 level and Rastelli procedure were important factors for an aortic diameter of the ascending aorta (r=0.56, P<0.01, r=0.59, P<0.01, r=0.39, P<0.05, respectively) in this population. There was no significant correlation with age, baPWV, NT-pro brain natriuretic peptide (BNP), repair age, shunt duration, aortic regurgitation or right aortic arch. On the other hand, patients with unrepaired or palliative TOF, who had obvious volume overload, showed no significant correlation with CAVI, baPWV or plasma TGF-β1 level. CAVI and plasma TGF-β1 level, not baPWV, correlate to aortopathy in adults with repaired TOF.

Seminal plasma transforming growth factor-β, activin A and follistatin fluctuate within men over time.

Do seminal plasma transforming growth factor-β (TGFB) cytokines vary within individuals over time, and does this relate to sperm parameters, age or prior abstinence? Activin A and follistatin, and to a lesser extent TGFB1, TGFB2 and TGFB3, vary within individuals over time, in association with duration of abstinence. Seminal plasma TGFB cytokines can influence sperm function and reproductive success through interactions with the female reproductive tract after coitus. Over time, individual sperm parameters fluctuate considerably. Whether seminal fluid TGFB cytokines vary similarly, and the determinants of any variance, is unknown. Between two and seven semen samples were collected from each of 14 fertile donors at 6-10 week intervals over the course of 12 months, then seminal plasma cytokines and sperm parameters were measured. The concentrations and total amounts per ejaculate of TGFB1, TGFB2, TGFB3, activin A and follistatin were determined using commercial assays. Sperm parameters were assessed according to WHO IV standards. Mixed model analysis was utilised to determine the relative contribution of between- and within-individual factors to the variance. Relationships between cytokines and sperm parameters, as well as effect of age and duration of abstinence, were investigated by correlation analysis. Within-individual variability contributed to the total variance for all cytokines and sperm parameters, and was a stronger determinant than between-individual variability for activin A and follistatin as well as for total sperm concentration and sperm motility. Positive correlations between each of the three TGFB isoforms, and activin and follistatin, suggest co-regulation of synthesis. Duration of abstinence influenced total content of TGFB1, TGFB2, activin A and follistatin. TGFB1 correlated inversely with age. A limited number of donors from a single clinic were investigated. Clinical information on BMI, nutrition, smoking and other lifestyle factors was unavailable. Further studies are required to determine whether the findings can be generalised to larger populations and different ethnicities. These data reveal substantial variation over time in seminal fluid cytokines and indicate that repeated analyses are required to gain precise representative data on an individual's status. Within-individual variation in seminal fluid components should be taken into account when investigating seminal fluid cytokines. This study was supported by grants from the National Health and Medical Research Council of Australia, ID453556 and APP1041332. The authors have no competing interests to disclose.

Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP

AbstractElevated expression of the activating Fcγ receptor (FcγR) I and FcγRIIa together with decreased expression of the inhibitory FcγRIIb are involved in the pathogenesis of primary immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) have been used clinically for the management of ITP; however, little is known about the effect of TPO-RAs on FcγR modulation in ITP. In this prospective study, we measured the alteration in monocyte FcγR expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of FcγRIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, FcγRI and IIa levels decreased remarkably, whereas FcγRIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of FcγR toward inhibitory FcγRIIb on monocytes was accompanied with a considerable decrease in monocyte/macrophage phagocytic capacity. The response to eltrombopag therapy in patients with ITP was associated with FcγR phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-β1 (TGF-β1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte FcγR balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61+ severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory FcγRII expression and downregulated activating FcγRI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of FcγR balance toward the inhibitory FcγRIIb on monocytes, and suggested that thrombopoietic agents have a profound effect on immune modulation in ITP. This study is registered at ClinicalTrials.gov as #NCT01864512.

Elevated levels of plasma transforming growth factor-β1 in idiopathic and heritable pulmonary arterial hypertension

BackgroundAberrant transforming growth factor (TGF)-β signaling is involved in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate the predictive value of the upstream ligand of TGF-β signaling (TGF-β1) on long-term mortality and the clinical characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) and heritable PAH (HPAH). Methods and resultsPlasma TGF-β1 levels were measured in 151 IPAH and 65 HPAH patients retrospectively enrolled between January 2008 and March 2013, and compared to 61 healthy subjects. Data for mortality over time were obtained from hospital databases and from telephone follow-ups. The main outcome was all-cause death. Plasma TGF-β1 was significantly higher in IPAH/HPAH patients compared to control subjects (4.74 vs. 2.61ng/mL, respectively; P<0.001). Mean follow-up time was 3.4±1.8years, during which 86 patients died. ROC curves were utilized to determine TGF-β1 cutoff values. Compared to patients with TGF-β1 of <3.74ng/mL, heart function was significantly impaired (percentage of patients with WHO functional class III/IV, 51.4% vs. 65.5%, P=0.043) and mortality risk was elevated (P=0.009) for patients with TGF-β1>3.74ng/mL. However, the difference in mortality rate between patients with higher and lower TGF-β1 levels was only statistically significant for female patients (P=0.004), despite a similar trend for male patients. Multivariate analyses revealed that TGF-β1 (HR after log transformation base of 10: 2.623; 95%CI: 1.228–5.603; P=0.013) emerged as the independent predictor for all-cause mortality. ConclusionHigh circulating levels of TGF-β1 were an independent predictor of a poor outcome for IPAH/HPAH patients.

Association of Plasma Transforming Growth Factor-β1 Levels and the Risk of Atrial Fibrillation: A Meta-Analysis.

IntroductionNumerous studies have demonstrated that plasma transforming growth factor-β1 (TGF-β1) may be involved in the pathogenesis of atrial fibrillation (AF), but some discrepancy remained. We performed a meta-analysis to evaluate the association between the plasma level of TGF-β1 and the risk of AF.MethodsPublished clinical studies evaluating the association between the plasma level of TGF-β1 and the risk of AF were retrieved from PubMed and EMBASE databases. Two reviewers independently evaluated the quality of the included studies and extracted study data. Subgroup analysis and sensitivity analysis were performed to evaluate for heterogeneity between studies.ResultsOf the 395 studies identified initially, 13 studies were included into our analysis, with a total of 3354 patients. Higher plasma level of TGF-β1 was associated with increased risk of AF when evaluated as both a continuous variable (SMD 0.67; 95%CI 0.29–1.05) and a categorical variable (OR 1.01, 95% CI 1.01–1.02).ConclusionsThis meta-analysis suggests an association between elevated plasma TGF-β1 and new onset AF. Additional studies with larger sample sizes are needed to further investigate the relationship between plasma TGF-β1 and the occurrence of AF.

Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction

Chronic kidney disease (CKD) is associated with an increase in serum retinol; however, the underlying mechanisms of this disorder are poorly characterized. Here, we found that the alteration of hepatic metabolism induced the accumulation of serum retinol in 5/6 nephrectomy (5/6Nx) mice. The liver is the major organ responsible for retinol metabolism; accordingly, microarray analysis revealed that the hepatic expression of most CYP genes was changed in 5/6Nx mice. In addition, D-box-binding protein (DBP), which controls the expression of several CYP genes, was significantly decreased in these mice. Cyp3a11 and Cyp26a1, encoding key proteins in retinol metabolism, showed the greatest decrease in expression in 5/6Nx mice, a process mediated by the decreased expression of DBP. Furthermore, an increase of plasma transforming growth factor-β1 (TGF-β1) in 5/6Nx mice led to the decreased expression of the Dbp gene. Consistent with these findings, the alterations of retinol metabolism and renal dysfunction in 5/6Nx mice were ameliorated by administration of an anti-TGF-β1 antibody. We also show that the accumulation of serum retinol induced renal apoptosis in 5/6Nx mice fed a normal diet, whereas renal dysfunction was reduced in mice fed a retinol-free diet. These findings indicate that constitutive Dbp expression plays an important role in mediating hepatic dysfunction under CKD. Thus, the aggravation of renal dysfunction in patients with CKD might be prevented by a recovery of hepatic function, potentially through therapies targeting DBP and retinol.

Preoperative administration of polysaccharide Kureha and reduced plasma transforming growth factor-β in patients with advanced gastric cancer: A randomized clinical trial.

Systemic abrogation of TGF-β signaling results in tumor reduction through cytotoxic T lymphocytes activity in a mouse model. The administration of polysaccharide-Kureha (PSK) into tumor-bearing mice also showed tumor regression with reduced TGF-β. However, there have been no studies regarding the PSK administration to cancer patients and the association with plasma TGF-β. PSK (3 g/day) was administered as a neoadjuvant therapy for 2 weeks before surgery. In total, 31 advanced gastric cancer (AGC) patients were randomly assigned to group A (no neoadjuvant PSK; n=14) or B (neoadjuvant PSK therapy; n=17). Plasma TGF-β was measured pre- and postoperatively. The allocation factors were clinical stage (cStage) and gender. Plasma TGF-β ranged from 1.85-43.5 ng/ml (average, 9.50 ng/ml) in AGC, and 12 patients (38.7%) had a high value, >7.0 ng/ml. These patients were largely composed of poorly-differentiated adenocarcinoma with pathological stage III/IV. All the six elevated cases in group B showed a significant reduction of plasma TGF-β (from 21.6 to 4.5 ng/ml, on average), whereas this was not exhibited in group A. The cases within the normal limits of TGF-β remained unchanged irrespective of PSK treatment. Analysis of variance showed a statistically significant reduction in the difference of plasma TGF-β between groups A and B (P=0.019). PSK reduced the plasma TGF-β in AGC patients when the levels were initially high. The clinical advantage of PSK may, however, be restricted to specific histological types of AGC. Perioperative suppression of TGF-β by PSK may antagonize cancer immune evasion and improve patient prognosis in cases of AGC.

NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain.

BackgroundCumulating evidence has revealed the effectiveness of acupuncture therapy in relieving pain via immunoregulation. However, its underlying mechanism remains unknown. The present study was designed to determine the changes of immunogenic responses at different time-points of electroacupuncture (EA) interventions in neuropathic pain rats.MethodsThe neuropathic pain model was established by ligature of the left sciatic nerve to induce chronic constriction injury (CCI). EA was applied at Zusanli (ST36) and Yanglingquan (GB34) for the EA groups. The thermal pain threshold was detected with an algesia-detector. The subgroups of plasma and splenic lymphocytes were determined via fluorescence-activated cell sorting. Specific inflammatory cytokines were assayed using an ELISA-based bead multiplex assay. The activities of splenic natural killer (NK) cells and cytotoxic T lymphocytes were detected by methyl thiazolyl tetrazolium colorimetric method. For confirming the involvement of NK cell in EA-analgesia, anti-asialo-ganglio-N-tetraosylceramide (anti-asialo-GM1) antibody was given to CCI rats before EA.ResultsFollowing CCI, the thermal pain threshold of the affected hind footpad was significantly decreased, and increased from the 3rd day to the 12th day after EA interventions, presenting a time-dependent tendency from the 5th day on. From day 3 to 5 of EA interventions, the percentages and activity of splenic NK cells, concentrations of splenic interleukin-2 (IL-2) and beta-endorphin (β-EP) were significantly increased. Meanwhile, the concentrations of plasma IL-2, IL-1β and gamma-interferon (IFN-γ) were significantly decreased and returned to the normal level on day 12 following EA. Plasma transforming growth factor-β (TGF-β) levels were considerably upregulated on day 5 and 12 following EA. The CD4+/CD8+ T cell ratio was markedly downregulated compared with the control and CCI groups on day 5 and returned to the normal level on day 12 following EA. After depleting NK cells by anti-asialo-GM1 antibody, the increased thermal pain threshold following EA intervention was obviously reduced.ConclusionsRepeated EA interventions have a time-dependent cumulative analgesic effect in neuropathic pain rats, which is closely associated with its regulatory effects on NK cells, splenic IL-2, β-EP, and plasma IL-2, IL-1β, IFN-γ and TGF-β levels.

Short leukocyte telomere length predicts poor prognosis and indicates altered immune functions in colorectal cancer patients.

Numerous studies indicate that the leukocyte telomere length is associated with the risk of cancers, including colorectal cancer (CRC). However, the prognostic value of leukocyte telomere length in CRC patients has not been investigated. Relative telomere length (RTL) of peripheral blood leukocytes (PBLs) from 571 CRC patients receiving surgical resection was measured using a polymerase chain reaction-based method. The Cox proportional hazards ratio model and the Kaplan-Meier curve were used to estimate the association between RTL and the clinical outcome of CRC patients in the training set (90 patients) and the testing set (86 patients). Finally, an independent cohort of 395 patients was used as an external validation set. The immunophenotype of PBLs and the plasma concentration of several immune-related cytokines were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. Patients with shorter RTL had significantly poorer overall survival and relapse-free survival than those with longer RTL in the training, testing and validation sets. Furthermore, leukocyte RTL and Tumor-Node-Metastasis (TNM) stage exhibited a significant joint effect in the prognosis prediction of combined CRC patients, indicating that patients with both short RTL and advanced stages had the worst prognosis, when compared with other subgroups. In addition, patients with short RTL showed the higher percentage of CD4(+) T cell and the lower percentage of B cell in peripheral blood mononuclear cells, as well as the lower concentration of plasma transforming growth factor-β1, suggesting a possibility that the immune functions changed with RTL alteration. Our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker complementing TNM stage and associated with the immune functions in CRC patients.

Kidney and heart: TGFβ1-mediated cross-talk

Rzeźnik et al. [1] in their recent paper published in ‘Kardiologia Polska’ found that revascularisation of unilateral or bilateral renal artery stenosis (RAS) leads to improvement in several echocardiographic parameters reflecting heart structure and function, as well as impacts on plasma transforming growth factor β1 (TGFβ1) and B-type natriuretic peptide. At least some of the effects on the heart (such as LVMI reduction) did not depend on the degree of blood pressure lowering. As can be concluded from the publication, patients did not suffer from symptomatic heart failure (HF; at least in NYHA class III–IV); however, it has been demonstrated recently that RAS revascularisation may also be associated with improvement in NYHA class and reduction in the risk of hospitalisation for HF in patients with concomitant RAS and HF [2]. The message delivered by this paper is very important for both nephrologists and cardiologists. TGFβ1 remains one of the key profibrotic growth factors in renal pathology. It is produced by damaged mesangial cells in the glomerulus (and is crucial for the development of glomerular sclerosis), injured tubular cells and resident interstitial fibroblasts (resulting in interstitial fibrosis). HF in the course of atherosclerotic RAS may develop according to least three different scenarios: (1) Both HF and RAS are consequences of the same, devastating, pathology, namely advanced atherosclerosis; (2) RAS contributes to heart remodelling and dysfunction due to significantly elevated and difficult-to-control hypertension; (3) Humoral mediators released from injured (ischaemic) renal parenchyma may remotely damage the heart (and this may be the case with TGFβ1). The role of TGFβ1 in the development of several heart diseases resulting in myocardial fibrosis has been well recognised for some years [3]. Experimental data suggest that RAS triggers the synthesis and release of several inflammatory and vasoconstrictive agents from the kidney, in addition to the activation of the renin–angiotensin–aldosterone (RAA) axis. These include, among others, endothelin, interleukin-6, TNFα and TGFβ1. It has been demonstrated that disruption of the Smad3 protein gene (signalling pathway essential for TGFβ1 effects) prevents fibrosis of the kidney supplied by stenotic artery even if stenosis persists [4]. Infusion of endothelial progenitor cells into the artery with stenosis significantly decreases plasma levels of several proinflammatory cytokines, prevents myocardial damage and remodelling, even in stenosis remains uncorrected and there is no change in systemic blood pressure [5]. TGFβ1 is one of the key effector molecules involved in epithelial-to-mesenchymal transition, the process of phenotypic change of epithelial tubular cells into fibroblast-like cells — now considered one of the most important mechanisms that lead to kidney fibrosis. A similar process has also been described for cardiac endothelium and was called ‘endothelial-to-mesenchymal transition’ (Endo-MT) [6]. These and other findings should lead to caution when interpreting apparently ‘negative’ trials published recently on RAS which did not demonstrate any substantial be nefit associated with renal artery revascularisation ± stenting vs. medical therapy — effects on blood pressure and/or kidney function were exactly the same in both types of intervention. Now it is tempting to speculate that successful RAS revascularisation might be a much more definite strategy compared to everyday use of RAA axis blockade in lowering TGFβ1 and thus in limiting the impact of this growth factor on the heart and the kidneys. It seems however plausible to expect some lag time between intervention and expected cardiac benefits, not necessarily apparent in the short time following intervention. The findings of Rzeźnik et al. [1] may hold some promise for more delayed, but possible, benefit following RAS revascularisation for the heart, and possibly for the kidneys.