Background: Gastrointestinal graft-versus-host disease (GI-GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Conditioning directly injures the intestinal epithelium, whereas antibiotics, nutritional disruption, and immunosuppression remodel the intestinal ecosystem; together, these exposures are associated with loss of obligate anaerobes and altered availability of microbiota- associated metabolites. This review examines how host tissues sense these metabolic changes and translate them into divergent biological outcomes. Methods: We integrate evidence on directly produced microbial metabolites, including short-chain fatty acids, tryptophan-derived indoles, and desaminotyrosine, as well as microbially modified bile acids, host–microbial co-metabolites such as trimethylamine N-oxide, and emerging microbiota-associated compounds. We then examine receptor-mediated pathways involving FFAR2/3, HCAR2, AhR, PXR, FXR, TGR5, and VDR, as well as receptor-independent mechanisms such as HDAC inhibition and mTORC1-STING-dependent regeneration. Results: We propose that metabolite activity in GI-GVHD is determined not by abundance alone, but by chemical form, concentration, tissue distribution, sensor identity, responding cell type, and disease stage. This framework explains how a metabolite may reinforce epithelial tolerance while promoting inflammatory myeloid or donor T-cell programs in another compartment. We further evaluate postbiotic replacement, receptor modulation, precision nutrition, defined microbial consortia, and fecal microbiota transplantation, highlighting pharmacokinetic, pharmacodynamic, infectious, and graft-versus-leukemia considerations. Conclusions: Cell- and compartment-resolved metabolite pharmacology may enable tissue-protective strategies that limit GI-GVHD without broadly suppressing antitumor immunity.
Background: Lipid nanoparticle (LNP) systems have emerged as leading platforms for nucleic acid delivery, with high transfection, biocompatibility, and clinical success in RNA therapeutics. However, oral nucleic acid delivery remains a major challenge, as nucleic acids and LNPs are highly susceptible to degradation under gastrointestinal (GI) conditions, which includes acidic pH, digestive enzymes, and bile salts. To address these limitations, we developed Eudragit® S 100-coated lipid nanoparticles (Eu-LNPs) as a pH-responsive system for oral nucleic acid delivery. Methods: We optimized LNPs formulated with the ionizable lipid SM-102, with and without Eu coating, by varying the nitrogen-to-phosphate (N/P) ratio, and evaluated them in vitro and in vivo. Results: Increasing the N/P ratio (3–10) significantly improved encapsulation, with N/P 10 achieving the highest nucleic acid loading while slightly reducing particle size and maintaining low polydispersity. Using a model luciferase-expressing mRNA, SM-102-based LNPs exhibited strong transfection in HEK-293 cells, with the highest luminescence-to-viability ratio observed at N/P 6. Similarly, using a GFP-expressing mRNA, strong GFP fluorescence was also observed in HEK-293, SW480, and RAW 264.7 cells, confirming efficient intracellular delivery. Subsequently, we coated the LNPs with Eudragit® S 100 to form Eu-LNPs. The coated nanoparticles preserved the encapsulated mRNA integrity for up to 7 days at 4 °C. In vivo studies in C57BL/6 mice showed that orally administered eGFP mRNA-loaded Eu-LNPs increased GFP fluorescence signal throughout the GI tract, whereas uncoated LNPs showed a negligible difference in fluorescence compared to the control. Conclusions: Overall, this study demonstrates that Eudragit® S 100-coated LNPs represent a promising approach for oral RNA delivery to the GI tract.
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet in children and adolescents it remains off-label and underused, constrained by safety concerns and scarce pediatric-specific evidence. Its benefits may extend beyond any single diagnostic category to severe, treatment-resistant dimensions of psychopathology that recur across diagnoses. This review traces clozapine’s history in youth, synthesizes the current evidence, and organizes it by domains of treatment resistance: psychosis, aggression, affective symptoms, suicidality and self-directed harm, and catatonia, with sections on real-world outcomes, clinical management, and safety. Randomized controlled data are confined to treatment-resistant early-onset schizophrenia and to one small trial in conduct disorder, with the first prospective open-label trial now available in autistic youth. Elsewhere the evidence is observational and of lower certainty, although convergent for aggression, suicidality, mood, and catatonia. The strongest transdiagnostic evidence is register-based and within-individual, drawn from cohorts aged 16 years and older, and spans psychotic and affective disorders; the pediatric gap concerns study design as well as sample size. Because pharmacovigilance data show that mortality is not concentrated in the hematological domain, safe use requires surveillance beyond blood counts, therapeutic drug monitoring, and safeguards over drug supply when suicide risk is present. Viewing clozapine as a treatment option defined by symptom severity and refractoriness may support rational use in severely ill youth, but the proposal remains preliminary: a conceptual framework that requires prospective, dimensionally designed pediatric studies. Clozapine’s potential transdiagnostic anti-suicidal effect merits priority investigation, given that suicide is a leading cause of death in adolescence.
Background/Objectives: Microbial exopolysaccharides (EPS) are complex biopolymers that mimic the native extracellular matrix and have emerged as promising biomaterials for tissue regeneration. Methods: This study aimed to evaluate the therapeutic potential of microbial EPS in the healing of cutaneous wounds through a systematic review and meta-analysis of in vivo experimental studies in rat models. Conducted in accordance with the PRISMA guidelines, a search of the Scopus, Embase, and ScienceDirect databases identified 2496 records. After rigorous screening, 17 rat studies were included in the quantitative synthesis, comprising 181 animals and 398 wounds (199 treated with EPS and 199 controls). Results: Treatment with EPS promoted a mean healing rate of 90.46% (range: 9.1% to 100%) on day 14, reflecting the heterogeneity of the included studies. The meta-analysis revealed an overall mean difference of 21.15% (95% CI: 17.89 to 24.42; p < 0.0001) in favor of EPS compared with the control group. Conclusions: These findings support the potential for translating EPS-based therapies from rodent models to human wounds, although the substantial heterogeneity of the evidence and the absence of clinical data indicate that controlled clinical trials remain essential to validate their application in humans.
Background/Objectives: Non-medical use of GHB poses a public health risk due to the risk of overdose. GHB exhibits nonlinear toxicokinetics mediated by monocarboxylate transporters (MCTs), and previous studies have demonstrated sex-related differences in transporter regulation and GHB toxicokinetics. This study investigated the impact of exogenous estrogen and progesterone on GHB toxicokinetics and toxicodynamics, and evaluated the efficacy of AR-C155858 (an MCT1 inhibitor) to treat GHB overdose. Methods: Ovariectomized (OVX) females and castrated (CST) male Sprague Dawley rats were treated with estrogen and/or progesterone or a corresponding placebo for 21 days. Rats received intravenous GHB (1000 or 1500 mg/kg) or GHB + AR-C155858 (1500 mg/kg + 1 mg/kg), and plasma and urine samples were collected for 8 h post-dose. GHB concentrations were quantified by a validated LC/MS assay. Results: Female sex hormones significantly affected GHB toxicokinetics. Treatment with estrogen and progesterone (alone or in combination) reduced GHB exposure in OVX and CST rats through altered GHB clearance. Alterations in renal and metabolic clearance were dose-dependent. GHB exposure was significantly decreased with the co-administration of AR-C155858, as a result of increased GHB renal clearance. Conclusions: Female sex hormones influence GHB toxicokinetics, with combined estrogen/progesterone treatment producing the greatest reductions in systemic GHB exposure and toxicity. Monocarboxylate transporter inhibition with AR-C155858 significantly decreased GHB exposure and sedative effect, supporting its potential as a therapeutic strategy for GHB overdose across diverse populations.
