N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q), a redox-active transformation product of the tire antioxidant 6PPD, has emerged as a pervasive urban contaminant. Although acute lethality (LC50 ≥ 100 μg/L) occurs above most environmental concentrations, growing evidence indicates that environmentally relevant levels (0.1-10 μg/L), which overlap with measured biological effect thresholds and can reach up to 19 μg/L in urban storm runoff, induce substantial sublethal toxicity across taxa. Using Caenorhabditis elegans as an in vivo model, this review synthesizes mechanistic evidence across multiple biological systems. At 0.1-10 μg/L, 6PPD-Q reduces neurotransmitter levels, including dopamine, glutamate, serotonin, and GABA, and promotes degeneration of dopaminergic and D-type motor neurons, resulting in behavioral impairment. Similar exposures decrease fecundity, trigger germline apoptosis, and activate ferroptosis through Fe[2+] accumulation and lipid peroxidation. Additional effects include intestinal barrier dysfunction, nutrient malabsorption, oxidative stress, immune suppression, and increased pathogen susceptibility. Systemically, 6PPD-Q disrupts mitochondrial electron transport, suppresses ATP production and mitophagy, dysregulates glucose and lipid metabolism, and alters amino acid homeostasis. Importantly, exposure to 1-10 μg/L induces transgenerational effects mediated by histone methylation, with unexposed F3-F5 progeny exhibiting neurodegeneration, metabolic dysfunction, and immune suppression. By integrating these findings within a systems-level framework of molecular initiating events and adverse outcome pathways, this review identifies critical knowledge gaps and priorities for toxicity testing and environmental risk assessment of tire-derived quinones.

Small intestinal bacterial overgrowth (SIBO) is a gastrointestinal disorder characterized by excessive bacterial colonization in the small intestine, leading to impaired digestion and nutrient malabsorption. Increasing evidence indicates that SIBO exerts systemic effects beyond the gut, contributing to metabolic, neurological, cardiovascular, dermatological, and autoimmune conditions. Current management strategies include nonsystemic antibiotics such as rifaximin, dietary interventions (low-FODMAP and biphasic diets), and nutraceuticals including berberine, oregano oil, peppermint oil, garlic derivatives, vitamins, and magnesium. Despite demonstrated clinical efficacy, challenges persist, including high recurrence rates, antimicrobial resistance, and long-term disruption of gut microbiota. Nutraceutical and dietary approaches offer promising patient-centered alternatives but require stronger clinical validation. This review critically examines the multifactorial pathophysiology of SIBO, emphasizing gut-brain axis dysregulation, microbial dysbiosis, oxidative stress, impaired intestinal motility, anatomical abnormalities, hypochlorhydria, bile acid malabsorption, and immune dysfunction. It synthesizes current diagnostic and therapeutic strategies, highlighting antibiotics, dietary approaches, and nutraceuticals, while distinguishing robust evidence from observational or preclinical findings. Finally, it identifies key research priorities, including improved diagnostics, global clinical trials, and microbiome- and genetics-based personalized treatments for sustained remission.

Celiac disease (CD) is classically associated with the HLA-DQ2.5 and HLA-DQ8 heterodimers; however, a clinically relevant subset of patients fulfilling diagnostic criteria lacks these canonical risk HLA-DQ molecules, indicating the presence of alternative antigen-presentation pathways. Among potential contributors, HLA-DQ5 and HLA-DQ9 remain poorly characterised at the immunopeptidomic level. In this study, we applied an integrated in silico framework to systematically investigate the gliadin-derived peptide repertoire presented by canonical and non-canonical HLA-DQ molecules. Peptides derived from α-, γ- and ω-gliadin families were generated following simulated tissue transglutaminase-mediated deamidation and multi-enzyme gastrointestinal digestion. Binding affinities to HLA-DQ2.5, DQ8, DQ5 and DQ9 were predicted using NetMHCIIpan 4.3 and integrated with peptide stability and sequence abundance into a composite Biological Plausibility score. The analysis identified γ-gliadin-derived peptides as the dominant immunogenic drivers across all investigated HLA-DQ molecules, owing to their enhanced digestive stability and high allelic promiscuity. Hierarchical clustering of binding profiles revealed a repertoire-dependent functional overlap between HLA-DQ9 and the canonical DQ8 molecule, particularly for γ-gliadin motifs. In contrast, HLA-DQ5 displayed functional complementarity, selectively presenting a distinct subset of gliadin peptides that were poorly recognised by classical risk HLA-DQ molecules. Collectively, these findings provide a mechanistic framework for CD pathogenesis in individuals lacking HLA-DQ2.5 and HLA-DQ8, demonstrating that non-canonical HLA-DQ molecules can sustain pathogenic CD4[+] T-cell responses through convergent and complementary antigen-presentation pathways. As a predictive in silico framework, this work refines the genetic paradigm of CD by emphasising functional organisation of the gluten immunopeptidome over simple allele presence and provides a mechanistic rationale for future experimental validation of non-canonical HLA-DQ-restricted gliadin presentation.

Polymorphisms of human leukocyte antigen (HLA) genes confer risks for human diseases. Predisposing effects related to T cell receptor (TCR) recognition of peptide-HLA can be selection of TCR repertoire and/or preferential presentation of disease-driving epitopes. In celiac disease (CeD), HLA-DQ2.5 predisposes by presenting gluten peptides to CD4[+] T cells that typically employ stereotyped TCRs. Here, we analyzed whether genetic variants within the HLA and TR loci shape the naive TCR repertoire. We sequenced the αβ TCR repertoires of naive CD4[+] T cells of 103 CeD subjects and 103 controls and performed gene usage quantitative trait loci analyses. The naive CD4[+] TCR repertoire was significantly affected by TRA, TRB, and in particular HLA polymorphisms. The presence of HLA-DQ2.5 influenced the TCR repertoire, resulting in significant enrichment of TCR genes being involved in recognition of gluten epitopes in the repertoires of CeD subjects versus controls. HLA thus affects disease risk by selection of a disease-relevant TCR repertoire.

Giardia duodenalis (synonyms G. lamblia and G. intestinalis) and Blastocystis sp. are prevalent zoonotic intestinal protozoans with significant public health and economic importance. Both parasites infect various hosts, including humans and most livestock. G. duodenalis can cause infections ranging from asymptomatic carriage to clinical manifestations such as acute diarrheal disease, growth stunting and malabsorption, whereas Blastocystsi sp. infection is often asymptomatic and its pathogenicity remains debated. Following the rapid expansion of modern equine industries (horse racing, equestrian sports, production, and tourism), concern about the spread of parasitic diseases caused by human-horse contact has gradually increased. In this study, 631 horse fecal specimens were collected from three geographical localities in Shanxi Province, North China. The prevalence and genetic characteristics of the two parasites were determined by amplification of multiple genetic loci (tpi, triosephosphate isomerase; gdh, glutamate dehydrogenase; bg, beta-giardin) for G. duodenalis and the small subunit ribosomal RNA (SSU rRNA) gene for Blastocystis sp. Overall, the prevalence of G. duodenalis and Blastocystis sp. in horses in Shanxi Province was 7.9% and 0.8%, respectively. Sequence analysis identified three assemblages (A, B, and E) of G. duodenalis and two subtypes (ST1 and ST5) of Blastocystis sp. in horses; assemblage B and subtype ST1 were detected more frequently than the other types (subtypes) in this data set. This study is the first to report G. duodenalis and Blastocystis sp. infections in horses in Shanxi Province, and these findings provide baseline molecular epidemiological data for horses in Shanxi Province and support continued hygiene management to reduce potential zoonotic transmission.