Search Results (250)

Hypertension remains a major driver of multi-organ damage, including cardiac remodeling and hepatic complications. The ketone body β-hydroxybutyrate (BHB) has emerged as a potential metabolic signaling molecule with anti-inflammatory properties. This study investigated whether BHB attenuates cardiac stress and hepatic injury in a salt-sensitive hypertensive model. Dahl salt-sensitive (DS) rats were fed a high-salt (HS) diet combined with a choline-deficient diet to induce cardiac inflammation and hepatic fibrosis. Rats received either BHB or a control vehicle. We found that BHB significantly suppressed hepatic lipid accumulation and fibrotic markers, including TGF-β and collagen III mRNA, even under severe dietary stress. In the heart, BHB attenuated the expression of inflammatory markers (TNF-α and ANP) despite the persistence of high systolic blood pressure. These results demonstrate that BHB exerts direct organ-protective effects through anti-inflammatory and anti-fibrotic actions that are independent of robust blood pressure reduction. Our findings suggest that BHB could be a promising metabolic intervention for managing multi-organ complications in hypertensive patients with metabolic comorbidities. Full article

Background: Natto, a well-known fermented soybean product beneficial for bone health, remains unclear in its mechanism. Methods: This study investigated its effect on secondary osteoporosis (OP) in mice. Results: Natto significantly inhibited weight loss, bone quality deterioration, and bone morphological damage, and regulated OPG/RANKL pathway protein expression (p < 0.05) in OP mice. Analysis of 16S rRNA revealed that natto increased gut microbiota α-diversity and the abundance of Sutterella, Roseburia, and Coprococcus, while reducing harmful bacteria such as Streptococcus, Shigella, and Helicobacter. These microbial changes positively correlated with body weight, bone size, and serum osteogenic metabolism in OP mice. Serum metabolomics showed differential metabolites of the natto group enriched in PPAR signaling and primary bile acid biosynthesis. Verification by mRNA and ELISA indicated that the upregulated liver and circulating PPARα by natto may regulate downstream bile acid pathways, linking gut microbiota to multi-organ metabolic functions. Conclusions: In summary, natto may act on gut microbiota to alleviate bone loss via the “gut microbiota–bile acid–OPG/RANKL” network, targeting multiple organs including gut, liver, and bone. This provides a theoretical basis for natto dietary intervention in osteoporosis prevention through the gut–bone axis. Full article

Sickle Cell Disease (SCD) is a pervasive monogenic disorder characterized by chronic hemolytic anemia, unpredictable vaso-occlusive crises, and progressive multi-organ damage, representing a significant global health burden. Driven by a point mutation in the β-globin gene, the resulting abnormal Hemoglobin S (HbS) polymerizes under deoxygenated conditions, leading to erythrocyte sickling and systemic endothelial dysfunction. While supportive therapies such as hydroxyurea and transfusions manage symptoms, the mandate for definitive curative therapies is urgent. Historically, allogeneic hematopoietic stem cell transplantation (HSCT) utilizing matched sibling donors (MSD) has been the sole curative option, offering high survival rates but constrained by limited donor availability and the risk of graft-versus-host disease (GVHD). Consequently, alternative donor sources, including matched unrelated donors, umbilical cord blood, and haploidentical donors, have expanded patient access, particularly with the integration of post-transplant cyclophosphamide (PTCy) to mitigate alloreactivity. Concurrently, the advent of autologous gene therapy, encompassing lentiviral gene addition (Lyfgenia) and CRISPR-Cas9 gene editing (Casgevy) offers a revolutionary donor-independent approach that eliminates GVHD risk. Lyfgenia employs a lentiviral vector to introduce an anti-sickling βT87Q hemoglobin variant into autologous hematopoietic stem cells, while Casgevy employs CRISPR-Cas9 to disrupt the erythroid-specific enhancer of the BCL11A transcription factor, derepressing γ-globin expression and elevating fetal hemoglobin. This review synthesizes the pathophysiological mechanisms of SCD, evaluates the clinical outcomes and limitations of both allogeneic HSCT and autologous gene therapies, and outlines the clinical decision-making paradigms and future innovations required to achieve equitable global access to these transformative treatments. Full article

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterised by elevated serum levels of IgG4 and multiorgan damage. Its diagnosis is challenging and requires a careful integration of clinical, radiological, serological and histological data. Pancreatic and biliary involvement is one of the most common manifestations of IgG4-RD, presenting as type 1 autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC), two entities that often occur synchronously and may mimic malignancy in the form of pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma, respectively. The main objective of this article is to illustrate the key imaging features of AIP and IgG4-SC on computed tomography (CT) and magnetic resonance imaging (MRI), providing a comprehensive review of their current diagnostic criteria and discussing their differential diagnosis with other benign and malignant conditions. Full article

Background: Acrylamide (ACR), a toxic compound formed during high-temperature cooking of carbohydrate-rich foods, is known to induce multi-organ toxicity, including oxidative and inflammatory lung injury. N-Acetylcysteine (NAC), a precursor of glutathione (GSH), possesses potent antioxidant and anti-inflammatory properties that may counteract ACR-induced pulmonary damage. This study investigated the protective effects of NAC against ACR-mediated lung toxicity, with an emphasis on the GSK-3β/Nrf2/NF-κB signaling axis. Methods: Forty male Wistar rats were allocated into four groups: control, NAC (250 mg/kg/day), ACR (50 mg/kg/day), and NAC + ACR. After 11 days of treatment, lung tissues were examined histopathologically using H&E, PAS, and Masson’s trichrome stains. Oxidative stress biomarkers (MDA, SOD, GPx, CAT, GSH) were quantified biochemically. Immunohistochemistry and qRT PCR assessed expression of Nrf2, NF-κB, IL-1β, and Caspase 3, while ELISA measured TNF α, IL-6, Bax, Bcl 2, and GSK 3β. Results: ACR exposure resulted in severe lung injury characterized by alveolar wall edema, epithelial hyperplasia, leukocytic infiltration, goblet cell hyperplasia, and peribronchiolar collagen deposition. These pathological changes were accompanied by a marked increase in MDA, NF-κB, IL-1β, TNF α, IL-6, Bax, Caspase 3, and GSK 3β, together with significant reductions in antioxidant enzymes and Nrf2/HO 1/NQO1 expression. NAC co-administration significantly ameliorated ACR-induced lung damage, restoring normal histological architecture, reducing fibrosis, and normalizing goblet cell activity. NAC also reversed oxidative stress, enhanced Nrf2 and downstream antioxidant responses, suppressed NF-κB-mediated inflammation, and mitigated apoptosis. Notably, NAC downregulated ACR-induced GSK 3β activation, thereby contributing to balanced redox and inflammatory signaling. Conclusions: NAC confers significant protection against ACR-induced pulmonary toxicity through its antioxidant, anti-inflammatory, and anti-apoptotic activities. These effects are mediated, at least in part, by modulation of the GSK 3β/Nrf2/NF-κB pathway. NAC demonstrates promising therapeutic potential for preventing chemically induced lung injury. Full article

Type 2 diabetes (T2D) is a multifactorial metabolic disorder characterized by chronic hyperglycemia, insulin resistance, and progressive β-cell dysfunction. Chronic hyperglycemia in T2D causes multi-organ and systemic damage, leading to a wide range of complications, including cardiovascular disease and metabolic dysfunction-associated steatotic liver disease (MASLD). Brown seaweeds are increasingly recognized as promising marine-derived functional foods because they contain structurally unique bioactive compounds, including fucoidan, alginate, phlorotannins, and fucoxanthin. A growing body of evidence suggests that these compounds influence glucose homeostasis through multiple mechanisms, including improvement of pancreatic β-cell function, regulation of gut-mediated metabolic processes, and modulation of glucose metabolism and insulin signaling in the liver, adipose tissue, and skeletal muscle, and attenuation of chronic inflammation and oxidative stress. Brown seaweed-derived bioactive compounds have also been reported to improve abnormal lipid metabolism, a key pathological process implicated in metabolic disorders associated with T2D, including MASLD. This review provides an overview of the antidiabetic potential of brown seaweeds, with a particular focus on the mechanisms of action of their major bioactive compounds, including fucoidan, alginate, phlorotannins, and fucoxanthin. Full article

Endotoxemia represents a life-threatening clinical disorder driven by an aberrant host immune response to pathogenic infection, often resulting in severe multiple organ dysfunction. Among its most devastating complications are acute lung injury (ALI) and endotoxemia-associated encephalopathy (EAE), both of which are associated with elevated mortality and currently lack effective targeted interventions. This study evaluated the therapeutic efficacy and underlying molecular mechanisms of recombinant human thymosin β4 (rhTβ4) in a murine model of lipopolysaccharide (LPS)-induced endotoxemia. Our results showed that treatment with rhTβ4 markedly enhanced survival rates and diminished the systemic overproduction of diverse proinflammatory cytokines and chemokines in endotoxemic mice. These systemic protective actions were achieved through the inhibition of the TLR4/NF-κB signaling cascade, the reduction in M1 macrophage polarization, and the simultaneous alleviation of mitochondrial impairment and oxidative stress. Moreover, rhTβ4 treatment significantly rescued EAE-related cognitive deficits and attenuated neuronal damage, primarily through the suppression of neuroinflammation and microglial overactivation. Integrative transcriptomic profiling and functional assays identified lysophosphatidic acid receptor 3 (LPAR3) as an important contributor, suggesting that rhTβ4 suppresses microglial-mediated neurotoxicity at least in part through LPAR3 downregulation. In conclusion, rhTβ4 confers robust multi-organ protection against endotoxemic injury by orchestrating the inhibition of systemic and central neuroinflammatory cascades, positioning it as a promising candidate for the treatment of endotoxemia-induced ALI and EAE. Full article

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of rare systemic autoimmune disorders marked by inflammation and damage to small- and medium-sized blood vessels. The clinical presentation of AAV is highly variable, ranging from isolated organ involvement to severe, life-threatening multisystem disease, posing significant challenges in diagnosis, treatment, and prognosis. Objective: To demonstrate the clinical heterogeneity and different outcomes in three pediatric cases of ANCA-positive disease and emphasize the importance of integrating clinical findings with laboratory and imaging investigations for accurate diagnosis. Methods: We present three pediatric patients (ages 12–15 years) with ANCA-positive results but distinct clinical presentations, evaluated at the Children’s Emergency Hospital “Louis Turcanu”, Timisoara, between 2020 and 2024. All cases were investigated according to EULAR/PRINTO/PReS criteria for pediatric vasculitis. Results: Case 1 (PR3-ANCA positive) developed severe multi-organ involvement, including granulomatosis with polyangiitis (GPA) with pulmonary hemorrhage, pericarditis, thrombotic events, and renal impairment, requiring intensive immunosuppression with cyclophosphamide, rituximab, and mycophenolate mofetil, ultimately developing chronic kidney disease stage 3a. Case 2 (BPI-ANCA positive) presented with purpuric lesions and painless joint swelling, responding favorably to corticosteroid therapy with subsequent remission. Case 3 (MPO-ANCA) manifested as polyarticular arthritis without other organ involvement and was ultimately diagnosed as seronegative juvenile idiopathic arthritis (JIA), achieving complete remission with adalimumab therapy. Conclusions: This case series highlights the diverse clinical and biological features of ANCA-positive conditions in children, emphasizing that ANCA positivity requires careful clinical correlation as it may indicate true vasculitis requiring aggressive treatment or alternative diagnoses such as JIA with incidental ANCA positivity. Tailored therapeutic strategies based on clinical presentation and continued research are essential to improve patient outcomes. Full article

This article discusses rheumatoid arthritis (RA) as a chronic, systemic autoimmune disease leading to progressive joint damage and multi-organ complications. The complex pathogenesis of the disease is presented, involving the interaction of environmental, genetic, and immunological factors, including the role of autoantibodies and proinflammatory cytokines. Particular attention is paid to leflunomide, a disease-modifying antirheumatic drug (DMARD), which primarily works by inhibiting the DHODH enzyme, leading to reduced T and B cell proliferation. The additional anti-inflammatory properties of the drug’s active metabolite, teriflunomide, and its impact on signaling pathways related to the immune response are also discussed. This article examines the variability in patient responses to leflunomide treatment in terms of both efficacy and toxicity, with particular emphasis on the potential role of pharmacogenetic factors. It was pointed out that polymorphisms in genes related to drug metabolism, transport, and mechanism of action may influence the pharmacokinetics and safety of the therapy. It was also emphasized that the available data are primarily derived from observational studies and small cohorts, and the results are often inconsistent. Although some genetic variants and plasma teriflunomide concentrations show potential as predictors of treatment response, the current level of evidence does not support the routine use of pharmacogenetic testing in clinical practice. The article emphasizes that the pharmacogenetics of leflunomide represents a promising, yet still exploratory, avenue of research in the context of personalized RA therapy. It emphasizes the need for larger, well-designed clinical trials and the development of standardized guidelines, which would be necessary before the potential implementation of such strategies in routine clinical practice. Full article

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and multi-organ damage. Abnormal B cell activation and autoantibody production constitute the core pathological mechanism of SLE. However, the proportion, BCR pairing types, clonal evolution patterns, and transcriptomic features of dual BCR B cells in SLE remain incompletely elucidated. In this study, we employed single-cell RNA sequencing (scRNA-seq) combined with single-cell B cell receptor repertoire sequencing (scBCR-seq) to preliminarily analyze the proportion and characteristics of dual BCR B cells in SLE model mice (MRL/Lpr and SLE.Yaa) as well as in peripheral blood from SLE patients. The results showed: (1) Compared with control groups, the proportion of dual BCR B cells in SLE model mice and patients exhibited a decreasing trend, whereas the diversity of the CDR3 repertoire decreased and clonality increased. Increased clonal sharing was observed between single BCR B cells and dual BCR B cells. The main pairing types of dual BCR B cells were H + κ1 + κ2, H1 + H2 + κ, and H1 + H2 + κ + λ, with preferential utilization of autoimmunity-associated V gene families such as IGHV4-34, and high expression of IGHG subtypes. (2) Tracking analysis of B cell receptor clonality and effector molecule expression revealed that in SLE, dual BCR B cells tend to enrich in IFN-α/γ responses, TNF-NFκB inflammation, and complement pathways, and highly express interferon-related genes such as Ly6a, Isg15, MX1, and IFI6. (3) In both single BCR B and dual BCR B cells from SLE patients, the proportion of the naïve B cell subset decreased, whereas the proportions of plasma and Breg subsets increased and exhibited clonal expansion. SLE dual BCR Breg cells highly expressed IL10, HSPA1A, and others. This study is the first to reveal, at the high-throughput single-B-cell level, that the proportion, subset origin distribution, CDR3 repertoire composition, and effector molecule expression of dual BCR B cells display unique characteristics in SLE model mice and patients, providing baseline comparative data and novel research perspectives for further investigation into B cell effector functions and mechanisms in SLE patients. Full article

Experimental diabetes models induced by streptozotocin (STZ) and alloxan are widely used in preclinical research; however, direct standardized comparisons in female rodents remain limited. The present study evaluated multiple chemical induction protocols in female Wistar rats, including STZ (40 and 65 mg/kg), STZ at the same doses combined with nicotinamide (110 mg/kg), and alloxan (130 mg/kg). Glycemic progression, oral glucose tolerance test, body weight evolution, oxidative stress markers, and multi-organ histopathology were assessed over a 14-day period. High-dose STZ (65 mg/kg) and alloxan produced rapid, sustained hyperglycemia (p < 0.0001), significant body weight reduction, increased lipid peroxidation (elevated MDA), nitric oxide overproduction, thiol depletion, and pronounced pancreatic and renal structural damage. In contrast, STZ–nicotinamide protocols generated moderate but stable hyperglycemia with partial preservation of islet architecture, attenuated oxidative imbalance, and improved systemic tolerability. Oral glucose tolerance test confirmed impaired glucose handling in the STZ–nicotinamide group, consistent with a type 2 diabetes-like phenotype rather than complete insulin deficiency. These results demonstrate that induction strategy critically determines metabolic stability, oxidative stress burden, and tissue remodeling patterns, supporting model selection according to specific experimental objectives. Full article

Fluorosis, a systemic condition caused by chronic excessive fluoride intake, poses significant threats to livestock health and agricultural productivity worldwide. This systematic review synthesizes current evidence on the modulatory effects of exercise against fluorosis, integrating human studies, animal experiments, and methodological considerations. Human studies indicate negative associations between fluoride exposure and cognitive development, muscle function, and exercise capacity, with exercise influencing fluoride pharmacokinetics in an exercise-intensity-dependent manner. Animal experiments consistently demonstrate that regular moderate-intensity exercise attenuates fluoride-induced damage across multiple organ systems through activation of the Nrf2/ARE antioxidant pathway, modulation of BMP-2/Smads and OPG/RANKL/RANK signaling, suppression of inflammatory responses, and preservation of intestinal barrier integrity. Substantial heterogeneity exists among current fluorosis models regarding exposure dosages, durations, and exercise protocols, underscoring the need for standardization and consideration of genetic background. Overall, exercise shows promise for mitigating fluorosis-induced multi-organ damage, although human evidence remains limited. Future research should prioritize model optimization, elucidation of molecular targets, and exploration of synergistic interventions to provide a foundation for veterinary clinical management. Full article

Titanium dioxide nanoparticles (TiO₂ NPs), widely used as food additives, frequently coexist with high-fat diets (HD) in modern dietary patterns, yet their combined in vivo toxicity remains poorly understood. This study investigated the multi-organ effects of co-exposure to TiO₂ NPs or food-grade E171 and HD in male C57BL/6J mice. Mice were randomly assigned to six groups and fed regular or high-fat diets containing 1 wt% TiO₂ NPs or E171 for 13 weeks. Histopathology, serum biochemistry, organ coefficients, and open-field behavioral tests were used to assess tissue injury and functional alterations. Co-exposure to TiO₂ NPs and HD markedly exacerbated tissue damage across multiple organs. In the liver, more severe ballooning degeneration, necrosis, and inflammatory infiltration were observed, accompanied by altered liver enzymes and reduced organ coefficients. Intestinal injury was characterized by crypt distortion and increased inflammation, particularly in the HD + TiO₂ group. Testicular tissues showed disorganized seminiferous tubules, loss of spermatogenic cells, and interstitial hyperplasia. In the brain, hippocampal neurons exhibited pyknosis and disarray, with decreased brain coefficients and impaired exploratory behavior. E171 induced similar but milder effects. These findings indicate that HD enhances TiO₂ NPs induced multi-organ toxicity, highlighting the health risks of realistic co-exposure to dietary nanoparticles and high-fat foods. Full article

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood–brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms—including viral vectors, mRNA-based constructs, and recombinant protein subunits—have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The “Kerala model” highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen. Full article

Zearalenone (ZEA) is an estrogenic Fusarium mycotoxin widely contaminating feed and feedstuffs, and posing significant risks to animal health. This preliminary study aimed to evaluate the toxicological effects of dietary exposure to purified ZEA at doses ranging from below to above the Chinese regulatory limit (0.15 mg/kg) in weaned female piglets. Twenty piglets were randomly assigned to five groups (four piglets per group) receiving 0, 0.075, 0.15, 0.3, or 0.6 mg/kg ZEA for 42 days. Results suggested that ZEA promoted systemic oxidative stress, evidenced by decreased serum total antioxidant capacity (T-AOC) and increased malondialdehyde (MDA) content in liver across all doses, and in jejunal mucosa at ≥0.15 mg/kg (p < 0.01). Growth performance declined only at 0.6 mg/kg during days 29–42 (p < 0.01), while hemoglobin (HGB) levels (p < 0.01) and ileal villus height (p < 0.05) were reduced at all doses. ZEA also caused inflammatory dysregulation, as evidenced by decreased interleukin-4 (IL-4) levels in serum, liver, and intestinal tissues across all doses (p < 0.01), and disrupted reproductive hormones even at 0.075 mg/kg, as indicated by suppressed serum luteinizing hormone (LH) levels (p < 0.01), which progressed to histopathological damage in uterine and ovarian tissues at higher doses. These preliminary findings, together with significant correlations between oxidative stress markers and multi-organ parameters, suggest that low doses of purified ZEA may induce systemic oxidative stress and subclinical multi-organ toxicity in weaned female piglets, highlighting the need to incorporate redox status into risk assessment and to explore potential antioxidant-based mitigation strategies. However, given the small sample size, these results should be interpreted with caution and warrant validation in larger samples. Full article