Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the PubMed database up to December 2025, with English as the only language restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition by concomitant drugs or compounds (herbal products or food) are sources of variability factors in drug response that may be predictable. Conclusions: This review article summarizes current evidence on the role of pharmacogenetics and opioid-related interactions, offering a framework to better understand interindividual variability in opioid response and to inform future multimodal approaches.

Background/Objectives: Recent studies have shown that GABA reduces visceral hypersensitivity and improves intestinal permeability in a post-inflammatory irritable bowel syndrome (IBS) rat model. We aimed to assess the efficacy of a GABA-based supplement in IBS patients with diarrhea (IBS-D), focusing on symptoms relief, quality-of-life improvement, mucosal barrier function, systemic microinflammation and gut microbiota. Methods: In this double-blind, placebo-controlled, crossover study, 20 IBS-D patients were randomized to receive GABA or placebo for two four-week treatment periods separated by a two-week washout. Efficacy was assessed using IBS Symptom Severity Score (IBS-SSS) and Short-Form Health Survey-36 (SF-36). Circulating levels of lipopolysaccharide-binding protein (LBP), Tumor Necrosis Factor-α (TNF-α) and interleukin (IL)-1β were measured before and after each treatment. Results: Eighteen patients completed the study. A clinical response (≥50-point reduction in IBS-SSS) was observed in 66.7% of patients during GABA treatment versus 33.3% with placebo. GABA produced a significant reduction in the IBS-SSS total score (p = 0.02) and in the bowel satisfaction item of the questionnaire (p = 0.02). Regarding quality of life, GABA significantly improved the “Emotional limitation” domain compared with placebo (p = 0.009). GABA treatment also led to a decrease in circulating LBP (p = 0.06) and IL-1β (p = 0.02) levels compared to placebo, although only the reduction in IL-1β reached statistical significance. In contrast, no substantial remodeling of the gut microbiota was observed. Conclusions: In this pilot study, GABA treatment led to a significant improvement in IBS-D symptoms compared with placebo and was also more effective in enhancing emotional wellbeing. GABA appeared to have a possible effect on intestinal permeability indirectly assessed through LBP, consistent with preclinical findings, and significantly reduced systemic inflammation. GABA may represent a promising therapeutic option for IBS, deserving further investigation in larger clinical trials.

(1) Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits, linked to dysbiosis and inflammation. Currently available treatments, focused on symptom management, displayed limited efficacy. Recent research highlights microbiota modulation as a potential therapeutic strategy to restore intestinal barrier integrity; (2) A dextran sulfate sodium (DSS)-induced mouse model of post-colitis IBS-like symptoms was performed to evaluate the effect of a novel mixture of Enterococcus lactis SF68^®, butyrate, and folate. Disease activity index and spleen weight were assessed. Markers of gut inflammation, intestinal barrier alterations, and gut butyrate bioavailability were measured. The activity of colonic mitochondria was also analyzed; (3) Supplementation with the novel mixture significantly reduced spleen weight and cytokine levels. The intestinal epithelial barrier was restored through an increase in claudin-1, occludin, and defensin 1–3 and a reduction in LBP plasma level. Treatment with the mixture enhanced the expression of butyrate transporters in mice. Mitochondrial activity markers, including citrate synthase and Cytochrome c oxidase, were improved by treatment; (4) The novel mixture containing Enterococcus lactis, butyrate, and folate exerted a protective effect against post-inflammatory IBS by reducing local inflammation, restoring intestinal barrier integrity, and enhancing butyrate bioavailability, suggesting its potential for managing post-inflammatory IBS symptoms effectively.

Background: Repeated endurance exercise induces transient inflammatory, oxidative and metabolic responses that drive skeletal muscle adaptation. This study investigated whether the consumption of San Carlo 1931® water, a mineral water with a human-like electrolyte profile, modulates these responses in a murine model of repeated swimming exercise. Methods: Male C57BL/6 mice underwent swimming exercise (10 min/day) for 2, 3 or 4 weeks while receiving either San Carlo 1931® water or control water. Grip strength, inflammatory cytokines (IL-6 and TNF), oxidative stress markers (MDA, GPx, and CAT), lactate metabolism (lactate, LDH, and monocarboxylate transporters), citrate synthase activity and the expression of PGC-1α, FNDC5, MuRF1 and myostatin were evaluated. Results: San Carlo 1931® water prevented the early decline in grip strength, attenuated the early exercise-induced inflammatory response, reduced circulating lactate and hepatic LDH activity, enhanced citrate synthase activity and progressively decreased MCT4 expression, indicating improved oxidative metabolism. No significant changes were observed in MCT1 protein expression. These adaptations were accompanied with unchanged PGC-1α expression, early FNDC5 induction and a time-dependent regulation of muscle remodeling markers, with transient progressive MuRF1 upregulation and myostatin induction. Conclusions: The consumption of San Carlo 1931® water modulate inflammatory and metabolic responses to repeated endurance exercise, suggesting a potential role in supporting physiological adaptation to exercise-induced stress.

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain metabolized in the liver via cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Methods: A narrative review of the literature was conducted by searching MEDLINE and PubMed databases up to October 2025, using the English language as the only restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in the CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition using concomitant drugs or compounds (herbal or food) are variability factors in drug response that may be predictable. Conclusion: This review article provides an overview of the role of pharmacogenetics and opioid interactions as a rationale for multimodal approaches aimed at optimizing treatment in clinical practice, in particular opioids should be tailored to each clinical indication and patients should be stratified to receive the appropriate dose.

Vascular aging is driven by a self-sustaining interplay between oxidative stress and chronic low-grade inflammation, collectively referred to as inflammaging. Diosmin, a citrus-derived flavonoid with antioxidant and anti-inflammatory properties, has not previously been investigated in this context. Young (10-week-old) and aged (40-week-old) male Sprague–Dawley rats received diosmin (50 mg/kg/day) or vehicle for 3 months. Vascular function was assessed in mesenteric resistance arteries using pressure myography, while oxidative stress was evaluated by dihydroethidium and mitoSOX staining. Circulating malondialdehyde (MDA), tumor necrosis factor (TNF), lipopolysaccharide-binding protein (LBP) vascular expression of Nos3, Gpx1, Sod2 and Xdh were measured. Aging was associated with impaired endothelium-dependent vasorelaxation, increased vascular DHE and MitoSOX fluorescence and elevated circulating MDA and LBP levels. Chronic diosmin supplementation partially restored endothelial function. The improvement in endothelial function was consistent with a partial preservation of NO-dependent endothelial function, although NO production and bioavailability were not measured directly. Diosmin also significantly reduced vascular DHE and MitoSOX fluorescence in aged animals. These effects were accompanied by decreased plasma MDA and LBP levels, whereas TNF remained unchanged. Diosmin did not significantly affect Nos3, Gpx1 or Sod2 gene’s expression, but it attenuated the age-related upregulation of Xdh. Overall, diosmin attenuated age-associated vascular oxidative stress and partially improved endothelial function in aged rats. Although the reduction in circulating LBP suggests a possible effect on selected systemic signals associated with endotoxin exposure, additional inflammatory markers and mechanistic studies will be required to determine whether diosmin modulates vascular inflammaging.