Lead exposure remains a pervasive environmental and public health threat, imposing a substantial burden of neurodevelopmental and cognitive dysfunction, yet safe mechanism-oriented interventions remain limited. Genistein, a soybean-derived isoflavone with antioxidant and neuroprotective potential, may counter heavy metal-induced neural injury; however, whether its efficacy is associated with redox–metabolic remodeling is unclear. Here, we evaluated genistein in lead-exposed C57BL/6J mice and lead-challenged HT22 hippocampal neurons. Genistein improved novel-arm exploration and spatial memory without altering locomotor or swimming performance, and attenuated neuronal disorganization and apoptosis in hippocampal CA1, CA3 and dentate gyrus regions. These protective effects were accompanied by reduced blood and hippocampal lead accumulation, restored glutathione redox balance, enhanced antioxidant capacity, preserved mitochondrial integrity, and suppressed Bax/Caspase-3-associated apoptotic signaling. Importantly, because genistein also reduced hippocampal lead accumulation, the in vivo neuroprotection may reflect both reduced target-tissue lead burden and improved glutathione-related redox homeostasis. Untargeted metabolomics identified 59 genistein-responsive metabolites enriched mainly in glutathione metabolism, oxidative phosphorylation, and ascorbate/aldarate metabolism, linking metabolic remodeling to behavioral recovery and reduced oxidative-apoptotic injury. In HT22 cells, blockade of glutathione synthesis by buthionine sulfoximine markedly weakened genistein-mediated cytoprotection, mitochondrial membrane potential recovery, and apoptosis inhibition. Collectively, genistein mitigates lead-induced hippocampal neurotoxicity and cognitive impairment by restoring glutathione-centered redox–mitochondrial homeostasis, supporting its further development as a mechanistically defined dietary candidate for environmental pollutant-associated neural injury.

Disruption of neuronal excitation–inhibition balance and mitochondrial quality control may contribute importantly to lead (Pb)-induced neurotoxicity, but nutritional modulators targeting these processes remain poorly characterized. This study investigated the protective effects and underlying mechanisms of ginsenoside Rh1, a ginseng-derived bioactive compound, in Pb-exposed mice and Pb-treated HT22 hippocampal cells. Chronic Pb exposure caused spatial recognition deficits, reduced exploratory activity, anxiety-like behaviors, and marked neuronal injury, accompanied by Pb accumulation in blood and brain tissues, elevated IL-1β, TNF-α, and IL-6 levels, oxidative stress, reduced Gama-aminobutyric acid (GABA) content, and dysregulated NKCC1/KCC2 expression. In HT22 cells, Pb increased intracellular ROS generation and disrupted mitophagy-related signaling, as indicated by alterations in PINK1, Parkin, LC3, P62, and GABARAP. Rh1 treatment alleviated Pb-induced behavioral abnormalities and neuronal pathology, reduced Pb burden, suppressed neuroinflammatory responses, enhanced antioxidant defenses, improved Pb-associated alterations in GABAergic regulation, and modulated mitochondrial quality-control signaling in vivo and in vitro. These findings suggest that Rh1 may represent a promising nutritional intervention strategy for mitigating Pb-associated neurotoxicity.

Inflammatory bowel disease is characterized by recurrent mucosal inflammation, epithelial barrier disruption, and dysregulated cell death, highlighting the need for safe, multi-target interventions. Natural astaxanthin, renewably sourced from Haematococcus pluvialis or Phaffia rhodozyma, has shown greater tissue accumulation or antioxidant activity than synthetic astaxanthin in some preparations. Based on the complementary antioxidant, anti-inflammatory, and intestinal barrier-protective activities of its individual components, the astaxanthin–turmeric extract–honeysuckle extract combination (ATH) was investigated for its protective effects in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Thirty-two male C57BL/6J mice were randomly allocated to four cohorts: Control, DSS, DSS + ATH, and ATH. ATH intervention mitigated the DSS-associated decline in body mass, lowered clinical disease scores, attenuated DSS-induced colon shortening, and ameliorated mucosal lesions. In DSS-treated mice, ATH attenuated goblet-cell loss, reduced intestinal permeability, and restored ZO-1 and occludin expression. ATH treatment also reduced DSS-induced increases in colonic IL-1β, IL-6, TNF-α, IL-18, and malondialdehyde levels while improving superoxide dismutase activity and glutathione content. At the signaling level, ATH reduced phosphorylated NF-κB and NLRP3 immunoreactivity and decreased N-GSDMD accumulation within E-cadherin-positive epithelial regions. Western blotting further showed reduced NLRP3 expression, caspase-1 cleavage, and N-GSDMD formation, although the p-NF-κB/NF-κB ratio was not significantly changed. Collectively, ATH alleviated DSS-induced colitis by improving mucosal barrier and redox–inflammatory homeostasis while attenuating the NLRP3/caspase-1/GSDMD pyroptotic cascade. These findings support the further development of ATH as a multi-component natural intervention for intestinal inflammatory injury.

Cigarette smoke exposure is a major preventable risk factor for respiratory disease and drives oxidative and inflammatory lung injury, highlighting the urgent need for safe, multi-target interventions beyond conventional anti-inflammatory therapy. Formononetin (FMN), a naturally occurring isoflavone with antioxidant, anti-inflammatory, and microbiota-modulating potential, may offer a dietary-botanical strategy against smoke-related pulmonary damage. This study evaluated FMN against cigarette smoke extract (CSE)-induced lung injury and explored its associations with intestinal barrier integrity, gut microbiota, taurine metabolism, SLC6A6 expression, and NF-κB activation. In a CSE-challenged mouse model, oral FMN, particularly at 70 mg/kg, improved body weight gain, reduced the lung index, attenuated pulmonary histopathological injury, restored GSH/GSSG and SOD, decreased MDA, and suppressed TNF-α, IL-1β, and IL-6 expression. FMN also ameliorated colonic injury and restored ZO-1 and occludin expression. Exploratory 16S rRNA sequencing and fecal metabolomics indicated FMN-associated alterations in gut microbial composition and metabolic profiles, with taurine and hypotaurine metabolism identified as a candidate pathway for further investigation. FMN further restored lung taurine content and SLC6A6 expression while inhibiting NF-κB activation. These findings suggest that FMN alleviates CSE-induced lung injury and that this improvement is associated with coordinated changes in gut microbiota composition, taurine metabolism, SLC6A6 expression, and NF-κB activation.