Insufficient intake of the essential trace element selenium can lead to cardiovascular disease through oxidative stress. The expression of Sirtuin 3 (Sirt3)/YME1-like 1 ATPase (YME1L1) deacetylase pathway related factors is highly sensitive to intracellular redox fluctuations. However, its functional role in selenium‑deficient (-Se) myocardial tissue remains unclear. A porcine model of selenium deficiency was established by feeding a diet containing 0.030 mg/kg selenium. To investigate the role of YME1L1 acetylation, YME1L1‑K237R and YME1L1‑K237Q plasmids were transfected into cardiomyocytes. Oxidative stress, myocardial structure, mitochondrial morphology, protein acetylation, and PANoptosis markers were evaluated using histology, transmission electron microscopy, immunoprecipitation, western blot, and qRT‑PCR. Selenium deficiency induced oxidative stress, which downregulated Sirt3 and increased YME1L1 acetylation at K237, leading to mitochondrial dysfunction characterized by impaired mitochondrial dynamics, reduced ATP production, and mtDNA release. The deacetylation‑mimetic YME1L1‑K237R mutant significantly rescued PANoptosis. These findings identify an oxidative stress‑mediated Sirt3/YME1L1 acetylation axis, with YME1L1‑K237 as the critical acetylation switch, as a novel driver of PANoptosis in selenium‑deficient myocardium, offering new insights into the cardiac function of selenium.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder worldwide lacking effective treatments. Protocatechuic acid (PCA), a natural polyphenol found in various foods and medicinal herbs, exhibits diverse bioactivities; but its role in AD remains unclear. This study investigated the neuroprotective effects and mechanisms of PCA. In vitro, PCA significantly attenuated glutamic-induced cytotoxicity, oxidative stress, calcium influx, and apoptosis in PC12, SH-SY5Y, and HT22 cells. In vivo, PCA improved cognitive performance in the Morris water maze, open field, and novel object recognition tests in a D-galactose/AlCl3-induced AD mice, and mitigated hippocampal and cortical histopathological damage. Integrated transcriptomic and network pharmacology analyses identified the apoptosis, p53, and MAPK as key pathways. RT-qPCR and western blot analyses revealed that PCA downregulated p53, GADD45B, GADD45G, and phosphorylated p38. Collectively, these findings demonstrate that PCA alleviates AD progression by inhibiting the p53/GADD45/MAPK axis, positioning it as a promising natural candidate for AD prevention.

Premenopausal females have higher docosahexaenoic acid (DHA, 22:6n-3) levels than males, with elongation of very long chain fatty acids-like 2 (Elovl2) implicated in regulating these differences. We employed a liver-specific Elovl2-KO model to determine how hepatic ELOVL2 activity influences sex differences in DHA synthesis and turnover rates in mice. LoxP flanked Elovl2:Alb-Cre[+/-] or Elovl2:Alb-Cre[-/-] C57BL/6J male and female pups (n=64 per sex) were allocated into one of four groups: 1) male liver Elovl2-KO, 2) female liver Elovl2-KO, 3) male control or 4) female control. Following 5-weeks low carbon-13 (δ[13]C)-eicosapentaenoic acid (EPA, 20:5n-3) feeding, mice were switched to high δ[13]C-EPA and blood/tissues collected up to 112 days post diet-switch to determine fatty acid levels and δ[13]C to support n-3 PUFA synthesis and turnover estimates. Following interaction effects (sex x genotype, p < 0.05), liver and serum DPAn-3 half-lives and plasma DPAn-3 turnover rates became longer in Elovl2-KO females compared to controls, but not males. Furthermore, heart DHA half-lives were longer in male Elovl2-KO only and heart DHA turnover sex differences in control were lost with Elovl2-KO. Genotype effects (p < 0.001) were observed for all tissue kinetic parameters of DPAn-3 and DHA. Gene expression revealed hepatic Fads1 was 64% higher (p<0.01) in females than males, while Fads2 was upregulated exclusively in female KO compared to female controls (71%, p<0.05). In conclusion, hepatic ELOVL2 regulates sex differences in n-3 PUFA metabolism in the liver and heart, with females demonstrating a potentially greater capacity to maintain DHA levels in the absence of ELOVL2.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of liver failure associated with hyperammonemia, oxidative stress, and neuroinflammation. This study investigated the hepatoprotective and neuroprotective effects of trans-ferulic acid (TFA), a dietary phenolic compound, administered alone or in combination with lactulose, in a thioacetamide-induced rat model of HE. TFA treatment significantly improved liver function, reduced serum ammonia, and restored hepatic and cerebral histoarchitecture. TAA-induced motor dysfunction and altered behavioral performance were also ameliorated by TFA and lactulose, with the combination treatment producing greater overall improvement. However, these behavioral effects were interpreted in the context of concomitant locomotor impairment, particularly for spatial learning and exploratory behavior. Mechanistically, TFA enhanced antioxidant defense by activating the Nrf2/HO-1 pathway, while suppressing hepatic and cerebral inflammation through inhibition of the TLR-4/NF-κB/NLRP3 inflammasome axis. These findings demonstrate that TFA exerts dual antioxidant and anti-inflammatory actions and enhances lactulose efficacy, highlighting its potential as a functional food-derived adjunctive strategy for HE management.

Recent studies have demonstrated that intestinal metabolites play a critical role in the pathogenesis of calcium oxalate (CaOx) nephrolithiasis; however, the underlying mechanisms remain largely elusive. In this study, we found that rats with renal CaOx crystallization exhibited distinct intestinal metabolite profiles, characterized by the enrichment of purine metabolism and a marked increase in adenine levels. Further experiments confirmed that adenine significantly promotes CaOx crystal deposition in both rat and Drosophila models. Mechanistically, adenine disrupts intestinal architecture, downregulates the expression of barrier-related tight junction proteins, and dysregulates intestinal oxalate transporters (SLC26A3 and SLC26A6), which is associated with increased net enteric oxalate absorption. Collectively, these findings suggest that adenine may enhance intestinal oxalate absorption while reducing excretion, ultimately contributing to hyperoxaluria and promoting renal CaOx crystallization. These findings reveal a previously unrecognized role of adenine in the pathogenesis of CaOx nephrolithiasis and highlight potential therapeutic targets for intervention.

Vitamin D deficiency is a widespread condition across the world. The rs2228570 (FokI) polymorphism in the vitamin D receptor (VDR) gene has been associated with vitamin D-related diseases, but its influence on circulating 25(OH)D levels remains unclear. This systematic review and meta-analysis aimed to assess the association between the rs2228570 polymorphism and serum 25(OH)D. The search was conducted in PubMed, Scopus, and Cochrane databases. Eligible studies included healthy adults with available genotyping of the VDR gene, and measurement of 25(OH)D. The exclusion criteria included pregnant or lactating women, obese participants, and individuals receiving supplements. Of the 66 articles that met the inclusion criteria, 45 were included in the meta-analysis, representing 15,256 participants mainly from Europe, Asia and America. The included studies were both case-control and cross-sectional, and study quality was assessed using standardized tools. No significant associations were observed in any of the genetic models analyzed (CC vs TT, CT vs TT, (CC+CT) vs TT, or (TT+CT) vs CC). Subgroup analyses by continent showed no significant associations (p>0.05), except for the American subgroup for the CT vs TT comparison (p=0.04). In Fair-quality studies, higher 25(OH)D levels were observed among C-allele carriers, although these findings were accompanied by substantial heterogeneity across comparisons (I[2] range: 81.4% to 95.1%). This meta-analysis found no evidence that the rs2228570 (FokI) polymorphism influences circulating 25(OH)D. These results contribute to delineate the limited influence of the FokI polymorphism in 25(OH)D levels and support the need for future studies integrating environmental and functional factors.

Dietary iron deficiency and excess may both disturb enterohepatic homeostasis, yet their differential effects on organ-specific iron distribution and the microbiota-bile acid-FXR signaling axis remain unclear. Here, we integrated multi-cohort cross-sectional analyses with mouse experiments, cell co-culture assays, organoid models, metabolomics, and fecal microbiota transplantation experiments. In population analyses, higher dietary iron, rather than serum iron, was associated with diarrhea, fatty liver, and liver fibrosis. In mice, iron deficiency induced widespread reductions in tissue iron content, whereas iron excess caused marked iron accumulation in the small intestine, colon, liver, spleen, kidney, and skeleton. Both iron-deficient and iron-excess diets impaired colonic barrier homeostasis, as indicated by reduced goblet cell abundance, lower Muc2 expression, disrupted tight junctions, and increased intestinal permeability. However, iron excess caused more profound gut microbiota dysbiosis, perturbed bile acid-related bacterial taxa, depleted primary bile acids, suppressed intestinal and hepatic farnesoid X receptor (FXR) signaling, and exacerbated hepatic steatosis, fibrosis, inflammation, and dysfunction. Importantly, chenodeoxycholic acid, cholic acid, and fecal microbiota transplantation partially restored bile acid-FXR signaling, improved barrier integrity, and alleviated liver injury under iron-excess conditions. Collectively, dietary iron imbalance disrupts enterohepatic homeostasis via the gut microbiota-bile acid-FXR signaling axis, with iron excess emerging as the predominant driver of bile acid dysregulation, impaired FXR signaling, and gut-liver injury. These findings identify dietary iron as an important determinant of enterohepatic homeostasis and support bile acid- and microbiota-targeted strategies for iron-related metabolic disorders.

Although silibinin (SIL), from milk thistle, has been reported to promise health promotion and disease treatment, the potential mechanism of SIL in improving obesity is still unknown. The fat accumulation was decreased by 78% and 49% in cellular and high glucose-induced (HGI) Caenorhabditis elegans (C.elegans) models. The decreased lipid droplets in both average size and quantity in the cytoplasm of the liver and EWATs were obtained by histology (hematoxylin & eosin) experiments. The promoted health effects in lifespan, stress ability, antioxidant ability, changed lipofuscin accumulation, pharyngeal pumping rate, and aging-related indexes of exercise were also confirmed. The increased expressions of daf-2, akt-1, daf-16, and skn-1, combined with the downstream target genes of IIS-mediated mTOR signaling factors (pha-4, hlh-30, lgg-1, and unc-51) and adipose-related factors (nhr-49, fat-5, fat-6, and fat-7) in C. elegans were verified through the insulin/insulin-like growth factor-1 signaling pathway. SIL was proposed as a potential adjuvant remedy or nutraceutical for improving obesity and promoting health.

We previously investigated whether maternal high-fat diet (HFD) exposure alters lupus nephritis (LN) progression in MRL/lpr offspring. Contrary to expectation, maternally HFD-exposed offspring showed delayed and attenuated nephritic progression compared with control diet offspring. The maternal HFD developmental impact on LN remains unclear. Here, integrated amniotic fluid metabolomics and fetal liver transcriptomics revealed that maternal HFD reshaped the intrauterine molecular environment, particularly involving steroid hormone biosynthesis and Wnt/β-catenin-associated regulatory networks. Methylome profiling further demonstrated broad CpG hypomethylation, immune-related differentially methylated region enrichment, and an inverse association between global CpG methylation and oxidative genomic DNA damage. Among candidate regulatory nodes, Axin2, a canonical Wnt/β-catenin target and feedback regulator, emerged as a potential link between fetal nutritional exposure, epigenetic remodeling, and persistent pathway modulation. Although whole-locus and gene body methylation of Axin2 were not markedly altered, promoter-region methylation showed an increasing tendency under maternal HFD exposure. In adult offspring, maternal HFD was associated with reduced Axin2 protein expression, decreased Wnt-responsive transcripts, increased peripheral corticosterone levels, and attenuation of LN progression. The inverse association between Axin2 expression and corticosterone further suggested coupling between suppressed Wnt pathway output and steroid hormone remodeling. Together, these findings support a developmental model in which maternal HFD reshapes the fetal intrauterine environment and establishes a persistent Wnt-steroid hormone-epigenetic regulatory axis that unexpectedly attenuates LN progression in genetically susceptible offspring.

Betulin (BE) is extracted from pentacyclic triterpenoids of many natural plants and has antioxidation activities. However, the neuroprotective effects and underlying mechanism of Betulin in Alzheimer's disease (AD) have remained limited. Integrate SuperPred, SEA, and Targeted Net databases, as well as KEGG pathway enrichment analysis, to predict and analyze BE-related target genes. Male APP/PS1 mice were treated intragastrically with Betulin for 4 weeks, followed by evaluation of cognitive function and pathological changes, and the levels of ROS, HO‑1, SOD2 and GPX4 were detected. Subsequently, molecular docking and molecular dynamics simulations were utilized to investigate the potential interaction between Betulin and KEAP1 protein, and KEAP1 mutant transfection was used to assess the involvement of KEAP1/NRF2 signaling in the antioxidant response to BE. Finally, KEAP1 and NRF2 protein levels were examined in the animal model. Our results showed that KEGG pathway enrichment analysis revealed that Betulin-related target genes were enriched in pathways associated with AD. Moreover, Betulin significantly alleviated cognitive impairment, neuronal damage, Aβ deposits and Tau phosphorylation in the APP/PS1 mice. Moreover, Betulin significantly increased GSH level, while significantly decreased MDA level. Meanwhile, Betulin significantly decreased ROS level, while significantly increased the levels of HO-1, SOD2, and GPX4 in vitro. Notably, molecular docking and molecular dynamics simulations suggested a potential interaction between Betulin and KEAP1, while KEAP1 mutant transfection attenuated the Betulin-induced increase in NRF2 and antioxidant proteins in vitro. Moreover, Betulin treatment was accompanied by decreased KEAP1 and increased NRF2 protein levels in APP/PS1 mice. These findings indicate that Betulin alleviates oxidative stress and modulates KEAP1/NRF2 signaling in AD models.

According to the Developmental Origins of Health and Disease (DOHaD), early-life nutritional exposure can affect long-term metabolic health. Gut microbiota development during lactation plays a pivotal role in regulating metabolism, with short-chain fatty acids (SCFAs) serving as key mediators connecting early microbial colonization to future metabolic outcomes. Diet composition strongly affects gut microbiome, and high-sucrose diets (HSD) promote dysbiosis and metabolic dysfunction. We investigated whether small litter size (SL) modulates susceptibility to HSD-induced metabolic disruptions by assessing gut microbiota composition, SCFA production, and microbial co-occurrence networks. Male Wistar rats (n=29) were allocated to control (CL, 8 pups/dam) or small litter (SL, 4 pups/dam) groups, then, after weaning, assigned to either a standard diet (STD) or HSD (30% sucrose) for 8 weeks. HSD reduced gut microbial diversity and increased the Firmicutes/Bacteroidetes ratio only in the CL group. In contrast, SL rats fed an HSD exhibited specific bacterial enrichment and maintained butyrate concentrations comparable to control rats, suggesting preserved metabolic stability. Network analysis revealed that HSD-SL rats developed complex microbial interactions driven by SCFA biosynthesis pathways. These findings suggest that early-life nutritional programming due to SL may promote greater functional stability of the gut microbiota under dietary challenges, potentially mitigating future metabolic disturbances.

Nonalcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM), posing a significant metabolic disorder with limited dietary intervention options. Cordycepin, a food‑derived nucleoside from the edible fungus Cordyceps militaris, exhibits hypoglycemic and hypolipidemic effects, but its role in T2DM combined with NAFLD remains unknown. Here, we established a mouse model of T2DM combined with NAFLD in male KM mice using high-fructose and high‑fat diet, and streptozotocin. Both cordycepin (COR) and C. militaris water extract (CWE) attenuated glucose intolerance, dyslipidemia, hepatic steatosis, liver injury, inflammatory response and oxidative stress, with cordycepin showing superior efficacy. Multi‑omics analysis revealed that cordycepin uniquely reshaped the gut microbiota by significantly enriching the c__Clostridia, including g__Acetatifactor, g__Anaerovorax, g__Monoglobus, s__Acutalibacter_muris, and further affected liver metabolism, which was characterized by enrichment of bile acid metabolism-related pathways. Targeted bile acid metabolomics demonstrated that cordycepin specifically promoted the production of cholic acid‑7‑sulfate (CA7S), a gut‑restricted secondary bile acid, through activation of the hepatic PXR/Sult2a1 pathway. Notably, integrated correlation analysis revealed a significant positive association between CA7S and c__Clostridia (e.g., g__Monoglobus, g__Lachnoclostridium, and g__Anaerovorax), suggesting that cordycepin enhances CA7S production by enriching these Clostridia members. And CA7S activated TGR5 to stimulate glucagon‑like peptide‑1 (GLP‑1) secretion, thereby improving glucose and lipid homeostasis. Therefore, these findings demonstrate that dietary cordycepin improves T2DM combined with NAFLD by modulating gut microbiota, particularly Clostridia, and affecting the PXR/Sult2a1/CA7S/GLP‑1 pathway, thereby exerting beneficial effects on glucose and lipid homeostasis.