Search Results (10,981)

Autism spectrum disorder is markedly heterogeneous and frequently accompanied by gastrointestinal symptoms that often correlate with behavioral phenotypes. Emerging evidence suggests that the microbiota–gut–brain axis may contribute to these associations through multiple bidirectional communication routes—including neural, immune, and endocrine pathways, as well as microbial metabolites such as short-chain fatty acids and tryptophan–kynurenine intermediates. This narrative review synthesizes clinical, mechanistic, and interventional evidence published between January 2010 and July 2025, clarifies the extent to which current data support association versus causation, evaluates key confounding factors, summarizes evidence for interventions such as probiotics, prebiotics, and fecal microbiota transplantation, and outlines future directions for precision research and targeted interventions based on functional pathways and stratified subgroups. Full article

Objective: T cell exhaustion is a major mechanism of immune evasion in cancer, characterized by the sustained expression of multiple inhibitory receptors. This study aimed to evaluate the expression of immune checkpoints in peripheral and tumor-infiltrating CD8⁺ T cells from cervical cancer patients. Methods: We enrolled 104 participants: 37 treatment-naïve patients, 36 treated patients, and 31 age-matched healthy donors. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Ten cervical biopsies were collected for tumor-infiltrating lymphocyte (TIL) isolation and paraffin fixation. Immune checkpoint expression was analyzed by multiparametric flow cytometry and immunohistochemistry. Results: In peripheral CD8⁺ T cells, we found a significant upregulation of exhaustion-associated markers PD-1, TIGIT, Tim-3, and LAG-3. In the tumor infiltrating lymphocytes, these same molecules, with the addition of NKG2A, were notably upregulated further. While BTLA and NKG2A showed no systemic changes, NKG2A increased in TILs and BTLA decreased in TILs. The co-expression of PD-1 with TIGIT, Tim-3, LAG-3, and NKG2A was notably enriched between 2- and 6-fold in TILs compared with patient PBMCs. The tumor microenvironment was highly immunosuppressive, characterized by enrichment with PD-1, PD-L1, and TIGIT; TIGIT was notably upregulated in locally advanced versus early-stage tumors. Conclusions: Our findings highlight the strongly immunosuppressive environment of cervical tumors in treatment-naïve patients and the presence of elevated inhibitory checkpoint expression in peripheral blood of both pre- and post-treatment patients. These results underscore the importance of investigating immune regulation within the tumor site itself and suggest that immune checkpoint co-expression may serve as a biomarker of T cell exhaustion and therapeutic resistance. Understanding how treatment alters these pathways could guide rational combination immunotherapies to restore CD8⁺ T cell function in cervical cancer. Full article

Vitamin C, a water-soluble micronutrient, is one of the most widely used dietary supplements pertaining to its vital role in maintaining overall human health, particularly through its potent antioxidant and immune-supportive functions. This mini review summarizes key pharmacokinetic constraints of vitamin C and evaluates formulation strategies aimed at improving its systemic availability. Achieving sustained optimal plasma levels of vitamin C remains challenging due to its dose-dependent absorption, tissue saturation, rapid renal clearance, and short half-life. These pharmacokinetic limitations restrict systemic retention, with high oral doses providing only marginal increases in plasma concentrations and necessitating multiple daily administrations. Conventional vitamin C supplements show efficient absorption only at low to moderate doses, while higher intakes are restricted by transporter saturation and increased renal excretion. Alternative delivery systems such as liposomal encapsulation, esterified derivatives, nano-emulsions, and co-formulations with bioenhancers have been examined; however, evidence for prolonged systemic retention remains inconsistent. The sustained-release formulation of vitamin C shows more reliable outcomes, demonstrating prolonged plasma exposure, higher steady-state concentrations, and potential for improved compliance through reduced dosing frequency. While further robust comparative studies are needed, current evidence suggest that advanced formulation approaches, particularly sustained-release delivery, may help overcome these pharmacokinetic limitations, thereby supporting improved clinical utility of vitamin C supplementation. Full article

Background: Celiac disease (CeD) is a chronic, immune-mediated enteropathy triggered by gluten ingestion in genetically predisposed individuals. While a lifelong gluten-free diet (GFD) remains the cornerstone of treatment, inadequate follow-up can lead to persistent symptoms, nutritional deficiencies, and long-term complications. Aim: This narrative review summarizes best practices in celiac disease follow-up, with emphasis on multidisciplinary, nutritional, clinical, and preventive care strategies to optimize long-term outcomes. Main Findings: High-quality follow-up requires coordinated care involving gastroenterologists, dietitians, primary care providers, and other specialists. Nutritional challenges of the GFD include high cost, limited fortification, suboptimal nutrient content, and increased risk of obesity and metabolic dysfunction. Patients also face psychosocial and behavioral burdens such as anxiety, social isolation, and disordered eating. Evidence-based strategies for follow-up include structured clinical and serologic monitoring, laboratory assessments, bone health evaluation, cancer risk reduction, and preventive care. Novel tools such as gluten immunogenic peptide testing, digital health platforms, and artificial intelligence are emerging as adjuncts to clinical management. Implications: Structured, patient-centered follow-up that integrates medical, nutritional, and psychosocial dimensions is essential to achieving mucosal healing, maintaining long-term health, and improving quality of life in individuals with CeD. Full article

Introduction: The COVID-19 pandemic posed additional challenges for this vulnerable population, such as Sjögren’s disease (SjD), underscoring the need for effective and safe vaccination strategies. Objective: To evaluate the immunogenicity and safety of COVID-19 vaccines in patients with SjD. Methods: This prospective, observational, longitudinal study included SjD patients from the SAFER cohort. Immunogenicity was assessed via anti-spike IgG (IgG-S) titers using chemiluminescence reported as geometric mean titers (GMT) and fold increase in GMT (FI-GMT). Disease activity was evaluated using the ESSDAI score. Adverse events and COVID-19 infections were also monitored. Assessments were conducted at four time points: pre-first dose (T1), pre-second dose (T2), pre-booster (T3), and four weeks post-booster (T4). Primary vaccination involved ChAdOx1 nCoV-19 or inactivated vaccine (CoronaVac), and boosters were either homologous (ChAdOx1 nCoV-19) or heterologous (BNT162b2). Results: Among 51 participants (mean age 46 years; 90% female), 41% had comorbidities and 27% (n = 14/51) were highly immunosuppressed. Among those 73% (n = 37/51) under low immunosuppression, n = 8/51 (13%) were not using any medication. At baseline, 11% (n = 4/35) showed moderate/high disease activity, which decreased to 6.5% (n = 2/31) at T4. Primary vaccination was ChAdOx1 in 94% (n = 48/51) and CoronaVac in 6% (n = 3/51); 73% (n = 37/51) received heterologous and 27% (n = 14/51) homologous boosters. COVID-19 infection post-booster occurred in 20% (n = 10/51). Seroconversion rates reached nearly 100% across all medication subgroups except for biologic users, who showed delayed but stable seroconversion by T4. IgG-S titers increased progressively through T4. Primary immunization induced an ascending GMT in both vaccine types. At T4, the GMT was significantly higher in the BNT162b2 group (2148.03 [1452.05–3155.84]; p < 0.001; 95% CI) than in the ChAdOx1 group (324.29 [107.92–974.48]; p < 0.001; 95% CI); the fold-increase in immune response was six times greater with BNT162b2 (5.98 [2.97–12.03]; p = 0.001; 95% CI). Seroconversion was 100% in the heterologous group versus 83% in the homologous group (p > 0.01). Those with prior infection showed significantly higher titers, particularly at T2 and T3 (p < 0.001 for T1–T3). Adverse events were mild and not statistically significant. Multivariate regression confirmed BNT162b2 as an independent factor for higher antibody titers. Conclusion: COVID-19 vaccination in patients with SjD was safe and induced high anti-spike antibody titers and seropositivity. Heterologous boosting, particularly with BNT162b2, demonstrated superior immunogenicity. No association was found between vaccination and SjD disease flares or worsening activity. Full article

The World Health Organization and the Centers for Disease Control and Prevention recommend seasonal influenza vaccination for all individuals aged 6 months and older. Despite high national immunization rates, the influenza vaccination coverage among Saudi children remains unclear. Parental knowledge and attitudes significantly impact children’s vaccination rates. Purpose: This study aims to evaluate parental knowledge, awareness, and attitudes regarding influenza vaccination and identify barriers to vaccination uptake among children in Al-Madinah City, Saudi Arabia. Methods: The population includes parents having children aged 6 months to 14 years. A cross-sectional survey utilizing a 33-item validated questionnaire was conducted to evaluate parental awareness, knowledge, and attitudes toward the influenza vaccine. Inferential statistics were employed to evaluate demographic factors influencing parental knowledge and attitudes toward vaccination. Results: This study surveyed 407 parents from Al-Madinah, focusing on their awareness, knowledge, and attitudes towards seasonal influenza vaccination. The sample was primarily Saudi (86.7%), with a mean age of 34 years. Most parents (95.6%) were aware of the vaccine, primarily through media and campaigns. Despite this, only 44.5% had vaccinated themselves or their children, citing perceptions of influenza as mild, vaccine ineffectiveness, and availability issues as primary reasons for non-vaccination. Knowledge about influenza varied, with most parents aware of its contagiousness (64.4%) and symptoms, but misconceptions persisted, such as believing the vaccine could cause the flu. Parental attitudes towards vaccination were mostly positive, with high trust in health information sources and a mean attitude score of 22.48 out of 35. Positive attitudes were correlated with better knowledge and more frequent infection control practices. Age, education, and medical profession status significantly influenced knowledge, while vaccine attitudes were most favorable among those vaccinated (p < 0.001). Conclusions: Most parents in Al-Madinah recognize the importance of vaccination; however, misconceptions about vaccine safety, perceived low need, and barriers such as vaccine availability persist. Sociodemographic factors, including education, income, and profession, are linked to better knowledge and more positive attitudes toward vaccination. Full article

Background/Objectives: Sublingual vaccination offers a non-invasive route for inducing both systemic and mucosal immunity, yet the formulation properties that govern its success remain poorly defined. This study investigated the relationships among key formulation parameters for sublingual vaccines, such as viscosity, mucoadhesion, and mucosal residence, to understand their impact on in vivo immune responses in the sublingual delivery context. Methods: Ovalbumin (OVA)-based vaccine formulations containing cholera toxin B (CTB) adjuvant and mucoadhesive excipients such as hydroxypropyl methylcellulose (HPMC) or methylglycol chitosan (MGC), were evaluated for: (1) their respective rheological properties—characterized by viscosity and mucoadhesion parameters, as well as (2) in situ mucosal retention (assessed using Cy7-labeled formulations tracked by IVIS in vivo imaging system) and (3) in vivo immunogenicity via systemic (IgG) and mucosal (IgA) responses measured by ELISA, following sublingual administration to mice. Correlations between rheology, in situ/ex situ mucosal residence, and in vivo immune outcomes were determined. Results: Sublingual vaccine formulations containing HPMC exhibited the highest viscosity, mucoadhesion, and mucosal retention profiles, but paradoxically elicited the weakest systemic and mucosal antibody responses. In contrast, chitosan-based formulations enhanced immune responses even at reduced antigen and adjuvant doses, likely due to its permeation-enhancing and adjuvant effects. Correlation analyses revealed that while formulation viscosity and mucoadhesive strength were positively associated with mucosal retention, both rheological and retentive properties showed a significant inverse relationship with immunogenicity in the context of sublingual vaccine delivery. Conclusions: While viscosity and mucoadhesion are essential for in situ retention of sublingual vaccines, prolonged residence driven by excipient’s excessive rheological strength was found to reduce vaccine immunogenicity—likely due to restricted antigen release and mucosal uptake. Accordingly, HPMC appears suboptimal as a sublingual vaccine excipient, while chitosan shows promise for sublingual delivery as a permeation-enhancing adjuvant. These findings may shift the design paradigm for sublingual vaccine formulations, highlighting the need to balance mucosal retention with efficient antigen absorption for maximizing immune responses. Full article

COVID-19 is associated with gut microbiome alterations that may influence disease outcomes through immune and inflammatory pathways. This systematic review and meta-analysis evaluated global evidence on gut dysbiosis in COVID-19. We searched PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane Library up to 5 October 2025 (PROSPERO CRD420251160970). Alpha-diversity indices and microbial taxa log-fold changes (logFC) were analyzed using random-effects models. The pooled standardized mean difference (SMD) for the Shannon index was −0.69 (95% CI −0.84 to −0.54; I² = 42%), confirming reduced microbial diversity. Faecalibacterium prausnitzii showed a significant pooled depletion (logFC = −1.24; 95% CI −1.68 to −0.80; k = 10; I² = 74%), while Enterococcus spp. was increased (logFC = 1.45; 95% CI 1.12–1.78). Egger’s test did not suggest publication bias (p = 0.32). Gut dysbiosis was consistently associated with reduced microbial diversity and enrichment of pathogenic taxa, correlating with increased disease severity and mortality (HR = 1.67). These findings highlight the potential of microbiome profiling as a prognostic tool in COVID-19, although clinical translation requires further validation. Full article

Cancer vaccines have emerged as a class of therapeutics designed to harness the immune system to stimulate durable anti-tumor responses with lower systemic toxicity than conventional therapies. Many platforms have been explored, including protein, peptide, DNA, RNA, and cell-based vaccines. Within this landscape, peptide vaccines remain a promising approach. Most clinical trials have examined peripheral immune responses and clinical outcomes, but there is growing interest in the vaccine site microenvironment (VSME) as a window to understand local immune activation and its implications for systemic immunity and tumor control. Studies of the VSME have investigated the effects of adjuvants, local immune cell dynamics, and their correlation with systemic responses and outcomes. Local adjuvants typically enhance immune cell infiltration, though there are concerns regarding VSME sequestration or dysfunction of immune cells, which could impact systemic efficacy. Repeated vaccination at a single site may improve antigen presentation and immune responses, but factors such as injection site location may be linked to variability in clinical outcomes. Current studies are limited by substantial variability in sampling, timing, and analyses used in VSME assessment. This limits the comparability of findings and broader inferences regarding the influence of vaccine site dynamics on therapeutic efficacy. Standardized VSME assessment as part of future vaccine trials may improve evaluation of immune responses and provide a more consistent surrogate for vaccine effectiveness. This refinement may inform optimal vaccine strategies and further support the development of next-generation cancer immunotherapies. Full article

Radiotherapy (RT) remains a cornerstone of cancer treatment, offering spatially precise cytotoxicity against malignant cells. However, emerging evidence reveals that ionizing radiation (IR) exerts biological effects beyond the targeted tumor volume, manifesting as radiation bystander effects (BEs) and other non-targeted effects (NTEs). These phenomena challenge the traditional paradigm of RT as a localized intervention, highlighting systemic and long-term consequences in non-irradiated tissues. This comprehensive review synthesizes molecular, cellular, and clinical insights about BEs, elucidating the complex intercellular signaling networks gap junctions, cytokines, extracellular vesicles, and oxidative stress that propagate damage, genomic instability, and inflammation. We explore the role of mitochondrial dysfunction, epigenetic reprogramming, immune modulation, and stem cell niche disruption in shaping BEs outcomes. Clinically, BEs contribute to neurocognitive decline, cardiovascular disease, pulmonary fibrosis, gastrointestinal toxicity, and secondary malignancies, particularly in pediatric and long-term cancer survivors. The review also evaluates countermeasures including antioxidants, COX-2 inhibitors, exosome blockers, and FLASH RT, alongside emerging strategies targeting cfCh, inflammasomes, and senescence-associated secretory phenotypes. We discuss the dual nature of BEs: their potential to both harm and heal, underscoring adaptive responses and immune priming in specific contexts. By integrating mechanistic depth with translational relevance, this work posits that radiation BEs are a modifiable axis of RT biology. Recognizing and mitigating BEs is imperative for optimizing therapeutic efficacy, minimizing collateral damage, and enhancing survivorship outcomes. This review advocates for a paradigm shift in RT planning and post-treatment care, emphasizing precision, personalization, and systemic awareness in modern oncology. Full article

Background/Objectives: Thiopurines remain a cornerstone in the management of inflammatory bowel disease (IBD) and gastrointestinal immune diseases but are associated with significant interindividual variability in efficacy and toxicity, mainly influenced by polymorphisms in Thiopurine S-methyltransferase TPMT and Nudix Hydrolase 15 NUDT15. This study aimed to assess the frequency of TPMT and NUDT15 variants in a pediatric cohort and evaluate their clinical impact to support a pharmacogenetic-guided approach to thiopurine therapy. Methods: Eighty-three pediatric patients with IBD and other autoimmune diseases were genotyped for clinically relevant TPMT and NUDT15 variants using two HRM-PCR assays and were confirmed with sequencing. Variant frequencies were compared to expected population data, and clinical records were reviewed to assess thiopurine dosing, tolerance, and adverse events. Results: Among the cohort, six carried heterozygous TPMT variants *1/*3A, while 2 carried the NUDT15 *1/*9 diplotype, with frequencies higher than expected. Among patients with TPMT variant alleles, some needed dose reductions or treatment discontinuation due to adverse effects, while others tolerated standard dosing without significant issues. Notably, no significant differences in adverse reactions were observed between NUDT15 *1/*9 carriers and wild-type patients. Conclusions: Our results confirm the clinical relevance of TPMT and NUDT15 genotyping to personalize thiopurine therapy in pediatric IBD. Routine implementation of rapid genetic testing, combined with therapeutic drug monitoring and a structured management algorithm, may optimize treatment outcomes and minimize preventable toxicity. Full article

Background and Objectives: The Hepatitis E Virus (HEV) is increasingly recognized as a cause of chronic infection in immunocompromised patients, but its precise role in cryptogenic cirrhosis (CC) is unclear. CC is defined as liver cirrhosis in which all known causes, including viral, autoimmune, metabolic, and alcohol-related etiologies, have been meticulously excluded. We aimed to address this gap by definitively assessing HEV’s etiological contribution in CC through seroprevalence comparison and evaluating its long-term prognostic impact on disease progression and adverse clinical outcomes. Materials and Methods: This is a retrospective, single-center, observational, and longitudinal cohort study, conducted between July 2017 and June 2025. The study included 52 CC patients, whose diagnosis was strictly confirmed by excluding all known etiologies, and 900 healthy blood donors from the same region. CC patients were retrospectively followed for five years to assess long-term clinical outcomes. We compared HEV seropositive and seronegative patients for accelerated disease progression (assessed by follow-up MELD-Na scores) and cirrhosis-related death. We employed multivariable logistic regression to adjust for demographic confounders in the prevalence comparison and multivariable COX regression for survival analysis to determine the independent prognostic role of HEV seropositivity. Results: The anti-HEV IgG seroprevalence in CC patients (42.3%) was significantly higher than in healthy donors (12.8%) (p < 0.001). Multivariable logistic regression confirmed CC status as an independent predictor of HEV seropositivity (Adjusted OR = 6.142, p < 0.001). During the five-year follow-up, the cirrhosis-related death rate was significantly higher in the anti-HEV IgG positive group (36.4% vs. 13.4%; p = 0.047), and their follow-up MELD-Na score was significantly higher (p = 0.029). However, multivariable COX analysis did not sustain anti-HEV IgG positivity as an independent risk factor for death (p = 0.294). Conclusions: HEV exposure is independently and significantly higher in CC patients. While anti-HEV IgG positivity correlates with higher mortality and accelerated disease progression in univariable analysis, its lack of independent prognostic significance suggests it may primarily function as a marker for a more advanced stage of CC or underlying immune dysfunction. Further rigorous prospective studies are necessary to precisely define HEV’s long-term prognostic role and evaluate its impact on disease progression. Full article

Silymarin and L-carnitine are individually used in fish diets, yet whether they exert interactive or additive effects when combined remains unclear. This study aimed to investigate the individual and combined impacts of dietary silymarin (S), L-carnitine (LC), and their combination (S + LC) on growth performance, digestive enzyme activity, antioxidant status, immune response, and gene expression in Nile tilapia. A total of 360 fish (initial body weight: 10.01 ± 0.03 g) were randomly allocated into 12 fiberglass tanks (30 fish/tank) and fed one of four diets for 84 days: control (basal diet), S (850 mg/kg), LC (500 mg/kg), and S + LC (425 mg/kg S + 250 mg/kg LC). Fish fed S and S + LC diets exhibited significantly higher final body weight, weight gain, and specific growth rate (SGR), along with improved feed conversion ratio (FCR) compared to the control (p < 0.05). All supplemented groups exhibited enhanced digestive enzyme activities (amylase, lipase, protease), with the S + LC group showing the highest values. Serum biochemical profiles revealed increased total protein and globulin and reduced glucose and cortisol levels. Innate immune responses (IgM, lysozyme activity, NBT%, and bactericidal activity) were significantly elevated, especially in the S + LC group. Antioxidant enzyme activities (SOD, CAT, GPx) increased, while malondialdehyde (MDA) levels declined. Gene expression analysis showed significant upregulation of IGF-1, IFNA-1, SOD, CAT, and Gsr, with the greatest expression in the S + LC group. These findings indicate that dietary silymarin and L-carnitine, particularly when provided together, produced complementary and enhanced effects on growth, immune competence, antioxidant capacity, and gene regulation in Nile tilapia. Full article

Indoor cat allergens, particularly the major allergen Fel d 1 protein, represent significant environmental triggers for allergic rhinitis, asthma, and other immune-related disorders in humans. With the continuous global increase in pet ownership, cat allergen proteins are prevalent in diverse settings and can even be transmitted to pet-free locations via clothing and animal fur, thereby posing health risks to sensitized individuals. This review systematically summarizes the molecular characteristics, distribution patterns, and mechanisms of human sensitization to indoor cat allergen proteins. It focuses on a comparative analysis of the principles, sensitivity, and application of commonly used immunological methods (such as various modified ELISAs, immunoblotting, and high-throughput multiplex detection technologies) alongside emerging real-time sensing platforms (including QCM, SAW, and LIF). Furthermore, this review summarizes key factors affecting indoor allergen concentrations, such as cat characteristics, architectural environments, human activities, and spatiotemporal variations. It also evaluates the efficacy and limitations of current allergy control strategies, covering source control (e.g., gene editing, immunomodulation), environmental management (e.g., air filtration), and medical treatments (e.g., allergen immunotherapy), and discusses future prospects. This review aims to offer a scientific foundation and systematic reference for the detection, control, and public health protection related to indoor cat allergens. Full article

The objective of this study was to evaluate the effects of 25-hydroxy-vitamin D₃ (25OHD₃) supplementation on reproductive performance, nutrient digestibility, lameness score, milk composition, and blood profiles in sows, as well as the performance and blood profiles of their offspring. From day 110 of gestation to 21 days of weaning, a total of 30 multiparous sows (Landrace × Yorkshire) were randomly assigned to one of three dietary treatments, with ten sows per treatment. The dietary treatments were: (1) CON, basal diet; (2) TRT1, CON diet plus 1114 IU 25OHD₃/kg (13.92 µg 25OHD₃/kg feed); and (3) TRT2, CON diet plus 2227 IU 25OHD₃/kg (27.84 µg 25OHD₃/kg feed). The reproduction performance and nutrient digestibility of sows were not affected by 25OHD₃ supplementation. However, the inclusion of graded levels of 25OHD₃ in the sow diet had significantly reduced their farrowing time (p < 0.001) compared to those fed the CON diet. Also, sows fed 25OHD₃ produced significantly higher (p < 0.05) number of piglets compared to the CON group. Piglets from supplemented sows exhibited greater (p < 0.05) average daily gain and weaning body weight. Moreover, colostrum protein content was higher (p < 0.05) in sows fed 25OHD₃ compared with the CON group. Similarly, the concentration of 25OHD₃ in colostrum and milk at weaning was markedly (p < 0.001) elevated. Furthermore, serum 25OHD₃ levels were significantly higher (p < 0.05) in both sows and piglets, and piglet serum immunoglobulin G (IgG) concentrations were also elevated (p < 0.05) in the supplemented groups. In summary, dietary 25OHD₃ in the sow diet not only improves their reproductive performance and milk quality but also enhances piglet growth, immunity, and overall vitality, suggesting that 25OHD₃ is a valuable nutritional strategy for optimizing sow productivity and promoting healthier offspring. Full article