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Amiodarone (AMD) is a widely used antiarrhythmic drug prescribed to treat cardiac tachyarrhythmias; however, AMD has been reported to provoke pulmonary fibrosis (PF) and hepatotoxicity. This study aimed to investigate the influence of alpha lipoic acid (ALA) on AMD-induced PF and hepatotoxicity in male Wistar rats. AMD administration resulted in elevated lung contents of hydroxyproline (Hyp), malondialdehyde (MDA), and increased serum levels of transforming growth factor beta-1 (TGF-β1), interferon-γ (IFN-γ), alanine amino transaminase (ALT), aspartate amino transaminase (AST), total cholesterol (TC), and glucose. On the other side, lung content of glutathione reduced (GSH) and serum levels of total anti-oxidant capacity (TAC) were significantly decreased. Histopathologically, AMD caused PF, produced a mild hepatic injury, and increased expression of alpha smooth muscle actin (α-SMA). Treatment with ALA produced a significant reversal of the oxidative stress, fibrosis, and inflammation parameters with reductions in α-SMA expressions, leading to amelioration of histopathological lesions. ALA might provide supportive therapy in AMD-receiving cardiovascular patients.

Background Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L -serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl- L -cysteine (12.75%), and 3.73 g L -carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 ( P  = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline ( P  = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration  ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

Background Differentiation of fibroblasts into myofibroblasts is necessary for wound healing, but excessive myofibroblast presence and persistence can result in scarring. Treatment for scarring is limited largely due to a lack of comprehensive understanding of how fibroblasts and myofibroblasts differ at the transcript level. The purpose of this study was to characterize transcriptional profiles of injured fibroblasts relative to normal fibroblasts, utilizing fibroblasts from the vocal fold as a model. Results Utilizing bulk RNA sequencing technology, we identified differentially expressed genes between four cell lines of normal fibroblasts (cVFF), one line of scarred fibroblasts (sVFF), and four lines of fibroblasts treated with transforming growth factor-beta 1 (TGF-β1), representing an induced-scar phenotype (tVFF). Principal component analysis revealed clustering of normal fibroblasts separate from the clustering of fibroblasts treated with TGF-β1; scarred fibroblasts were more similar to normal fibroblasts than fibroblasts treated with TGF-β1. Enrichment analyses revealed pathways related to cell signaling, receptor-ligand activity, and regulation of cell functions in scarred fibroblasts, pathways related to cell adhesion in normal fibroblasts, and pathways related to ECM binding in fibroblasts treated with TGF-β1. Although transcriptomic profiles between scarred fibroblasts and fibroblasts treated with TGF-β1 were relatively dissimilar, the most highly co-expressed genes were enriched in pathways related to actin cytoskeleton binding, which supports the use of fibroblasts treated with TGF-β1 to represent a scarred cell phenotype. Conclusions Transcriptomics of normal fibroblasts differ from myofibroblasts, including from those retrieved from scar and those treated with TGF-β1. Despite large differences in transcriptomics between tVFF and sVFF, tVFF serve as a useful in vitro model of myofibroblasts and highlight key similarities to myofibroblasts extracted from scar pathology, as well as expected differences related to normal fibroblasts from healthy vocal folds.

Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodeling. In this context, we aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor beta-1 (TGF-β1) in an in vivo model. Six-week-old male wild-type (WT) and TGF-β1-overexpressing transgenic (TGF-β1-TG) mice were infused with subhypertensive doses of Ald for 2 weeks and/or treated orally with eplerenone from postnatal day 21. Thehearts’ ventricles were examined by morphometry, immunoblotting to assess the intracellular signaling pathways and RT qPCR to determine hypertrophy and fibrosis marker genes. The TGF-β1-TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis and exhibited a higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in the ventricular-heart-weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but a less pronounced increase in interstitial fibrosis in the transgenic compared to the WT mice (23.6% vs. 80.9%, p < 0.005). Ald increased the phosphorylation of p44/42 and p38 in the WT but not the TGF-β1-TG mice. While the eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in the WT controls, it completely protected against additional fibrosis in transgenic mice. Ald appears to induce cardiac hypertrophy independently of TGF-β1, while in the case of fibrosis, the downstream signaling pathways of these two factors probably converge.

Oral submucous fibrosis (OSF) is a chronic, progressive, and precancerous condition mainly caused by chewing areca nut. Currently, OSF therapy includes intralesional injection of corticosteroids with limited therapeutic success in disease management. Therefore, a combined approach of in silico , in vitro and in vivo drug development can be helpful. Polyphenols are relatively safer than other synthetic counterparts. We used selected polyphenols to shortlist the most suitable compound by in silico tools. Based on the in silico results, epigallocatechin-3-gallate (EGCG), quercetin (QUR), resveratrol, and curcumin had higher affinity and stability with the selected protein targets, transforming growth factor beta-1 (TGF-β1), and lysyl oxidase (LOX). The efficacy of selected polyphenols was studied in primary buccal mucosal fibroblasts followed by in vivo areca nut extract induced rat OSF model. In in vitro studies, the induced fibroblast cells were treated with EGCG and QUR. EGCG was safer at higher concentrations and more efficient in reducing TGF-β1, collagen type-1A2 and type-3A1 mRNA expression than QUR. In vivo studies confirmed that the EGCG hydrogel was efficient in improving the disease conditions compared to the standard treatment betamethasone injection with significant reduction in TGF-β1 and collagen concentrations with increase in mouth opening. EGCG can be considered as a potential, safer and efficient phytomolecule for OSF therapy and its mucoadhesive topical formulation help in the improvement of patient compliance without any side effects. Graphical abstract Highlights Potential polyphenols were shortlisted to treat oral submucous fibrosis (OSF) using in silico tools Epigallocatechin 3-gallate (EGCG) significantly reduced TGF-β1 and collagen both in vitro and in vivo EGCG hydrogel enhanced antioxidant defense, modulated inflammation by reducing TGF-β1 and improved mouth opening in OSF rat model.

Tissue remodeling contributes to ongoing inflammation and refractoriness of chronic rhinosinusitis (CRS). During this process, epithelial-mesenchymal transition (EMT) plays an important role in dysregulated remodeling and both microRNA (miR)-29b and heat shock protein 47 (HSP47) may be engaged in the pathophysiology of CRS. This study aimed to determine the role of miR-29b and HSP47 in modulating transforming growth factor (TGF)-β1-induced EMT and migration in airway epithelial cells. Expression levels of miR-29b, HSP47, E-cadherin, α-smooth muscle actin (α-SMA), vimentin and fibronectin were assessed through real-time PCR, Western blotting, and immunofluorescence staining. Small interfering RNA (siRNA) targeted against miR-29b and HSP47 were transfected to regulate the expression of EMT-related markers. Cell migration was evaluated with wound scratch and transwell migration assay. miR-29b mimic significantly inhibited the expression of HSP47 and TGF-β1-induced EMT-related markers in A549 cells. However, the miR-29b inhibitor more greatly induced the expression of them. HSP47 knockout suppressed TGF-β1-induced EMT marker levels. Functional studies indicated that TGF-β1-induced EMT was regulated by miR-29b and HSP47 in A549 cells. These findings were further verified in primary nasal epithelial cells. miR-29b modulated TGF-β1-induced EMT-related markers and migration via HSP47 expression modulation in A549 and primary nasal epithelial cells. These results suggested the importance of miR-29b and HSP47 in pathologic tissue remodeling progression in CRS.

Background & objectives: In this study, we aimed to investigate the relationship between serum TGF-β1 and PDGF-B levels with the pathogenesis, clinical course and prognosis of adult Crimean-Congo hemorrhagic fever (CCHF) patients. Methods: 50 adult patients and 30 healthy individuals as a control group were included in the study, who were followed up and treated with the diagnosis of CCHF at the Atatürk University Faculty of Medicine Infectious Diseases and Clinical Microbiology Clinic, between March 2017 and September 2019 in Eastern Anatolia Region in Turkey. Blood samples were taken from patients on the first day of their hospitalization and on the sixth day of their complaints. TGF-β1 and serum PDGF-B levels were studied by ELISA method using commercial kits, from serum samples taken from CCHF patient group and individuals in healthy control group and stored at -80°C. Results: While the serum TGF- β1 levels of patients with CCHF were found to be significantly higher on the sixth day of their complaints compared to the first day of hospitalization (42.33 ± 15.42, 28.40 ± 7.06, p = 0.001, respectively), the serum PGDF-B levels were found to be significantly lower on the sixth day of their complaints compared to those measured on the day of hospitalization (62.14 ± 19.75, 93.96 ± 20.02, respectively, p = 0.001). Interpretation & conclusion: Serum TGF-β1 levels are higher and PDGF-B levels are lower in CCHF patients with severe disease, indicating that serum TGF-β1 and PDGF-B play an important role in the pathogenesis of CCHF.

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFβ-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

Background and Objectives: Microvascular flap surgery is a widely used reconstructive technique for the repair of various defects. Biomarkers have become an essential tool for monitoring flap viability, early detection of complications, and prediction of surgical outcomes. Studies focusing on immunomodulatory cytokines in the early prediction of microvascular flap complications are lacking. We aimed to investigate the predictive value of postoperative changes in transforming growth factor beta-1 (TGF-β1) for microvascular flap complications. Materials and Methods: This prospective observational study comprised 44 adults scheduled for elective microvascular flap surgery. Preoperative blood samples for analysis were obtained before surgery, prior to the administration of intravenous fluids. Postoperative blood draws were collected after surgery, before leaving the operating room. Preoperative and postoperative serum concentrations of TGF-β1, as well as preoperative plasma albumin, total protein, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, full blood count, albumin, interleukin-6, C-reactive protein, and fibrinogen, were determined. Results: Postoperative changes in TGF-β1 were higher in cases with flap loss compared to patients with healthy recovery or patients with minor flap complications (0.403 log10 of ng/mL [0.024–0.782] vs. 0.157 [0.029–0.285] vs. −0.089 [−0.233–0.056], p = 0.002). Increased postoperative TGF-β1 was positively linked to preoperative C-reactive protein (p = 0.021), fibrinogen (p = 0.020), hematocrit (p = 0.039), and hemoglobin (p = 0.009). Conclusions: The postoperative increase in circulating TGF-β1 was associated with microvascular flap complications. Assessment of the postoperative changes in circulating TGF-β1 may be valuable for the early postoperative prediction of true flap loss.

Objectives: We aimed to investigate the therapeutic effects of thymoquinone (TMQ) treatment in osteonecrotic rats by evaluating protein levels, osteonecrosis (ON) levels, fatty acid degeneration, oxidative status, and plasma levels of Urotensin-II (U-II) and transforming growth factor-beta (TGF-β1). Materials and Methods: 40 weight-matched adult male Wistar rats were grouped as control (n = 10), methylprednisolone acetate (MPA) (n = 10), thymoquinone (TMQ) (n = 10), and MPA + TMQ (n = 10). To induce ON, 15-week-old animals were subcutaneously injected with MPA at a dose of 15 mg/kg twice weekly for 2 weeks. TMQ was injected into 15-week-old rats via gastric gavage at a dose of 80 mg/kg per day for 4 weeks. The rats in the MPA + TMQ group were administered TMQ 2 weeks before the MPA injection. At the end of the treatments, cardiac blood samples and femur samples were collected for biochemical and histological evaluations. Results: In the control and TMQ groups, no ON pattern was observed. However, in tissues exposed to MPA, TMQ treatment resulted in significantly decreased ON levels compared to the MPA group. The number of cells that were positive for 8-OHdG and 4-HNE was significantly lower in the MPA + TMQ group than in the MPA group (p < 0.05). In terms of TGF-β1 and U-II levels, we observed that both TGF-β1 (367.40 ± 23.01 pg/mL vs. 248.9 ± 20.12 pg/mL) and U-II protein levels (259.5 ± 6.0 ng/mL vs. 168.20 ± 7.90 ng/mL) increased significantly in the MPA group compared to the control group (p < 0.001). Furthermore, TGF-β1 (293.50 ± 14.18 pg/mL) and U-II (174.80 ± 4.2 ng/mL) protein levels were significantly decreased in the MPA + TMQ group compared to the MPA group (p < 0.05 and p < 0.01, respectively). There was a statistically positive correlation (p < 0.05) between the TGF-β1 and U-II protein levels in all groups (p = 0.002, rcontrol = 0.890; p = 0.02, rTMQ = 0.861; p = 0.024, rMPA+TMQ = 0.868) except for the MPA group (p < 0.03, rMedrol = −0.870). Conclusions: As far as we know, this is the first study to demonstrate the curative functions of TMQ on ON by causing a correlated decrease in the expression of U-II and TGF-β1 in the femoral heads of rats.