Search Results (1,032)

Vascular endothelial cells form a selective barrier that regulates the passage of substances and leukocytes between the bloodstream and surrounding tissues, thereby maintaining vascular homeostasis. Although endothelial barrier dysfunction is implicated in numerous diseases, the molecular mechanisms that protect against such dysfunction remain incompletely defined. Thrombin, an inflammatory mediator, increases endothelial permeability by inducing myosin light chain (MLC) phosphorylation through Rho/Rho-associated kinase (Rho-kinase)-mediated inhibition of myosin phosphatase. This process disrupts vascular endothelial cadherin (VE-cadherin)-based junctions and promotes radial stress fiber formation. Here, we demonstrate that the green tea catechin (–)-epigallocatechin-3-gallate (EGCG) reduces phosphorylation of the myosin phosphatase regulatory subunit MYPT1 at inhibitory sites and suppresses Rho-kinase signaling in endothelial cells. Together, these EGCG-mediated effects reduce MLC phosphorylation, inhibit radial stress fiber formation, and preserve VE-cadherin-mediated cell–cell adhesion, thereby maintaining endothelial barrier integrity. Full article

Yellow bells (Tecoma stans) is a popular ornamental flowering plant used in public spaces. Its flowers are considered a medicinal herb rich in bioactive compounds. This study aimed to investigate the effect of using dried yellow bells flower (YB) as a dietary supplement for Nile tilapia (Oreochromis niloticus). Nile tilapia (0.74 ± 0.01 g body weight) were divided into six groups for an eight-week feeding trial, during which their diets were supplemented with 5 different levels by weight of YB: 2, 4, 6, 8, and 10%. The control group received a non-supplemented diet. Parameters related to growth, feed utilization, skin and fillet coloration, gut functionality, fillet quality, blood parameters, and whole-body composition were observed. Survival, feed utilization, and skin and fillet coloration were unaffected by YB supplementation, and growth performance was generally maintained up to 8% dietary inclusion. However, at 4 to 6% YB intestinal cellulase activity and gastrointestinal radical-scavenging activities were significantly increased, while amylase and protease activities, and the amylase/trypsin ratio, were maintained. Fillet quality was improved at 4% YB, with higher myosin and total myofibrillar protein contents but without changes in RNA, total protein, or RNA/protein ratio. At moderate YB inclusion levels, white blood cell counts were lower and packed cell volume and hemoglobin levels were higher, indicating improved physiological status. Whole-body crude protein and ash were increased at higher YB levels, whereas moisture and lipid were unchanged. Overall, dietary inclusion of around 4% YB was associated with favorable improvements in gut functionality, fillet quality, blood parameters, and whole-body composition in Nile tilapia. Full article

Background/Objectives: Guidelines for obstructive hypertrophic cardiomyopathy (HCM) recommend treatment with disopyramide as an add-on to beta-blockers or calcium-channel blockers when symptoms persist. Data pertaining to effective disopyramide use in practice beyond single-center experience are very limited. This study aimed to quantify disopyramide use in patients with obstructive HCM in England, France and Germany, before the availability of cardiac myosin inhibitors. Methods: This retrospective study used nationally representative databases from England (Clinical Practice Research Datalink and Hospital Episode Statistics, 2010–2019), France (National Healthcare Data System, 2012–2019) and Germany (German statutory health insurance, 2011–2019). Adults (18+) with obstructive HCM were included, based on diagnostic codes for obstructive HCM or any HCM with septal reduction therapy. Disopyramide usage was defined as ≥1 prescription for a patient in a calendar year. Results: Overall, 3730, 6823 and 1141 patients diagnosed with obstructive HCM were identified in the English, French and German databases, respectively. In England, disopyramide use ranged from 4.7% to 5.6% per year with use generally stable over time. The equivalent usage for France was 1.7% to 2.6% per year. As expected, no recorded reimbursed use was reported in Germany during the study period. Conclusions: Disopyramide use is very low in patients with obstructive HCM, possibly due to treatment-related issues, availability or lack of reimbursement. These barriers may drive the uptake of alternative guideline recommended therapies for obstructive HCM treatment. Full article

Research on mule and donkey muscle composition remains limited despite their global importance as working equids. The objective of this study is to identify Mammoth donkey jacks with higher percentage of fast twitch fibers for racing mule production. A total of 33 animals were biopsied; however, only 12 samples were suitable for analysis, including racing mules (n = 7) and male Mammoth donkeys (n = 5). Animals were sedated with detomidine (10 µg/kg body weight) and butorphanol (20 µg/kg body weight). Middle gluteal muscle biopsies were collected using a 6 mm Bergström biopsy needle at a site located 20 cm dorsocaudal to the tuber coxae at a 45° angle to the base of the tail. Collection depth was 7.5 cm in adult mules and 5 cm in donkeys. Samples were prepared aseptically, anesthetized subcutaneously with lidocaine hydrochloride, and frozen in liquid nitrogen. Histochemical analysis included myosin adenosine triphosphatase (ATPase) staining at pH 9.5, 4.6, and 4.3. Fibers were classified as Type I, Type IIA, or Type IIB, and CSA measurements were obtained using NIH ImageJ software. Statistical analysis included group contrasts, summarized as mean ± SD with 95% confidence intervals, while Bayesian ANOVA outputs were presented as exploratory evidence summaries. Type IIA fibers were greater in mules (47.84 ± 7.30%) than donkeys (38.47 ± 4.48%). Results suggest that differences in equid muscle architecture may be associated with variation in Type IIA fiber composition related to work or use. Full article

This study assessed the impacts of dietary net energy (NE) levels on growth performance, meat quality and intestinal health in Tunchang Black pigs. Forty-eight pigs with an initial body weight of 11 kg were allocated into four groups and fed diets containing 10.65 (N1), 10.15 (N2, control), 9.65 (N3) and 9.15 (N4) MJ/kg NE respectively over a 42-day experimental period. The N4 group presented lower average daily gain and carcass weight relative to the N1 group, while no significant differences in growth performance were detected between N2 and N3. The N3 group displayed superior meat quality characteristics, manifested as decreased contents of saturated fatty acids (C10:0, C12:0), elevated selenium concentration, upregulated expression of slow-twitch myosin heavy chain (MyHC I) and downregulated expression of fast-twitch MyHC IIb, alongside increased ileal occludin expression. Moreover, the N3 treatment improved antioxidant capacity, as reflected by higher serum GSH and SOD levels and lower serum MDA content. In conclusion, decreasing dietary NE from 10.15 to 9.65 MJ/kg exerted no detrimental influence on growth performance yet effectively ameliorated meat quality, antioxidant status and intestinal barrier function in Tunchang Black pigs. Full article

Due to the complex pathophysiology and serious outcomes of autoimmune myocarditis, we sought to determine whether ethanolic lemon balm extract (LBE) could attenuate disease progression and development of dilative cardiomyopathy (DCM). EAM was induced in Dark Agouti rats by immunization with porcine myosin. Fifty animals were allocated to five groups: healthy controls, untreated EAM, and EAM treated with LBE (50, 100, or 200 mg/kg) for six weeks. Hemodynamic parameters were monitored, and echocardiography assessed cardiac structure and function. Inflammatory, oxidative, fibrotic, and apoptotic markers were analyzed. Immunological profiling revealed that LBE significantly decreased proinflammatory cytokines (IL-1, IL-6, TNF-α, IL-4, IL-17) while restoring anti-inflammatory IL-10 levels (p < 0.05). Antioxidant activity was confirmed by reduced levels of O₂⁻, H₂O₂, and TBARS, accompanied by significant increases in SOD, CAT, and GSH activity (p < 0.05), and upregulation of SOD1 and SOD2 gene expression. Additionally, LBE (200 mg/kg) markedly reversed fibrotic remodeling through suppression of TGF-β expression and collagen deposition, as shown by Sirius Red staining, and mitigated apoptosis by modulating Bax/Bcl-2 balance and reducing TUNEL-positive cells. Collectively, these findings suggest that LBE exerts strong cardioprotective effects in EAM by regulating inflammatory, oxidative, fibrotic, and apoptotic pathways, thereby preventing myocarditis progression toward DCM. Full article

The colonic epithelial barrier is a multilayered defense system comprising the mucus layer, intestinal epithelial cells (IECs), and the underlying lamina propria. These components collectively maintain mucosal homeostasis and restrict microbial translocation. Disruption of this barrier is a hallmark of chronic intestinal inflammation particularly in IBDs, and is primarily driven by pro-inflammatory cytokines, such as TNF-α, IFN-γ, IL-1β, and IL-6. TNF-α and IFN-γ synergistically induce epithelial cell apoptosis and tight junction disassembly through mechanisms involving TNFR2 upregulation, myosin light chain kinase (MLCK) activation, and adherens junction destabilization. IL-1β amplifies paracellular permeability via NF-κB-dependent MLCK induction and OCLN downregulation, while IL-6 promotes barrier leakiness by upregulating CLDN-2 and sustaining self-reinforcing inflammatory loops that maintain chronic inflammation and impede epithelial repair. This leads to persistent immune-cell infiltration, chronic tight junction remodeling, and failure of barrier replenishment. Consequently, leaky colon facilitates microbial and antigen translocation into the lamina propria, further activating immune cells and perpetuating pro-inflammatory signaling. This review synthesizes current evidence and studies on the cooperative and self-reinforcing roles of pro-inflammatory cytokines, providing insight into the mechanisms underlying chronic intestinal barrier dysfunction and highlighting the need for therapeutic strategies that simultaneously target multiple inflammatory axes to restore barrier integrity in inflammatory bowel disorders. Full article

Tropomyosins (Tpm) are the family of actin-binding proteins encoded by four genes in humans. Missense mutations in the TPM1 gene associated with cardiomyopathies have been studied in the sarcomeric isoform Tpm1.1. The cardiomyopathy-causing mutations E40K and E54K are located in exon 2b of the TPM1 gene and may be expressed in non-muscle cytoplasmic Tpm isoforms, including Tpm1.7, which is associated with early tissue development. In the present work, we investigate the effects of mutations E40K and E54K on the properties of Tpm1.7. The E40K and E54K mutations caused destabilization of the Tpm1.7 molecule at the N- and C-termini parts. Neither mutation affected the Tpm1.7 affinity for filamentous actin (F-actin). The bending stiffness of F-actin/Tpm1.7 E40K filaments was lower compared to F-actin/Tpm1.7 WT (wild-type). The interplay of Tpm1.7 and motor proteins was studied in an in vitro motility assay with skeletal myosin. Tpm1.7 WT reduced the sliding velocity of F-actin by half; the velocity of F-actin with Tpm1.7 E54K did not differ from that of bare F-actin; and Tpm1.7 E40K decreased the F-actin velocity by approximately threefold. While Tpm1.7 E40K did not affect the protective effect of Tpm1.7 against F-actin severing by cofilin-1, the E54K mutation enhanced protection against cofilin-1. Thus, cardiomyopathic mutations in the TPM1 gene can affect the properties of non-muscle Tpm isoforms, which indicates that this should be taken into account when studying the molecular mechanisms of the pathogenesis of these diseases. Full article

Metabolic syndrome (MetS) drives cardiac remodeling and fibrosis, contributing to diastolic dysfunction and heart failure with preserved ejection fraction, but chamber-specific mechanisms remain poorly defined. New Zealand White rabbits were fed a high-fat/high-sucrose diet for 28 weeks to induce experimental MetS. Systemic phenotype, cardiac structure (echocardiography), myocardial fibrosis (Picrosirius red histology), myosin/collagen gene expression (qRT-PCR), and chamber-specific proteomics were assessed across left/right atria and ventricles. The model reproduced central obesity, glucose intolerance, dyslipidemia, and mild hypertension, with concentric left ventricular hypertrophy and selective ventricular fibrosis, as follows: increased collagen in left ventricle (LV) and right ventricle (RV), unchanged in atria. Ventricular α-myosin heavy-chain gene expression was upregulated, while collagen I and α-smooth muscle actin transcripts showed ventricular-specific downregulation. Proteomics revealed atrial metabolic and cytoskeletal adaptations with minimal extracellular matrix involvement; ventricles displayed early profibrotic cues (galectin-3 in LV), metabolic inefficiency (impaired glycolysis/ATP production in LV; lipid oxidation shift in RV), and diminished provisional matrix support. Conclusions: concentric LV hypertrophy and great vessel enlargement occurred without systolic/diastolic dysfunction; ventricular-selective fibrosis, α-myosin heavy-chain upregulation, type I collagen/α-smooth muscle actin downregulation, and chamber-specific proteomic changes showed atrial adaptation versus ventricular early profibrotic/metabolic inefficiency. Full article

Human unilateral cleft lip morphopathogenesis is a complex process involving multiple genes and proteins. Factors such as myosin heavy chain 3 (MYH3), interferon regulatory factor 6 (IRF6), and Gremlin 1 (GREM1) are implicated in craniofacial development; however, their precise role in unilateral cleft formation remains unclear, limiting improvements in treatment strategies. Immunohistochemistry (IHC) for MYH3, IRF6, and GREM1 proteins and chromogenic in situ hybridization (CISH) for IRF6 and GREM1 genes were used to analyze postnatal unilateral right cleft lip tissue (ten patients) and control tissue (six patients). The semi-quantitative counting method was applied, followed by statistical analysis. IHC revealed increased MYH3 expression in cleft muscle tissue and elevated IRF6 expression in the epithelium, whereas GREM1 showed low expression, with significant differences in connective tissue. CISH demonstrated increased IRF6 gene expression in the cleft epithelium, whereas GREM1 expression did not differ from controls. Multiple statistically significant correlations were identified, highlighting their potential involvement in cleft morphopathogenesis. Full article

Crop losses driven by fungal pathogens remain a major constraint to global food production, reinforcing agriculture’s dependence on fungicide-based disease control. Soil acts as a long-term reservoir and key hotspot for the evolution and persistence of antifungal-resistant Fusarium. The intensive, prolonged use of overlapping single-site fungicides in agriculture strongly selects for both intrinsic and acquired resistance in soilborne Fusarium populations, contributing to major crop losses, food insecurity, and One Health concerns. This review synthesizes current knowledge on (i) target-site (CYP51, β-tubulin, cytochrome b, SDH, myosin-5) and non-target-site (ABC/MFS efflux, multidrug resistance, epigenetic regulation) resistance mechanisms across the genus Fusarium; (ii) the influence of management practices and fungicide characteristics and behaviour in soil in reshaping microbial communities and selecting for resistant Fusarium; (iii) the consequences for plant disease management and the limitations of practices like cultural and biological control; and (iv) innovative strategies for plant disease management, as well as the monitoring and detection of antifungal resistance in soils. These aspects show that soil reservoirs of antifungal-resistant Fusarium are compromising fungicide-based control and increasing risks across sectors, highlighting the urgent need for sustainable, multi-layered, integrated pest management strategies combined with robust, molecularly informed resistance monitoring. Full article

The management of obstructive hypertrophic cardiomyopathy (HCM) has been transformed by the advent of cardiac myosin inhibitors (CMIs), such as mavacamten and aficamten. Unlike traditional pharmacotherapy, which primarily addresses symptoms, CMIs target the underlying mechanism of sarcomeric hypercontractility, offering significant reductions in left ventricular outflow tract (LVOT) gradients and improved functional capacity. This review evaluates the evolving role of CMIs in refining surgical candidate selection and postoperative care. Clinically, CMIs function as an in vivo “biological test” to distinguish between dynamic, functional obstruction—often manageable with medication—and fixed anatomical obstruction driven by complex septal or mitral substrates. While clinical trials demonstrate that CMIs can delay or prevent the need for SRT in a significant proportion of patients, surgery remains the definitive solution for those with dominant structural anomalies or drug intolerance. Consequently, the therapeutic paradigm is shifting from a binary “drugs or surgery” approach to a synergistic model. In this framework, CMIs optimize the identification of patients truly requiring structural myectomy while serving as a valuable adjunct for managing residual hypercontractility, ultimately facilitating a personalized, multidisciplinary approach to HCM treatment. Full article

Introduction: Soft tissue sarcomas (STS) exhibit profound molecular heterogeneity. While recurrent gene fusions hold significant diagnostic and therapeutic value—guiding treatment selection and identifying novel molecular targets—our understanding of their broader clinical implications remains limited. Materials and Methods: We performed next-generation sequencing (NGS; FusionPlex Sarcoma v2, Archer™) and bioinformatic analysis (STAR v.2.7, Arriba) on formalin-fixed paraffin-embedded (FFPE) core needle biopsy specimens. The cohort consisted of patients enrolled in a phase II clinical trial (NCT03651375) who received preoperative chemoradiotherapy according to the UNRESARC protocol. Results: The analysed cohort comprised nine adult patients (median age 66 years; range 44–73) diagnosed with undifferentiated pleomorphic sarcoma (UPS; n = 3), malignant peripheral nerve sheath tumour (MPNST; n = 3), myxofibrosarcoma (MFS; n = 2), and leiomyosarcoma (LMS; n = 1), predominantly high-grade (G3; 5/9) and extremity-localised (6/9). Gene fusions were detected in one-third of patients (3/9), exclusively in G3 tumours. Specifically, we identified an SGSH-PRKCA fusion in MFS (thigh), a LINC01133-OGA fusion in MPNST (thorax), and a concurrent JAZF1-MYH7B (chr7:27995037 intronic-chr20:33563203 exon/splice-site, out-of-frame but preserving myosin domains) with a PRKCA-associated intergenic rearrangement (chr1, retaining C1/kinase domains) in UPS (upper back). Notably, the SGSH-PRKCA and JAZF1-MYH7B pairs have not been previously described in the literature for these STS subtypes. Fusion-positive (F1) cases showed stable radiological disease (RECIST 1.1 SD) and EORTC C/D pathological responses with 5–20% residual viable tumour, whereas fusion-negative (F0) cases showed a wider range of radiological and pathological outcomes, including partial response, progression, and stable disease. Conclusions: Our analysis suggests that broad genomic profiling may provide complementary molecular information in diagnostically challenging cases managed at specialised sarcoma centres, particularly when morphology and immunohistochemistry are insufficient. In the present series, however, the detected rearrangements did not alter systemic treatment, and the data do not support claims of prognostic, predictive, or therapeutic actionability. Full article

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein (CREB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. Full article

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease in the general population, with a variable phenotypic expression and symptomatology. Atrial fibrillation (AF) is the most common arrhythmia identified among patients diagnosed with HCM. Treatment of both AF and HCM has continuously evolved over time, leading to a significant improvement in the prognosis and life expectancy of symptomatic patients. Numerous studies have demonstrated that the risk of developing this arrhythmia correlates with atrial morphological, functional and electrical remodeling, a process known as atrial myopathy. Once a first episode of AF is diagnosed, permanent anticoagulation is required among patients diagnosed with HCM, regardless of the CHA₂ DS₂-VA score. Additionally, atrial cardiomyopathy is associated with an increased thromboembolic risk, independent of AF presence, in patients with stable sinus rhythm, in the context of atrial mechanical and endothelial dysfunction. This article aims to evaluate the current scientific evidence and treatment approaches in patients diagnosed with HCM. Full article