Search Results (4,915)

Chronic kidney disease (CKD) is a progressive disorder that is characterized by the gradual loss of kidney function, often leading to end-stage renal failure. Recent research has highlighted the role of gut dysbiosis and its metabolic byproducts in the pathogenesis of CKD, with a particular focus on short-chain fatty acids (SCFAs). SCFAs, including acetate, propionate, and butyrate, are primarily produced by the fermentation of dietary fibers by the gut microbiota and are known for their systemic anti-inflammatory and immunomodulatory properties. In CKD, gut dysbiosis results in a reduction in SCFA-producing bacteria and an increase in uremic toxin-producing microorganisms, contributing to systemic inflammation, oxidative stress, and renal fibrosis. The depletion of SCFAs has been shown to exacerbate glomerular injury, whereas their presence supports integrity of the glomerular barrier and confers protection against damage. These protective effects are mediated by several mechanisms, including the modulation of immune responses, preservation of epithelial barrier function, and activation of specific receptors, such as G protein-coupled receptor 41 (GPR41), GPR43, and GPR109A. The present review provides a comprehensive overview of current understanding of SCFA-mediated pathways in glomerular protection during CKD progression. It highlights the therapeutic potential of targeting the gut–kidney axis to mitigate CKD progression by examining the complex interplay between gut microbiota and disease development, with a particular focus on strategies to protect the glomerular structure and function. Full article

Chronic periodontitis has emerged as a potential modifiable risk factor for several tumors, yet its role remains underexplored beyond epidemiological associations. This perspective review examines the immunological and molecular interplay between periodontitis and various cancers—including prostate, colorectal, oral squamous cell carcinoma, and oral potentially malignant disorders—highlighting shared inflammatory mediators and immune dysregulation. Special attention is given to immune cell profiles, cytokine expression, dysbiosis, and common miRNA signatures. Recent evidence suggests that periodontitis may act not only as a co-factor in tumor development but also, in some contexts, as a marker of therapeutic response, particularly in patients undergoing immune checkpoint inhibitor therapy. In our view, future research should prioritize mechanistic studies to define common immune–inflammatory pathways and clarify whether periodontitis functions as a field cancerization process or as a facilitator of malignant transformation in already compromised tissues. The relationship between cancer and periodontitis underscores the need to integrate oral health into oncologic care and immunotherapy management. Full article

As the hub of energy metabolism and the cell’s fate arbiter, mitochondria are essential for preserving cellular homeostasis and converting it from pathological states. Therefore, through mechanisms that drive metabolic reprogramming, oxidative stress, and apoptosis resistance, mitochondrial dysfunction (including mitochondrial DNA mutations, mitochondrial dynamics imbalance, mitochondrial autophagy abnormalities, mitochondrial permeability abnormalities, and metabolic disorder) can promote the progression of thyroid cancer (TC), resistance to treatment, and reshaping of the immune microenvironment. This article reviews the molecular mechanisms and characteristic manifestations of mitochondrial dysfunction in TC. It focuses on providing a summary of the main strategies currently used to target the mitochondria, such as dietary intervention and targeted medications like curcumin, as well as the clinical translational value of these medications when used in conjunction with current targeted therapies for TC and radioactive iodine (RAI) therapy in patients with advanced or RAI-refractory TC who rely on targeted therapies. The application prospects and existing challenges of emerging therapeutic methods, such as mitochondrial transplantation, are also discussed in depth, aiming to provide new perspectives for revealing the molecular mechanisms by which mitochondrial dysfunction drives the progression of TC, drug resistance, and the reshaping of its immune microenvironment, as well as providing new diagnostic and therapeutic strategies for patients with advanced or RAI-refractory TC who are reliant on targeted therapies. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation, progressive joint destruction, and systemic complications. Despite significant progress in targeted therapies, major clinical challenges persist, including heterogeneous treatment responses and therapeutic resistance. This review aims to critically evaluate emerging immunomodulatory strategies—focusing on immune checkpoints, microRNAs (miRNAs), and cell-based therapies—as potential diagnostic and therapeutic tools. Methods: This non-systematic literature review involved a comprehensive analysis of recent studies to investigate emerging immunomodulatory strategies in RA. Special attention was given to immune checkpoint pathways—cytotoxic T-lymphocyte antigen 4 (CTLA-4); programmed death-1 (PD-1) and its ligand, PD-L1; and inducible T-cell costimulator (ICOS)—as well as cell-based therapies. Additionally, miRNA-based interventions were examined for their diagnostic and therapeutic potential. Results: Immune checkpoint modulation has demonstrated preclinical efficacy in attenuating inflammatory responses and restoring immune tolerance. Concurrently, miRNAs have emerged as both biomarkers and therapeutic agents, with exosome-based delivery systems enhancing their function. Cell-based therapies have shown robust immunoregulatory effects with acceptable safety profiles. Notably, integrative strategies that combine checkpoint inhibitors, cell-based interventions, and miRNA delivery exhibit synergistic effects and offer a promising avenue for personalised treatment, when guided by molecular and transcriptomic profiling. The majority of these approaches remain at the preclinical or early translational stage. Conclusions: Targeted immunomodulation is poised to transform RA management. The integration of cell therapies, checkpoint inhibition, and miRNA manipulation with omics technologies holds promise for enhancing therapeutic precision and safety. Advancing towards personalised immunotherapy will necessitate a multidisciplinary and patient-centred effort. Full article

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders globally. The molecular relationship between common respiratory infections (RIs) and idiopathic Parkinson’s disease (iPD) remains a controversial issue. Multiple studies have linked acute respiratory infections to PD, but the molecular mechanism behind this connection is not significantly defined. Therefore, the aim of our study was to investigate potential molecular interactions between RIs and PD. We retrieved eight publicly available RNA-seq datasets from the NCBI Gene Expression Omnibus (NCBI GEO) and performed extensive bioinformatics analysis, including differential gene expression (DGE) analysis, the identification of overlapped differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), pathway and functional enrichment analysis, the construction of protein–protein networks, and the identification of hub genes. Additionally, we applied a machine learning method, a Random Forest model (RF), to external RIs datasets to identify the most important genes. We found that ribosomal subunits, mitochondrial complex proteins, proteasome subunits, and proteins encoding ubiquitin are simultaneously downregulated and co-expressed in RIs and PD. Dysregulation of these proteins may disturb multiple pathways, such as those responsible for ribosome biogenesis, protein synthesis, autophagy, and apoptosis; the ubiquitin–proteasome system (UPS); and the mitochondrial respiratory chain. These processes have been implicated in PD’s pathology, namely in the aggregation of α-synuclein, mitochondrial dysfunction, and the death of dopaminergic neuron cells. Our findings suggest that there are significant similarities in transcriptional responses and dysfunctional molecular mechanisms between RIs, PD, and aging. RIs may modulate PD-relevant pathways in an age- or immune-dependent manner; longitudinal studies are needed to examine the RIs risk factor. Therefore, future studies should experimentally investigate the influence of age, vaccination status, infection type, and severity to clarify the role of RIs in PD’s pathogenesis. Full article

Ischemic stroke is a neurological disorder resulting from localized brain injury due to focal cerebral ischemia, typically caused by the blockage of one or, in some cases, a few cerebral arteries. This arterial obstruction leads to hypoxia and energy failure, culminating in primary brain damage. Although reperfusion is critical to salvage viable tissue, it often intensifies injury through oxidative stress, inflammation, and cell death—a phenomenon called ischemia–reperfusion (I/R) injury. Milk fat globule-EGF factor 8 (MFG-E8), a multifunctional glycoprotein secreted by stem and immune cells, is a key regulator of inflammation and tissue repair. By modulating microglial activation, attenuating proinflammatory cytokine releases, and preserving neuronal integrity, MFG-E8 mitigates ischemia–reperfusion injury and emerges as a novel therapeutic target for ischemic stroke. Full article

Background: Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness with complex etiologies involving both genetic and environmental factors. While environmental stress is a known risk factor of MDD, the molecular mechanisms linking stress exposure to persistent depressive phenotypes remain incompletely understood. Methods: We established a 24-hour restraint stress-induced depression model in mice and performed integrated transcriptomic and proteomic analyses of the medial prefrontal cortex (mPFC) to investigate stress-related molecular alterations. Results: Behavioral assessments confirmed persistent depression-like phenotypes, including anhedonia and behavioral despair, lasting up to 35 days post-stress. RNA sequencing identified differentially expressed genes related to dopaminergic signaling and oxidative stress. Proteomic analysis identified 105 differentially expressed proteins involved in immune response and energy metabolism. Integrated multi-omics analysis highlighted convergent disruptions in immune regulation, metabolism, and epigenetic processes. Notably, clemastine exerts its antidepressant-like effects in part by mitigating neuroinflammation and preserving mitochondrial function. Conclusions: These findings provide novel insights into the molecular basis of stress-induced depression and suggest that clemastine is a potential therapeutic candidate. Full article

Anti-lipid autoantibodies are produced in systemic lupus erythematosus (SLE). These antibodies are associated with clinical manifestations of the disease, such as thrombosis, cardiovascular events, and neurological disorders. However, the cellular and molecular mechanisms that lead to the production of these antibodies are not well known. We developed a mouse model of lupus by administering liposomes bearing non-bilayer phospholipid arrangements (NPA) stabilized by chlorpromazine. These mice produce anti-NPA antibodies that trigger a lupus-like disease. In previous studies, we demonstrated that these antibodies are primarily produced by germinal centers and that NK1.1⁺ CD4⁺ T cells provide help to B cells, enabling them to produce these IgG antibodies. However, additional immune cells may contribute to the production of these antibodies. Therefore, in this work, we analyzed the in vivo responses of γδ T cells and macrophages in this mouse model. We found that γδ T cells from mice that produce anti-NPA antibodies produce IFNγ and IL-17, which can contribute to B cell class switching and production of anti-NPA IgG antibodies via germinal centers. Additionally, we found that macrophages are polarized into a proinflammatory M1 phenotype and produce IL-6 that can exacerbate inflammation and potentially lead to autoimmunity. Full article

Vitiligo is an acquired depigmentation disorder characterized by the selective destruction of melanocytes, resulting in the progressive loss of pigment in the skin and hair. This condition frequently leads to significant psychological distress. Its pathogenesis is complex and multifactorial, involving a combination of genetic susceptibility, metabolic derangement related to oxidative stress, defective melanocyte adhesion to the basal epidermis, and dysregulated innate and adaptive immune responses, ultimately converging in the targeted elimination of melanocytes. Despite the availability of several therapeutic modalities, current corrective options are often limited in efficacy and are associated with high relapse rates. There remains a pressing need for novel, safe, and more effective therapeutic strategies to improve patients’ quality of life. Growing evidence indicates that the immune system plays a pivotal role in vitiligo onset and progression, as most triggers converge on inflammatory and autoimmune pathways targeting melanocytes. However, immunosuppressive therapies alone have shown limited effectiveness in halting disease progression and achieving lasting repigmentation. Targeting only immunological processes without addressing the underlying triggers of their activation likely represents a significant limitation in restoring pigmentation. In contrast, interventions aimed at upstream events may help prevent the initiation of the immune response. Consequently, combinatorial therapeutic approaches that target multiple pathogenic pathways and incorporate diverse pharmacological agents are being explored to improve clinical outcomes. This review aims to re-evaluate the intrinsic cellular abnormalities and associated dysregulated signaling pathways in vitiligo, with the goal of identifying novel, effective, nonimmunological treatment strategies. Full article

Macrophages are essential for immune homeostasis, playing crucial roles in immune responses from initiation to resolution. They trigger acute inflammation to promote elimination of pathogens and regulate excessive immune reactions to prevent chronic inflammation and autoimmune diseases. Consequently, macrophage dysfunction contributes to the progression of many disorders that involve inflammation. Cannabinoid Receptor 2 (CB2) has emerged as a promising therapeutic target due to its role in regulating macrophage-mediated immune functions, including via modulation of cytokine secretion, migration, phagocytosis, and polarisation. CB2 activation can produce beneficial outcomes via suppressing macrophage-mediated inflammatory pathways in animal models for various diseases that involve acute or chronic central or peripheral inflammation, whereas blocking CB2 may have utility when macrophage polarisation to a “resolving” phenotype is deleterious, such as in tumour-associated macrophages. However, despite abundant promising preclinical results, the relatively few CB2-selective agonists tested in clinical trials to date have exhibited limited efficacy. Here, we provide an overview of the roles of macrophages in health and disease, thoroughly review in vitro and in vivo preclinical findings on CB2-mediated modulation of macrophage function, summarise current progress in clinical trials for CB2-targeted compounds, and discuss approaches for addressing current challenges in ongoing efforts toward developing safe and effective CB2-targeted therapeutics. Full article

This comprehensive review examines the multifaceted interactions between influenza viruses and the ocular system, integrating viral pathogenesis, clinical manifestations, and vaccine-related considerations. Influenza A subtypes (H7, H1N1, H5N1) and influenza B viruses induce a spectrum of ocular complications, from mild conjunctivitis—predominantly associated with H7 avian strains—to sight-threatening disorders like uveal effusion syndrome, acute macular neuroretinopathy, and optic neuritis. Experimental evidence confirms viral replication in human corneal and retinal cells, with H7N7 demonstrating unique tropism for ocular tissues via NF-κB-mediated inflammatory pathways. Clinical cases highlight direct viral invasion and immune-mediated mechanisms, such as Vogt–Koyanagi–Harada disease exacerbation and retinal vasculitis. Rarely, influenza vaccination has been linked to oculorespiratory syndrome, uveitis, and demyelinating events, though large-scale epidemiological studies (e.g., WHO safety reports) confirm vaccines’ favorable risk–benefit profile, distinguishing true adverse events from temporal associations. This synthesis emphasizes the need for ophthalmologists to prioritize surveillance during influenza seasons, integrating diagnostic tools like conjunctival RT-PCR and optical coherence tomography. Future research should focus on defining viral receptor-binding mechanisms in ocular tissues and developing targeted therapies for severe retinopathies, while reinforcing vaccination as a cornerstone of public health despite rare ocular risks. Full article

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain’s resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies. Full article

Background/Objectives: Children with Down syndrome (DS) present unique and multifaceted nutritional challenges arising from genetic, metabolic, and developmental factors. Despite growing interest in the health of individuals with DS, dedicated nutritional guidelines tailored to their specific needs remain lacking. This narrative review aims to summarize current scientific evidence on nutritional status, challenges, and therapeutic strategies in children with DS, with an emphasis on clinical implications and practical recommendations for healthcare professionals. Methods: A literature search was conducted across four databases (PubMed, Scopus, Web of Science, and Google Scholar) for English-language publications from 1993 to June 2025. Thirty-five peer-reviewed articles were included, comprising original studies, narrative reviews, and expert guidelines (e.g., the American Academy of Pediatrics [AAP], the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN], and the European Federation of Associations of Dietitians [EFAD]). The selection process followed the PRISMA protocol. Studies were categorized according to key themes: energy requirements, comorbidities, feeding difficulties, nutrient needs, and therapeutic interventions. Results: Children with DS typically exhibit lower basal metabolic rates and altered body composition (i.e., higher fat mass and reduced lean mass), which increase their risk of both obesity and nutrient deficiencies. Common comorbidities—such as hypothyroidism, celiac disease, and gastrointestinal or immune disorders—further complicate dietary management. Feeding difficulties, including sucking/swallowing impairments, food selectivity, neophobia, and delayed independence in eating, are prevalent and significantly affect diet quality. Key nutrients of concern include protein, omega-3 fatty acids, fiber, vitamins B12 and D, iron, and antioxidants. Although no official nutrition guidelines currently exist for this population, existing recommendations from pediatric and dietetic organizations provide partial guidance that can be adapted to clinical practice. Conclusions: There is an urgent need to develop evidence-based, population-specific dietary guidelines for children with Down syndrome. Clinical nutrition care should be individualized, multidisciplinary, and proactive, integrating regular assessments of growth, feeding abilities, and biochemical markers. Dietitians must play a central role in both early intervention and long-term management. Further research, particularly interventional studies, is essential to optimize dietary strategies and improve health outcomes in this vulnerable population. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD)—previously known as non-alcoholic fatty liver disease (NAFLD)—is currently the most common chronic liver disease globally. Observational studies have reported that MASLD is independently associated with extrahepatic disorders, such as chronic kidney disease (CKD). Severe forms of MASLD (i.e., steatohepatitis and liver fibrosis) are even more strongly associated with the risk of incident kidney dysfunction. Hypothetically, MASLD could directly promote CKD through liver-derived endocrine and metabolic mediators, hemodynamic alterations, immune-mediated mechanisms, and oxidative or cellular stress. However, proving that MASLD directly causes CKD is difficult due to the multiple shared cardiometabolic and systemic risk factors, such as obesity, hypertension, and type 2 diabetes mellitus, which serve as confounding variables. Moreover, studies on the association between MASLD and CKD have differed in their designs, sampling methods, disease definitions, and inclusion criteria, precluding more robust evidence supporting a causal relationship. Furthermore, few studies have explored specific issues, such as the new nomenclature for steatotic liver disease, the relationship between these diseases in pediatric populations, the impact of MASLD plus alcohol intake (MetALD) on CKD, and therapeutic options targeting MASLD and CKD simultaneously. Answers to these issues are essential, as the appropriate management of patients with MASLD may prevent or ameliorate kidney dysfunction. The aims of the present study are to describe shared risk factors between MASLD and CKD, the possible direct pathogenic effect of MASLD on kidney structure and function, and gaps in the current literature, to indicate future research directions. Full article

Introduction: Bovine leukemia virus is a single-stranded RNA virus that targets B cell CD5⁺ lymphocytes in cattle. Only a tiny percentage of individuals develop malignant lymphoproliferative disorders, while most remain healthy carriers or experience persistent lymphocytosis. The exact mechanisms leading to lymphoma development are complex and not fully understood. RNA-seq analysis of cows’ peripheral blood leukocytes (PBLs) with and without Bovine leukemia virus (BLV) antibodies was conducted to gain a deeper understanding of molecular events beyond BLV infection. Method: Eighteen samples were selected, and their RNA was sequenced. For gene expression analysis and protein–protein network interactions, three groups were selected, including healthy negative samples (CT, n = 7), asymptomatic carriers (AC, n = 5), and persistent lymphocytosis (PL, n = 6), to provide the differentially expressed gene (DEG) and protein–protein interaction network (PPIN) outputs. Results: Our results demonstrated that in comparison to CT, ACs upregulated TLR7 and transcription activation factors. In the CT vs. PL group, MHC class II, transcription activation factors, and anti-inflammatory cytokines increased, while the acute-phase proteins, antiviral receptors, and inflammatory cytokines decreased. Additionally, antiviral receptors, acute-phase proteins, and inflammatory receptors were downregulated in the PL versus the AC groups. Moreover, PPINs analysis suggested that nuclear receptor corepressor 1 (NCOR1), serine/arginine repetitive matrix 2 (SRRM2), LUC7 like 3 pre-mRNA splicing factor (LUC7L3), TWIST neighbor (TWISTNB), U6 small nuclear RNA and mRNA degradation associated (LSM4), eukaryotic translation elongation factor 2 (EEF2), ubiquitin C (UBC), CD74, and heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNP A2B1) are possible hub gene candidates in the PL group. Conclusions: Our results suggest that innate and cellular immune responses are more loose in severe BLV infectious conditions, while the PPINs revealed that new protein interactions are necessary for oncogenesis. Full article