Search Results (15,462)

IgA nephropathy (IgAN) is the most common primary chronic glomerular disease worldwide. Its clinical features include proteinuria and complement pathway activation, which are the strongest predictors of progression to renal failure. This disease can occur at any age. Approximately 30–40% of IgAN patients progress to end-stage renal disease (ESRD) within 20–25 years after diagnosis, making it one of the major causes of ESRD. As understanding of the autoimmune development of IgA nephropathy (IgAN) grows, research shows that BAFF and APRIL promote B-cell activation by binding to the receptors TACI, BCMA, and BAFF-R. This results in the overproduction of galactose-deficient IgA1 (Gd-IgA1), which helps drive the progression of IgA nephropathy. B-cell and plasma cell-targeted therapies, such as biologics against BAFF/APRIL, can precisely and effectively improve patient symptoms. Corresponding agents have now been successfully developed and are administered via subcutaneous or intravenous injection. Clinical trials have demonstrated the significant effectiveness of this approach, especially in reducing proteinuria, stabilizing eGFR, and lowering Gd-IgA1 levels. Although current trial data for BAFF/APRIL-targeted biologics in IgA nephropathy are promising, these new treatments need ongoing clinical monitoring for long-term infection risks and potential drug resistance. This article focuses on the application of BAFF/APRIL biologics in the treatment of IgA nephropathy, addressing gaps in existing literature. While prior studies have emphasized the mechanisms of action of these drugs in IgA nephropathy, they have lacked a comprehensive summary of the current status of specific drug research and clinical progress. Full article

Lower respiratory tract infections caused by Pseudomonas aeruginosa are a global concern. Patients with chronic lung diseases such as cystic fibrosis and non-cystic fibrosis bronchiectasis often do not receive adequate antibiotic delivery through conventional routes. P. aeruginosa employs several mechanisms, including biofilm formation and efflux pumps to limit the accumulation of bactericidal drug concentrations. Direct drug delivery to the lung epithelial lining fluid can increase antibiotic concentration and reduce treatment failure rates. This review discusses current research and developments in inhaled antibiotic formulations for treating P. aeruginosa infections. Recent studies on particle engineering for the dry powder inhalers of antibiotics emphasized three fundamental principles of development: micro, nano, and nano-in-microparticles. Carrier-free microparticles showed potential for high-dose delivery but suffered from poor aerosolization, which could be improved through a drug–drug combination. Amino acids in a co-spray-dried system improved powders’ aerodynamics and reduced moisture sensitivity while incorporating the chitosan/poly(lactic-co-glycolic acid) (PLGA)-modified release of the drug. Nano-in-microsystems, embedding lipid carriers, showed improved antibiofilm activity and controlled release. We also highlight emerging biologics, including antibacterial proteins/peptides, vaccines, bacteriophages, and probiotics. Research on antibiotics and biologics for inhalation suggests excellent safety profiles and encouraging efficacy for some formulations, including antimicrobial peptides and bacteriophage formulations. Further research on novel molecules and synergistic biologic combinations, supported by comprehensive animal lung safety investigations, will be required in future developments. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by the viral spike proteins, which are key structural components that mediate host cell binding and entry and alter downstream signaling through multiple interactions with endothelial surface receptors. Endothelial dysfunction is a central consequence of COVID-19, contributing to vascular inflammation, barrier disruption, thrombosis, and multi-organ injury affecting the pulmonary, cardiovascular, cerebral, and renal systems. Emerging evidence demonstrates that spike protein-mediated effects, independent of productive viral infection, disrupt endothelial homeostasis through angiotensin-converting enzyme 2 (ACE2) dysregulation, integrin engagement, altered calcium signaling, junctional protein remodeling, oxidative stress, and pro-inflammatory and pro-apoptotic pathways. This review is intentionally focused on spike (S) protein-driven mechanisms of endothelial dysfunction; pathogenic vascular effects attributed to other SARS-CoV-2 structural proteins, including the nucleocapsid (N) protein, are beyond the scope of this discussion. In this review, we synthesize current experimental and translational data detailing the molecular mechanisms by which the SARS-CoV-2 spike protein drives endothelial dysfunction across multiple organ systems and discuss potential therapeutic strategies aimed at preserving endothelial integrity in acute COVID-19 and its long-term vascular sequela. Full article

Since its emergence in 2019, SARS-CoV-2 has resulted in more than 7.1 million deaths worldwide. It has been shown that co-infection with influenza A virus (IAV) can worsen clinical symptoms in COVID-19 patients and small animal models have been used to elucidate the molecular mechanisms of co-infection between SARS-CoV-2 and IAV. This study aimed to establish a co-infection model in pigs, a natural reservoir for IAV but resistant to SARS-CoV-2 infection, by determining whether pigs become susceptible to SARS-CoV-2 following a primary IAV infection. Here, pigs were primarily infected with swine influenza A virus (SIV) via the intratracheal route and, 3 days later, secondarily challenged with SARS-CoV-2. SIV was isolated from nasal swabs, and pigs seroconverted to SIV. In contrast, SARS-CoV-2 RNA was detected in nasal and oropharyngeal swabs only at day 1 post-secondary challenge, with no evidence of seroconversion against SARS-CoV-2. These data indicate that pigs are not susceptible to SARS-CoV-2 following SIV infection and therefore are not a suitable model for IAV/SARS-CoV-2 co-infection research. Full article

Diabetic foot complications represent a major global health burden and arise from a multifactorial interaction between neuropathy, ischemia, infection, and impaired wound repair. Increasing evidence suggests that, beyond traditional vascular and metabolic risk factors, endocrine dysregulation plays a central role in shaping vascular dysfunction and tissue vulnerability in patients with diabetes. This narrative review provides an updated overview of the endocrine–vascular axis in the development, progression, and healing of diabetic foot ulcers (DFUs), integrating evidence from experimental and clinical studies identified through targeted searches of PubMed, Embase, and Scopus. We examine how alterations in insulin signaling, relative glucagon excess, adipokine imbalance, dysregulation of stress hormones, and thyroid dysfunction interact with chronic hyperglycemia, dyslipidemia, mitochondrial dysfunction, and low-grade inflammation to impair endothelial homeostasis. These disturbances promote oxidative stress, reduce nitric oxide bioavailability, and compromise microvascular perfusion, thereby creating a pro-ischemic and pro-inflammatory tissue environment that limits angiogenesis, extracellular matrix (ECM) remodeling, immune coordination, and effective wound repair. By linking pathophysiological mechanisms to clinical relevance, this review highlights potential biomarkers of endocrine–vascular dysfunction, implications for risk stratification, and emerging therapeutic perspectives targeting metabolic optimization, endothelial protection, and hormonal modulation. Finally, key knowledge gaps and priority areas for future translational and clinical research are discussed, supporting the development of integrated endocrine-based strategies aimed at improving DFU prevention, healing outcomes, and long-term limb preservation in patients with diabetes. Full article

Cardiovascular disease (CVD) is increasingly recognized as a significant comorbidity in people living with HIV (PWH), contributing to increased morbidity and mortality. Epidemiological studies indicate that PWH have a 1.2–2-fold higher risk of myocardial infarction (MI) and other CVD events compared to HIV-negative individuals. While the mechanisms underlying HIV-associated CVD are not fully understood, they are likely to include a combination of cardiovascular-related adverse effects of HIV medications, vascular dysfunction caused by HIV-induced monocyte activation, and cytokine secretion, in addition to existing comorbidities and lifestyle choices. This comprehensive review examines the complex relationship between HIV infection and CVD, highlighting key pathophysiological mechanisms such as chronic immune activation, inflammation, endothelial dysfunction, and the role of antiretroviral therapy (ART) in promoting cardiovascular risk. Alongside conventional risk factors such as smoking, hypertension, and dyslipidemia, HIV-specific elements, especially metabolic abnormalities associated with ART, significantly contribute to the development of CVD. Prevention strategies are crucial, focusing on the early identification and management of cardiovascular risk factors as well as optimizing ART regimens to minimize adverse metabolic effects. Clinical guidelines now recommend routine cardiovascular risk assessment in PWH, emphasizing aggressive management tailored to their unique health profiles. However, challenges exist in fully understanding the cardiovascular outcomes in this population. Future research directions include exploring the role of inflammation-modulating therapies and refining sustainable prevention strategies to mitigate the growing burden of CVD in PWH. Full article

Interferon-stimulated genes (ISGs) are classically recognized for their direct antiviral functions, such as viral genome degradation or replication blockade. However, emerging evidence reveals that ISGs orchestrate a broader landscape of host defense by rewiring cellular metabolism. These mechanisms are still not fully understood in the context of antiviral immunity. This review synthesizes recent advances in understanding how ISGs modulate metabolic pathways (e.g., glycolysis, lipid metabolism, amino acids, and nucleotide metabolism) to create an antiviral cellular environment. However, viruses have developed strategies to evade or counteract ISG-encoded proteins, and some even hijack certain ISGs to their advantage. Therefore, we further explore how viruses subvert these ISG-driven metabolic to evade host defenses. Overall, we summarize the current state of knowledge on the interactions between viruses and ISGs and propose that ISGs act as “protective” or “pathogenic” regulators at the dimensions of metabolism, offering new perspectives for targeting host-centered pathways to combat viral infections. Full article

Plum (Prunus salicina Lindl.), belonging to the genus Prunus in the Rosaceae family, is one of the most widely cultivated deciduous fruit trees globally. Plums are renowned for their round, sweet fruits, which are rich in a variety of bioactive compounds and are deeply loved by consumers. However, in 2021, alarming reddish-brown–dark brown sunken lesions appeared on the fruits of Qingcui plums in Wanzhou, Chongqing, China. The pathogens were identified as Colletotrichum nymphaeae, Fusarium sulawesiense, and Fusarium pernambucanum. The present study further describes the growth patterns and pathogenic differences of these strains in different environments, elucidating their infection mechanisms and pathogenic characteristics; these findings provide a theoretical basis for the efficient management of plum brown spot disease. Additionally, we determined that fluazinam is the most effective control agent against the plum brown rot caused by these pathogens. Notably, this study is the first to document plum brown spot disease induced by C. nymphaeae in China. These findings are intended to provide a vital theoretical framework for the scientific management and control of plum brown spot; furthermore, they underscore the necessity of proactive prevention strategies in agricultural settings. Full article

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and constitute a substantial economic burden. Despite population aging, recent years have witnessed an increasing prevalence of conditions such as heart failure (HF), including among young adults. In this context, coronary artery disease (CAD) has also become an increasingly discussed issue. It has long been recognized that control of risk factors is crucial for prevention. Researchers stress the need to monitor these factors from the earliest stages of life, and detailed analyses indicate an influence of the prenatal period on the development of chronic diseases, including cardiovascular disorders. Transgenerational and intergenerational epigenetic mechanisms are also taken into account. This review aims to systematically evaluate the existing literature and summarize the mechanisms that may link these factors. We consider epigenetic, metabolic, immunological, and inflammatory influences. We describe examples of environmental exposures, such as air pollution, maternal diet, toxins, and infections, and analyze data derived from clinical studies. We discuss gaps in the literature and identify limitations, outlining directions for future research and emphasizing the need for CVD prevention initiated at the earliest stages of life. Full article

Epstein–Barr virus (EBV) is a key oncogenic pathogen implicated in the development of lymphomas, particularly among HIV-positive and immunocompromised individuals. While the association between EBV and lymphoma is well established, the mechanisms underlying progression from infection to malignancy—especially in the head and neck region—remain incompletely understood. This review offers a comprehensive analysis of the pathophysiological pathways by which EBV and HIV contribute to lymphomagenesis, with an emphasis on latency patterns, immune evasion, and epigenetic “hit and run” oncogenesis. Notably, it integrates novel findings on the diagnostic implications of EBV latency proteins, explores HIV-mediated B-cell dysregulation, and evaluates the emerging landscape of targeted therapies, including monoclonal antibodies and lytic cycle inducers. By focusing specifically on head and neck lymphomas, this review underscores a clinically underrepresented domain and offers insights that may guide future diagnostics, surveillance, and treatment strategies in vulnerable patient populations. This review also highlights the pressing need for improved animal models and continued research into EBV-specific therapeutic targets. Full article

During viral infection, NLR family CARD domain-containing protein 5 (NLRC5) participates in innate immunity through multiple mechanisms. These include regulating type I interferon and related immune factor expression, as well as modulating immune cell functions, such as cytotoxic T lymphocytes (CTLs) and macrophages, thereby promoting antiviral defence and maintaining immune homeostasis. Our study demonstrates that (1) Enterovirus 71 (EV71) infection upregulates NLRC5 expression through the RIG-I-IRF3-mediated IFN-β pathway, which in turn promotes MHC-I molecule expression and (2) NLRC5 suppresses EV71 replication and simultaneously restrains excessive inflammatory responses by fine-tuning IFN-β production through a negative feedback loop. This loop operates via two distinct mechanisms, namely, direct downregulation of key IFN-β pathway mediators (e.g., RIG-I and IRF3) and binding to the 5′UTR of the EV71 genome to inhibit viral replication, thereby indirectly dampening the IFN-β signal. Furthermore, we show that EV71 activates the NLRC5-dependent MHC-I response in an IFN-β-dependent manner. Collectively, these results elucidate the dual role of NLRC5 during EV71 infection, offering novel insights into viral pathogenesis and highlighting potential targets for antiviral drug development. Full article

Tomato spotted wilt virus (TSWV) is one of the most important plants segmented negative-strand RNA viruses (NSVs). Plants employ the ubiquitin–proteasome system (UPS) and autophagy pathways to degrade viral effector proteins, forming a key antiviral defense layer. SnRK1 functions as a central energy sensor and plays pivotal roles in plant growth and development, as well as immune defense. However, whether SnRK1 modulates the infection of plant segmented NSVs and the underlying regulatory mechanisms remains elusive. In this study, we found that nonstructural protein NSs, a viral suppressor of RNA silencing (VSR) encoded by TSWV, specifically interacts with the catalytic α subunit of host SnRK1 (SnRK1α). NbSnRK1α promotes the degradation of NSs via the 26S proteasome pathway, independently of autophagy. Transient silencing of NbSnRK1α led to increased accumulation of the NSs protein. Furthermore, we found that NbSnRK1α significantly impairs the VSR activity of NSs by promoting its degradation, thereby restoring the host’s RNAi-mediated antiviral defense. Subsequent viral infection assays confirmed that NbSnRK1α inhibits TSWV replication, whereas silencing NbSnRK1α enhances the susceptibility of Nicotiana. benthamiana to TSWV infection and facilitates systemic viral spread and disease symptom development. Our study uncovers a new antiviral defense case by which NbSnRK1α enhances host antiviral immunity through targeting a segmented negative-strand RNA viral effector for 26S proteasomal degradation, broadening the understanding of the NbSnRK1’s role in broad-spectrum antiviral defense. Full article

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that relies on the molecular chaperone heat shock cognate 70 kDa protein (HSC70) and the lysosomal receptor LAMP-2A. By recognizing substrate proteins containing KFERQ-like pentapeptide motif, CMA plays a central role in multiple infectious contexts. In host defense and cellular homeostasis, CMA contributes to organelle quality control by selectively degrading damaged or misfolded proteins, including stress- or organelle-associated substrates, thereby limiting pathogen replication while mitigating infection-induced stress and preserving cellular function. Although its detailed mechanisms remain incompletely defined, CMA is thought to involve coordinated steps in which molecular chaperones recognize specific target sequences, recruit autophagy-related components, and deliver substrates for lysosomal translocation and degradation. Recent studies have revealed substantial progress in understanding CMA during viral, bacterial, and fungal infections, identifying key regulatory nodes and signaling pathways. These advances underscore the therapeutic potential of CMA-targeted strategies, such as stabilizing LAMP-2A or enhancing HSC70-mediated substrate recognition. However, the spatiotemporal specificity of CMA’s pro- or antiviral effects remains a major challenge for clinical translation. This review summarizes current progress in this emerging field and highlights unresolved questions, particularly whether tissue- or cell-type-specific regulation of CMA occurs during infection and how precise modulation of CMA activity might achieve optimal anti-infective outcomes. Full article

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder, often accompanied by low-grade inflammation, visceral hypersensitivity and gut microbiota dysbiosis. In this study, the therapeutic potential of Lactiplantibacillus plantarum LPPerfectus001 (L. plantarum 001) was investigated to alleviate IBS symptoms. Using an Lipopolysaccharides (LPS)-induced RAW264.7 macrophage model, L. plantarum 001 demonstrated significant anti-inflammatory properties by inhibiting Nitric Oxide production and downregulating pro-inflammatory cytokines. Furthermore, in a mouse model of IBS induced by Citrobacter rodentium infection and water avoidance stress, L. plantarum 001 intervention reduced fecal moisture, improved intestinal barrier integrity via up-regulating of ZO-1 and MUC2, and attenuated visceral hypersensitivity. Transcriptomic analysis combining with RT-qPCR revealed that L. plantarum 001 modulated the NF-κB signaling pathway and Th1/Th2 cell differentiation, reducing expression of key inflammatory genes. Additionally, 16S rRNA sequencing showed that L. plantarum 001 restored gut microbiota diversity, enriched beneficial butyrate-producing Odoribacter, and suppressed pro-inflammatory Pseudomonadota. These findings suggested that L. plantarum 001 alleviates IBS through multi-targeted mechanisms involving barrier repair, microbiota modulation, and anti-inflammatory signaling, highlighting its potential as a probiotic therapy for IBS. Full article

Aging is accompanied by progressive gastrointestinal structural and functional decline, increased intestinal permeability, dysbiosis, and impaired mucosal immunity, collectively elevating susceptibility to infections, chronic inflammation, and multimorbidity. These age-related changes are further exacerbated by polypharmacy, metabolic disorders, and lifestyle factors, positioning the gastrointestinal tract as a central driver of systemic physiological decline. Gut-centered interventions have emerged as critical strategies to mitigate these vulnerabilities and support healthy aging. Dietary modulation, prebiotic and probiotic supplementation, and microbiota-targeted approaches have demonstrated efficacy in improving gut microbial diversity, enhancing short-chain fatty acid production, restoring epithelial integrity, and modulating immune signaling in older adults. Beyond nutritional strategies, non-nutritional interventions such as molecular hydrogen and medical ozone offer complementary mechanisms by selectively neutralizing reactive oxygen species, reducing pro-inflammatory signaling, modulating gut microbiota, and promoting mucosal repair. Hydrogen-based therapies, administered via hydrogen-rich water or inhalation, confer antioxidant, anti-inflammatory, and cytoprotective effects, while ozone therapy exhibits broad-spectrum antimicrobial activity, enhances tissue oxygenation, and stimulates epithelial and vascular repair. Economic considerations further differentiate these modalities, with hydrogenated water positioned as a premium wellness product and ozonated water representing a cost-effective, scalable option for geriatric gastrointestinal care. Although preclinical and early clinical studies are promising, evidence in older adults remains limited, emphasizing the need for well-designed, age-specific trials to establish safety, dosing, and efficacy. Integrating dietary, microbiota-targeted, and emerging non-nutritional gut-centered interventions offers a multimodal framework to preserve gut integrity, immune competence, and functional health, potentially mitigating age-related decline and supporting overall health span in older populations. Full article