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关键词： Rheumatoid Arthritis   G. mellonella hemolymph   MiR-146a   Immunomodulators   Osteocalcin   In-silico simulation  

摘要： Rheumatoid arthritis (RA) is an inflammatory autoimmune illness that persistently and recurrently affects joints. In RA, miR-146a functions as a key regulator, modulating inflammation by targeting and downregulating cytokines that promote inflammation, such as TNF-alpha and IL-6, whereas osteocalcin, a bone metabolism marker, plays a role in bone remodeling and joint health. The interplay between these molecules significantly influences RA progression and severity by balancing inflammation and bone integrity. Conventional antirheumatic drugs often cause varying levels of side effects. As sustainable development initiatives grow, insects are gaining interest as sustainable food sources and potential medicinal agents. Notably, the increasing Galleria mellonella (G. mellonella) population has raised concerns about the spread of honeybee viruses, affects bee products and food security, and drives economic losses in the therapeutic market. Accordingly, hemolymph has crucial defensive and immunological effects in insects and has recently been investigated as an immunomodulatory agent in parasitic in-vitro and in-vivo rat models. This work was designed to elucidate the potential immunomodulatory impact of G. mellonella hemolymph on the crosstalk between miR-146a, IL-6, TNF-alpha, and osteocalcin in the context of RA, utilizing both computational molecular modeling and in-vivo validation. Computer-aided molecular simulation for immune and RA mediators is applied through specific cell annotation, targeted pathways, and in-silico protein-protein and gene-gene interactions with a gene relative-tissue expression heatmap, which is based on gas chromatographic-mass spectrometric analysis of hemolymph. Our study is the first to adapt a preliminary test to optimize hemolymph dosing and toxicity. The rats were subsequently divided into four groups: healthy control, Freund's adjuvant-induced arthritis (utilized as a model that mimics human RA), methotrexate-treated arthritis, and hem

关键词： miR-126b   IL-4R alpha 1   Th2 immune response   MAPK pathway   mTOR pathway   Large yellow croaker ( Larimichthys crocea )  

摘要： The closely related cytokines Interleukin-4 (IL-4) and IL-13 regulate the Th2 immune response by interacting with their specific receptor complexes. MicroRNAs (miRNAs) modulate various biological pathways through mechanisms that either repress mRNA translation or promote messenger RNA degradation. The miRNA miR-126b is implicated in fish embryonic development. However, its role in regulating the Th2 immune response remains unclear. Here, the mature sequence of miR-126b was identified in large yellow croaker (Larimichthys crocea), which is highly conserved among vertebrates. MiR-126b was confirmed to directly target the 3 '-UTR of LcIL-4R alpha 1. Overexpression of miR-126b in primary head kidney leukocytes (PKLs) resulted in a remarkable reduction of LcIL-4R alpha 1 mRNA levels. Upon transfection with miR-126b mimics and subsequent stimulation by LcIL-4/13A and LcIL-4/13B proteins, the phosphorylation levels of MEK1/2 and 4E-BP1, which serve as essential components of the MAPK and mTOR cascades, were notably decreased in PKLs. Furthermore, overexpression of miR-126b also attenuated the activation effects of LcIL-4/13A and LcIL-4/13B on both T cell proliferation and differentiation, as well as B cell proliferation. These results indicated that miR-126b regulates the Th2 immune response by targeting IL-4R alpha 1, thereby disrupting IL-4/13A and IL-4/13B-mediated signal transduction. These findings highlight a crucial regulatory role of miR-126b in the Th2 immunity in teleost fish.

关键词： WGA   IMDA   PCR-SSP   HLA ligands   Dengue patients  

摘要： BackgroundHigh-throughput DNA sequencing technologies have revolutionized genetic studies of populations and diseases. These methods provide deeper insights into gene structure and variation, offering more comprehensive immunogenetic data with stronger relevance to protein function and biological impact. However, the widespread adoption of high-resolution sequencing is hindered by factors such as cost and limited accessibility. Furthermore, successful implementation requires high-quality and sufficient quantities of genomic *** and resultsThis study addresses the challenges of limited DNA yields, a common issue in clinical samples, by employing whole-genome amplification (WGA) with isothermal multiple displacement amplification (IMDA). We investigated HLA ligands in 253 dengue samples with low DNA quantity. A multiplex PCR-SSP method was developed to determine HLA ligands in population, including HLA-C1, HLA-C2, HLA-A (Bw4), HLA-Bw4 (I80), HLA-Bw4 (T80), and HLA-A*11. The study successfully demonstrates the applicability of a multiplex PCR-SSP method for HLA genotyping in a large cohort of dengue patients. Our findings highlight the high prevalence of HLA-C1 (92.1%) and HLA-A*11:03 (78.3%) in dengue patients, providing valuable data for further investigations into the role of HLA polymorphisms in *** study demonstrates the utility of our approach for investigating HLA ligands in clinical samples with limited DNA. WGA-IMDA effectively overcomes the challenge of low DNA availability, making this approach suitable for resource-constrained settings. The multiplex PCR-SSP method provides a simple and cost-effective solution for immunogenetic studies.

关键词： TNFR1 signaling   Body-brain interaction   Metabolic inflammation   Necroptosis   Blood-brain barrier (BBB) permeability   Therapeutic targeting  

摘要： Body-brain interaction (BBI) plays a critical role in coordinating the communication between peripheral organs and the brain, contributing to the comorbidity of metabolic disorders and neurological disorders. In the context of obesity, one of the key mediators driving systemic and neuroinflammatory responses is the soluble form of tumor necrosis factor (TNF), which primarily signals through TNF receptor 1 (TNFR1) to regulate inflammation and cell death. In this review, we examine how TNF/TNFR1-mediated metabolic inflammation in obesity disrupts cellular homeostasis across multiple organ systems, including the brain. In peripheral tissues, TNF is overproduced and secreted by activated macrophages, leading to lipid dysmetabolism, insulin resistance, and metabolic dysfunction in key cell types such as adipocytes and hepatocytes. Elevated circulating TNF also increases the permeability of the blood-brain barrier, enabling peripheral inflammatory mediators to infiltrate the brain and activate glial cells, thereby amplifying neuroinflammation. Within the brain, TNF induces metabolic and autolysosomal dysfunction in neurons, resulting in elevated reactive oxygen species, accumulation of toxic protein aggregates, and impaired insulin signaling, contributing collectively to neuronal death and the progression of neurodegeneration. We further highlight the metabolic-inflammatory crosstalk within the BBI as a potential therapeutic target, focusing on anti-inflammatory strategies that modulate TNF/TNFR1 signaling. Lastly, we provide future perspectives on the implications of body-brain axes, cell type-specific mechanisms, and disease comorbidities in the context of obesity.

关键词： Inborn Errors of Immunity   IL10RA Deficiency   Hematopoietic cell Transplantation   Japan   Fludarabine   Busulfan   Melphalan  

摘要： Background IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. Methods We retrospectively analyzed patients with IL10RA deficiency in Japan. Results Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT;one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. Conclusion In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250)

关键词： Major histocompatibility complex   Shark   Allelic lineages  

摘要： The major histocompatibility complex (MHC) constitutes a functionally relevant multigene family playing an essential role in the adaptive immune responses of jawed vertebrates, being directly involved in pathogen recognition. MHC diversity, driven by pathogen-mediated selection, is vital for species survival and is characterized by high genetic diversity in many taxa, namely at the sequence, allelic and haplotype levels. Chondrichthyans, the most basal jawed vertebrates with an adaptive immune system, exhibit a high diversity of MHC gene lineages conservatively organized in a compact region of the genome. Such genomic architecture suggests linkage among MHC genes, where alleles from different genes possibly co-segregate together. Such condition may have major implications on immune response, individual fitness and evolution. In this study, we examine MHC II beta haplotype diversity in a model shark species, the small spotted catshark, Scyliorhinus canicula. Making use of pedigree data, we reconstructed MHC II beta haplotypes to understand allele transmission from parent to offspring. Results indicate allele co-segregation consistent with tight linkage among MHC II beta genes, suggesting the presence of functional stable haplotypes inherited from parents to offspring. The reconstructed haplotypes suggested extensive haplotype diversity characterized by variable allele numbers and allelic lineage composition, as well as marked allelic divergence, consistent with previous population-level data on this species. These findings underscore the complexity of MHC genetics (and of MHC evolution) in chondrichthyans. Accurate reconstruction of MHC haplotypes and assessment of its functional significance are crucial for better understanding adaptive immune responses and MHC evolutionary dynamics in chondrichthyans.

关键词： Superantigen   SPEA   TNF-alpha   TNFR2   Regulatory T cells  

摘要： Bacterial superantigens are potent immune activators that trigger T cell proliferation and intensive release of cytokines, leading to toxic shock syndrome. Also, they impair host immune responses, increasing bacterial carriage and transmission. Several studies proposed that superantigens can induce regulatory T (Treg) cells, which may suppress immune responses against bacterial infection. However, the mechanism of Treg cell induction by superantigens is still elusive. We here demonstrated that streptococcal pyrogenic exotoxin A (SPEA) promoted human CD4+CD25+Foxp3+ T cell induction in a dose- and time-dependent manner and the induction required antigen-presenting cells (APCs). SPEA-induced CD4+CD25+ T cells could suppress allogeneic T cell proliferation and IL-2 secretion. Flow cytometric analyses demonstrated high expression of TNFR2 on SPEA-induced CD4+CD25+Foxp3+ T cells. Blocking the interaction between TNF-alpha and TNFR2 reduced SPEA-induced CD25+Foxp3+ Treg cells. Our present study suggests a mechanism that the TNF-alpha and TNFR2 axis is required for the induction of human CD4+CD25+Foxp3+ Treg cells by SPEA, which implicates a potential strategy to enhance the clearance of Group A streptococcus infection through reducing Treg cell induction by the inhibition of TNFR2 signaling.

关键词： Selenium   T-2 toxin   Spleen injury   P38 MAPK   NF-kappa B   IL-6  

摘要： Both T-2 toxin and selenium (Se) cause immune impairment in the spleen, but the mechanism of their occurrence is not clear. In this experiment, the Se content of the spleen was tested by atomic fluorescence spectrometry after a 12-week intervention in Sprague-Dawley (SD) rats, divided into normal, normal + T-2 toxin (10 ng/g), normal + T-2 toxin (100 ng/g), low Se, low Se + T-2 toxin (10 ng/g), and low Se + T-2 toxin (100 ng/g) groups. The pathological changes and fibrosis of spleen tissue were observed using hematoxylin-eosin (HE) staining and Masson staining, respectively. Mitogen-activated protein kinase p38 (p38 MAPK), phosphorylated protein-38 (P-p38 MAPK), nuclear factor kappa-B (NF-kappa B), and interleukin-6 (IL-6) expression levels in spleen tissues were analyzed by Western blotting (WB) and immunohistochemistry (IHC) staining. This study found that both Se deficiency and T-2 toxin induced inflammatory injury and fibrotic changes in rat spleen, but low selenium and low selenium combined with T-2 toxin intervention showed more intense splenic injury. Se deficiency combined with T-2 toxin intervention aggravated spleen injury, and the mechanism of occurrence involved an increase in the inflammatory injury in the spleen by elevating the expression levels of p38 MAPK, NF-kappa B, and IL-6 in rat spleen.

关键词： Orthognathic surgery   Saudi Vision 2030   aesthetic concern   cultural beliefs   decision-making   dentofacial deformities   functional concerns   healthcare professionals   social stigma  

摘要： INTRODUCTION:Orthognathic surgery is essential for addressing severe dentofacial deformities, improving both function and aesthetics. In Ha'il, Saudi Arabia, the decision-making process for this surgery is influenced by a range of medical, psychological, and social factors. This study examined the key factors influencing patients' decisions to undergo orthognathic surgery in Ha'il. METHODS:A cross-sectional study was conducted from 2019-2023, involving 27 patients in Ha'il who either required or had undergone orthognathic surgery. Data were collected through structured interviews covering demographics, medical history, consultation experiences, and decision influences. Statistical analyses, including chi-square tests and logistic regression models, were performed with a significance level of  < 0.05. RESULTS:Among the participants, 59.3% were male, and Class III malocclusion was the most prevalent deformity (59.3%). Aesthetic concerns were the primary motivator for 48.1% of patients, while functional concerns drove 18.5%. Only 44.4% of participants reported receiving comprehensive information about the surgery's risks and benefits. Healthcare professionals were the main decision influencers, cited by 51.9% of participants, while social stigma impacted 25.9%. Cultural beliefs had minimal influence on the decision-making process. CONCLUSION:The decision to undergo orthognathic surgery in Ha'il is predominantly driven by aesthetic concerns, with healthcare professionals playing a crucial role in patient education. Cultural beliefs have little influence, though social stigma is a notable factor. Enhancing patient education could improve decision-making, aligning with Saudi Vision 2030's healthcare goals.