Search Results (18,259)

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, representing a complex clinical syndrome in which the heart’s ability to pump blood efficiently is impaired. HF can be subclassified into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), each with distinct pathophysiological mechanisms and varying levels of severity. The progression of HF is significantly driven by cardiac fibrosis, a pathological process in which the extracellular matrix undergoes abnormal and uncontrolled remodelling. Cardiac fibrosis is characterized by excessive matrix protein deposition and the activation of myofibroblasts, increasing the stiffness of the heart, thus disrupting its normal structure and function and promoting lethal arrythmia. MicroRNAs, long non-coding RNAs, and circular RNAs, collectively known as non-coding RNAs (ncRNAs), have recently gained significant attention due to a growing body of evidence suggesting their involvement in cardiac remodelling such as fibrosis. ncRNAs can be found in the peripheral blood, indicating their potential as biomarkers for assessing HF severity. In this review, we critically examine recent advancements and findings related to the use of ncRNAs as biomarkers of HF and discuss their implication in fibrosis development. Full article

Introduction: The efficacy of anti-CD20 antibodies has significantly contributed to advancing our understanding of disease pathogenesis and improved treatment outcomes in relapsing-remitting multiple sclerosis (RRMS). A comprehensive analysis of the peripheral immune cell profile, combined with prospective clinical characterization, of RRMS patients treated with ocrelizumab (OCR) or ofatumumab (OFA) was performed to further understand immune reconstitution following B-cell depletion. Methods: REBELLION-MS is a longitudinal analysis of RRMS patients treated with either OCR (n = 34) or OFA (n = 25). Analysis of B, T, natural killer (NK) and natural killer T (NKT) cells at baseline, month 1, and 12 was performed by multidimensional flow cytometry. Data were analyzed by conventional gating and unsupervised computational approaches. In parallel, different clinical parameters were longitudinally assessed. Twenty treatment-naïve age/sex-matched RRMS patients were included as the control cohort. Results: B-cell depletion by OCR and OFA resulted in significant reductions in CD20⁺ T and B cells as well as B-cell subsets, alongside an expansion of CD5⁺CD19⁺CD20⁻ B cells, while also elevating exhaustion markers (CTLA-4, PD-1, TIGIT, TIM-3) across T, B, NK, and NKT cells. Additionally, regulatory T-cell (T_REG) numbers increased, especially in OCR-treated patients, and reductions in double-negative (CD3⁺CD4⁻CD8⁻) T cells (DN T cells) were observed, with these DN T cells having higher CD20 expression compared to CD4 or CD8 positive T cells. These immune profile changes correlated with clinical parameters, suggesting pathophysiological relevance in RRMS. Conclusions: Our interim data add weight to the argumentation that the exhaustion/activation markers, notably TIGIT, may be relevant to the pathogenesis of MS. In addition, we identify a potentially interesting increase in the expression of CD5+ on B cells. Finally, we identified a population of double-negative T cells (KLRG1+HLADR+, in particular) that is associated with MS activity and decreased with CD20 depletion. Full article

The endocannabinoid system (ECS) plays a crucial role in maintaining homeostasis by regulating immune response, energy metabolism, cognitive functions, and neuronal activity. It consists of endocannabinoids (eCBs), cannabinoid receptors (CBRs), and enzymes involved in eCB biosynthesis and degradation. Increasing evidence highlights the involvement of the ECS under several pathological conditions, making it a promising therapeutic target. Recent research efforts have focused on modulating endogenous eCB levels, particularly through the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of the major eCB anandamide. Natural substances, including plant extracts and purified compounds, can inhibit FAAH and represent a promising area of pharmacological research. Natural FAAH inhibitors are particularly attractive due to their potentially lower toxicity compared to synthetic compounds, making them safer candidates for therapeutic applications. Phytocannabinoids, flavonoids, and flavolignans have been shown to efficiently inhibit FAAH. The structural diversity and bioactivity of these natural substances provide a valuable alternative to synthetic inhibitors, and may open new avenues for developing innovative pharmacological tools. Full article

Airway basal cells from chronic obstructive pulmonary disease patients show a reduction in HOXA1 expression and generate an abnormal airway epithelium. Because the specific role of HOXA1 in airway basal cells is not known, we investigated the contribution of HOXA1 in the generation of the airway epithelium, which depends on basal cell proliferation, polarization, and differentiation. Airway stem cells were transduced with an inducible HOXA1 shRNA lentivector to knock down HOXA1 in either proliferating cells or100% confluent cells. The bronchial epithelium expresses HOXA1 near the basement membrane, likely representing basal cells. HOXA1 knockdown in proliferating basal cells attenuated cell proliferation. HOXA1 knockdown in confluent monolayers of basal cells generated an abnormal airway epithelium characterized by goblet cell hyperplasia and an inflammatory phenotype. Compared to the control, HOXA1 knockdown cells showed a decrease in transepithelial resistance, localization of occludin and E-cadherin to the intercellular junctions, reduced expression of occludin but not E-cadherin, and increased expression of TNF-α. Blocking TNF-α increased the expression of occludin in HOXA1 K/D cells. Based on these results, we conclude that HOXA1 plays an important role in cell proliferation, polarization, and differentiation, which are essential steps in airway epithelial generation. Additionally, HOXA1 may regulate occludin expression by inhibiting TNF-α expression. Full article

Interstitial cells of Cajal (ICCs) play a key role in gastrointestinal smooth muscle contractions, but their relationship with anal canal function in advanced haemorrhoidal disease (HD) remains poorly understood. This study uses deep neural network (DNN) models to estimate ICC presence and quantity in anal canal tissues affected by HD. Haemorrhoidectomy specimens were collected from patients undergoing surgery with the LigaSure device. A YOLOv11-based machine learning model, trained on 376 immunohistochemical images, automated ICC detection using the CD117 marker, achieving a mean average precision (mAP50) of 92%, with a recall of 86% and precision of 88%. The DNN model accurately identified ICCs in whole-slide images, revealing that one-third of grade III HD patients and 60% of grade IV HD patients had a high ICC density. Preoperatively, pain was reported in 35% of grade III HD patients and 41% of grade IV patients, with a significant reduction following surgery. A significant decrease in bleeding (p < 0.0001) was also noted postoperatively. Notably, patients with postoperative bleeding, diagnosed with stage IV HD, had high ICC density in their anorectal tissues (p = 0.0041), suggesting a potential link between ICC density and HD severity. This AI-driven model, alongside clinical data, may enhance outcome prediction and provide insights into HD pathophysiology. Full article

Tumor-derived extracellular vesicles (EVs) play an important role in cancer progression. Neutral sphingomyelinases (nSMases) are lipid-modifying enzymes that modulate the secretion of EVs from cells. How nSMase activity and therefore ceramide generation affect the composition and functionality of secreted EVs is not fully understood. Here, we aimed to investigate the expression of nSMases 1 and 2 in prostate cancer (PCa) tissue and their role in EV composition and secretion for prostate cancer cell migration. Reduced nSMase 1 and 2 expression was found in prostate cancer and correlated with the age of the patient. When nSMase 2 was inhibited by GW4869 in PCa cells (PC3 and DU145), the EV secretome was significantly altered, while the number of EVs and the total protein content of released EVs were not significantly changed. Using proteomic analysis, we found that extracellular matrix proteins, such as SDC4 (Syndecan-4) and SRPX-2, were differentially secreted on EVs from GW4869-treated PC3 cells. In scratch wound migration assays, GW4869 significantly increased migration compared to control PC3 cells but not DU145 cells, while SDC4 knockdown significantly reduced the migration of PC3 cells. These and other nSMase-2-dependent secreted proteins are interesting candidates for understanding the role of stress-induced EVs in the progression of prostate cancer. Full article

Extracellular vesicles (EVs) have been explored as promising vehicles for drug delivery. One of the most valuable features of EVs is their ability to cross physiological barriers, particularly the blood–brain barrier (BBB). This significantly enhances the development of EV-based drug delivery systems for the treatment of CNS disorders. The present review focuses on the factors and techniques that contribute to the successful delivery of EV-based therapeutics to the brain. Here, we discuss the major methods of brain targeting which includes the utilization of different administration routes, capitalizing on the biological origins of EVs, and the modification of EVs through the addition of specific ligands on to the surface of EVs. Finally, we discuss the current challenges in large-scale EV production and drug loading while highlighting future perspectives regarding the application of EV-based therapeutics for brain delivery. Full article

Metamorphosis is a common developmental process in invertebrate development. It is essential for the degeneration of larval organs, formation of adult organs, and adaptation transformation of the living environment. However, the underlying molecular regulatory mechanism remains to be elucidated. In this study, we used tail regression of ascidian Styela clava as a model to understand the gene regulation pathway and molecular mechanism in organ metamorphosis. The TGFβ signaling pathway was screened and demonstrated to be involved in tail regression based on RNA sequencing on the different larval stages and verification with inhibitor treatment experiments. We further investigated the downstream gene network of the TGFβ signaling pathway through comparative transcriptome data analysis on the TGFβ pathway inhibition samples. Together with qRT-PCR verification, we identified four critical gene functional categories, including ion transporters/water channel, extracellular matrix structural constituent, extracellular matrix organization, and cell polarity establishment. Furthermore, a cross-species comparative analysis between Ciona robusta and S. clava was performed to understand the conservation and divergence of gene regulation in ascidians. Overall, our work identifies a crucial gene regulation pathway in ascidian tail regression and provides several potential downstream targets for understanding the molecular mechanism of larval metamorphosis. Full article

Aging involves progressive physiological changes, including the dysregulation of water homeostasis, essential for cellular function, neuronal signaling, and musculoskeletal integrity. This review explores the emerging role of water loss as a central and underestimated driver of functional decline in aging, with a focus on the dog, both as a clinically relevant target species and as a model for human aging. Age-related alterations in water metabolism—driven by changes in body composition, aquaporin (AQP) expression, electrolyte imbalances, reduced thirst perception, and impaired urine concentration—lead to intracellular and extracellular dehydration, exacerbating functional decline. We examine molecular mechanisms of water regulation involving AQPs and osmolytes, and describe how dehydration contributes to structural and metabolic dysfunction across key biological compartments, including the kidney, brain, bone, and skeletal muscle. Physiological dehydration, a hallmark of aging, intensifies inflammaging, accelerating tissue degeneration. In particular, we highlight how water loss impairs solvent capacity, solute transport, protein conformation, and cellular communication. Despite the known role of macronutrients in geriatric nutrition, hydration remains an often-overlooked factor in aging management. We argue for its inclusion as a fourth pillar in the nutritional approach to veterinary geriatrics, alongside protein, fat, and fiber. By investigating aging-associated water loss in dogs—species that share environments and lifestyle patterns with humans—we propose hydration-centered strategies to promote healthy aging in both veterinary and comparative medicine. Full article

A20 is a ubiquitin-editing enzyme that has emerged as a key regulator of inflammatory signaling with paradoxical roles in cancer. Acting as both an oncogene and a tumor suppressor gene depending on the cellular context, A20 modulates important cell pathways, such as NF-κB signaling and autophagy. In this review, we summarize the dual roles of A20 in tumorigenesis, highlighting its ability to promote tumor progression in cancers, such as breast and melanoma, while functioning as a tumor suppressor in lymphomas and hepatocellular carcinoma. We discuss the interplay of A20 with autophagy, a process that is important for maintaining cellular homeostasis and influencing tumor dynamics. By integrating recent findings, we provide insight into how dysregulation of A20 and its associated pathways can either suppress or drive cancer development, which may lead to improved therapeutic intervention. Full article

CRISPR-associated endoribonucleases (Cas RNases) cleave single-stranded RNA in a highly sequence-specific manner by recognizing and binding to short RNA sequences known as direct repeats (DRs). Here, we investigate the potential of exploiting Cas RNases for the regulation of target genes with one or more DRs introduced into the 3′ untranslated region, an approach we refer to as DREDGE (direct repeat-enabled downregulation of gene expression). The DNase-dead version of Cas12a (dCas12a) was identified as the most efficient among five different Cas RNases tested and was subsequently evaluated in doxycycline-regulatable systems targeting either stably expressed fluorescent proteins or an endogenous gene. DREDGE performed superbly in stable cell lines, resulting in up to 90% downregulation with rapid onset, notably in a fully reversible and highly selective manner. Successful control of an endogenous gene with DREDGE was demonstrated in two formats, including one wherein both the DR and the transgene driving expression of dCas12a were introduced in one step by CRISPR-Cas. Our results establish DREDGE as an effective method for regulating gene expression in a targeted, highly selective, and fully reversible manner, with several advantages over existing technologies. Full article

Asthma is a complex, multifactorial inflammatory disorder of the airways, characterized by recurrent symptoms and variable airflow obstruction. So far, two main asthma endotypes have been identified, type 2 (T2)-high or T2-low, based on the underlying immunological mechanisms. Recently, extracellular vesicles (EVs), particularly exosomes, have gained increasing attention due to their pivotal role in intercellular communication and distal signaling modulation. In the context of asthma pathobiology, an increasing amount of experimental evidence suggests that EVs secreted by eosinophils, mast cells, dendritic cells, T cells, neutrophils, macrophages, and epithelial cells contribute to disease modulation. This review explores the role of EVs in profiling the molecular signatures of T2-high and T2-low asthma, offering novel perspectives on disease mechanisms and potential therapeutic targets. Full article

The role of a simulated microgravity environment on soybean growth was investigated. The root grew more under simulated microgravity conditions than in the presence of gravity. However, root shortening due to salt stress did not occur in simulated microgravity conditions. To reveal these mechanisms by simulated microgravity environment on soybean root, a proteomic analysis was conducted. Proteomic analysis revealed that among 1547 proteins, the abundances of proteins related to phytohormone, oxidative stress, ubiquitin/proteasome system, cell organization, and cell wall organization were altered under stimulated microgravity compared with gravity. Membrane-localized proteins and redox-related proteins were inversely correlated in protein numbers due to salt stress under gravity and the simulated microgravity condition. Proteins identified by proteomics were validated for protein accumulation by immunoblot analysis. Superoxide dismutase and ascorbate peroxidases, which are reactive oxygen species-scavenging proteins, increased in soybean root under salt stress but not in the simulated microgravity conditions even under stress. The accumulation of 45 kDa aquaporin and 70 kDa calnexin in soybean root under salt stress were increased in the simulated microgravity conditions compared to gravity. These findings suggest that soybean growth under salt stress may be regulated through improved water permeability, mitigation of reactive oxygen species production, and restoration of protein folding under simulated microgravity conditions. Full article

Tuberculosis, primarily caused by Mycobacterium tuberculosis, is an airborne lung disease and continues to pose a significant global health threat, resulting in millions of deaths annually. The current treatment for tuberculosis involves a prolonged regimen of antibiotics, which leads to complications such as recurrence, drug resistance, reinfection, and a range of side effects. This scenario underscores the urgent need for novel therapeutic strategies to combat this lethal pathogen. Over the last two decades, microbiome therapeutics have emerged as promising next-generation drug candidates, offering advantages over traditional medications. In 2022, the Food and Drug Administration approved the first microbiome therapeutic for recurrent Clostridium infections, and extensive research is underway on microbiome treatments for various challenging diseases, including metabolic disorders and cancer. Research on microbiomes concerning tuberculosis commenced roughly a decade ago, and the scope of this research has broadened considerably over the last five years, with microbiome therapeutics now viewed as viable options for managing drug-resistant tuberculosis. Nevertheless, the understanding of their mechanisms is still in its infancy. Although autophagy has been extensively studied in other diseases, research into its role in tuberculosis is just beginning, with preliminary developments in progress. Against this backdrop, this comprehensive review begins by succinctly outlining tuberculosis’ characteristics and assessing existing treatments’ strengths and weaknesses, followed by a detailed examination of microbiome-based therapeutic approaches for drug-resistant tuberculosis. Additionally, this review focuses on establishing a basic understanding of microbiome treatments for tuberculosis, mainly through the lens of autophagy as a mechanism of action. Ultimately, this review aims to contribute to the foundational comprehension of microbiome-based therapies for tuberculosis, thereby setting the stage for the further advancement of microbiome therapeutics for drug-resistant tuberculosis. Full article

The combined application of single-cell RNA sequencing (scRNA-seq) and single-cell B-cell receptor sequencing (scBCR-seq) offers a multidimensional perspective for dissecting the immunopathological mechanisms of B cells in autoimmune diseases. This review systematically summarizes the principles of these techniques, the analytical framework, and their key applications in diseases such as systemic lupus erythematosus et. al. It reveals the dynamic correlations between the transcriptome of B-cell subsets and B-cell receptor (BCR) clones. Furthermore, we focus on the potential roles of dual BCR B cells and B/T biphenotypic cells in autoimmunity, emphasizing their exacerbation of disease progression through abnormal clonal expansion and autoantibody secretion. By sorting through cutting-edge advancements and bottleneck issues, this article aims to propel the innovation of multi-omics research and precision treatment paradigms for autoimmune diseases. Full article