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Probiotics have garnered considerable attention due to their multifunctional properties, which encompass the maintenance of intestinal homeostasis, the modulation of immune responses, and the exertion of antioxidant activities. Thus, this study used the Caenorhabditis elegans model and in vitro techniques to assess the activity of gut microbiota from healthy individuals. The study investigated the anti-aging effects of the Lactobacillus paracasei JS-3 (JS-3) strain on C. elegans, as well as its regulatory role in the gut microbiota of elderly individuals. The results demonstrated that JS-3 significantly increased the mean lifespan of C. elegans by 28.02%, surpassing the 15.34% increase achieved with β-nicotinamide mononucleotide (NMN). Furthermore, JS-3 significantly increased the survival rate of C. elegans under thermal and oxidative stress conditions, improving their motility. Further analysis revealed that JS-3 reduced lipofuscin accumulation and lowered reactive oxygen species (ROS) levels within the C. elegans, while boosting antioxidant enzyme activity and decreasing malondialdehyde (MDA) content. These results demonstrate the considerable potential of JS-3 in anti-aging and antioxidant applications. In vitro fermentation results indicated that JS-3 effectively modulates the composition of gut microbiota in elderly populations, specifically by reducing the abundance of harmful bacterial genera while promoting the proliferation of beneficial bacterial genera, such as Bifidobacterium, Bacteroides, and Veillonella. These results suggest that JS-3 has the potential to be an anti-aging probiotic and provide a scientific rationale for developing novel anti-aging products.
Gut-brain communication is mediated by metabolic and signaling pathways that play important roles in brain development and cognitive function. Recently, the bidirectional role of the gut microbiota in the gut-brain axis has drawn greater scientific attention. The gut microbiota, a group of bacteria that naturally colonize the gastrointestinal tract of mammals, may play a role in healthcare burden neurodegeneration, which affects many of the body's activities. Lately, it has been reported that some mediators produced by changes in the gut microbiota are associated with neurodegenerative diseases. Additionally, the host immune system plays a role in gut-brain communication, as gut microbiota are potent modulators of immune cells that reside in the central nervous system. Unfortunately, the majority of current strategies are based on pre-clinical studies, with little known about the causes and molecular mechanisms. Herein, we summarize the evidence supporting an integrated hypothesis of mediators in neurodegenerative diseases and gut-brain communication, which result from biologically conserved interactions and factors related to the distinct composition of the gut microbiota. We also mention the need for establishing a standardized approach for particular focal parts of the microbiota-gut-brain axis, thorough biological sample analyses, dietary strategies, and recognition of a new therapeutic paradigm. A stronger emphasis on omics technologies and on advanced in vitro and in vivo models is also urgently needed. This will enable research on the microbiota-gut-brain axis to proceed to the next stage, allowing us to identify practical opportunities to modify the microbiota for enhanced brain health.
Global environmental fluoride contamination causes damage to multiple organs, with the male reproductive system being particularly susceptible. Nevertheless, the precise pathophysiological mechanisms underlying this vulnerability remain poorly defined. This study aimed to elucidate how excessive fluoride exposure leads to impairment of the male reproductive system. Initially, bioinformatics analyses were conducted to screen for the potential involvement of the ferroptosis pathway in fluoride-induced reproductive toxicity. Subsequently, in vitro and in vivo models confirmed that fluoride exposure elicited reproductive damage through the induction of ferroptosis. The results revealed that fluoride exposure significantly suppressed the activity of the Nrf2/FSP1 antioxidant pathway. This suppression led to elevated levels of malondialdehyde, a lipid peroxidation marker, and ferrous ions (Fe2+), along with a reduction in coenzyme Q10, an essential component of the mitochondrial electron transport chain. Concurrently, histological examination of testicular tissue revealed structural alterations, and a decline in epididymal sperm quality was observed in the fluoride-exposed group. Intervention with Ferrostatin-1 (a ferroptosis inhibitor) and Tert-butylhydroquinone (an antioxidant) partially alleviated the inhibitory effects of fluoride exposure on the Nrf2/FSP1 pathway. This intervention reduced the incidence of ferroptosis, as indicated by decreased levels of malondialdehyde and Fe2+, and consequently mitigated the reproductive damage caused by fluoride exposure. In conclusion, excessive fluoride exposure inhibited the Nrf2/FSP1 pathway, resulting in a marked increase in reactive oxygen species generation and subsequent lipid peroxidation. This cascade of events induced ferroptosis in the testicular tissue of Sprague-Dawley rats and GC-1 spermatogonial cells, ultimately leading to reproductive dysfunction.
Exercise is effective in combating obesity and regulating the composition of the gut microbiota. However, the molecular mechanism by which exercise alters gut microbiota and its metabolites to exert weight loss has not been fully elucidated. In this study, the mechanism of gut microbiota and microbial metabolites reshaped by exercise in weight loss were investigated by macrogenomic sequencing, metabolomics analysis and fecal microbiota transplantation (FMT). The results showed that exercise significantly increased the abundance of beneficial bacteria such as Oscillibacter, Lachnoclostridium, and unclassified_f__Lachnospiraceae, and decreased the abundance of Lactobacillus and Desulfovibrio. Meanwhile, exercise significantly increased medium- and long-chain fatty acid (MCFA and LCFA) content, as well as butyric acid, and decreased fructose levels. These metabolites were associated with fatty acid degradation, and unsaturated fatty acid synthesis pathways. In addition, FMT from exercised mice significantly reduced high-fat diet (HFD)-induced obesity and lipid accumulation, increased insulin sensitivity, and improved glucose homeostasis, with decreased the levels of serum lipids and lipopolysaccharide (LPS). FMT also attenuated hepatic and pancreatic dysfunction, as well as hepatic steatosis. Notably, FMT from exercised mice significantly increased the content of MCFAs and LCFAs in the intestines of HFD-treated mice and upregulated the expression of genes related to glycolipid metabolism and the secretion of Glucagon-like Peptide-1 (GLP-1). Finally, caprylic, lauric, cardamic and stearic acids can significantly increase GLP-1 levels in Caco-2 cells. Taken together, the mechanism by which exercise suppresses obesity may inhibit appetite by optimizing the intestinal microbiota, promoting the synthesis of MCFAs and LCFAs, and up-regulating GLP-1 secretion.
L-theanine (LT), a characteristic amino acid found in tea, possesses diverse biological activities, including antioxidant, growth-promoting, and immune-enhancing effects, and is widely used in supplements. However, the regulatory role of LT in milk synthesis in dairy cows remains unclear. This study aimed to elucidate the effects of LT on milk synthesis and its underlying molecular mechanisms in primary bovine mammary epithelial cells (BMECs). We isolated primary BMECs and investigated the effects of LT treatment (100 µM), utilizing overexpression and knockdown techniques for TAS1R1, FERM domain containing 6 (FRMD6), and mTOR. Results showed that 100 µM LT significantly promoted BMECs proliferation and the synthesis of milk protein and fat. Knockdown of its putative receptor, TAS1R1, reversed these stimulatory effects of LT. Transcriptome sequencing analysis revealed FRMD6 as a key target gene mediating the LT-induced promotion of BMEC proliferation and milk synthesis. Mechanistic studies further indicated that LT enhanced the interaction between FRMD6 and mTOR, promoted mTOR translocation from the cytoplasm to the lysosomal surface, subsequently leading to the activation of the mTORC1 signaling pathway, ultimately promoting milk synthesis. The clinical experiment results on dairy cows show that Rumen-Protected LT can significantly increase the milk production of mid-lactation cows and improve the quality of their milk. In conclusion, our research provides strong preclinical evidence for LT as a potential functional feed additive to promote milk synthesis.
Different evidence suggests that ketogenic diet (KD) ameliorates neurological dysfunctions including core symptoms of autism spectrum disorders (ASD). In view of this, we have hypothesized that KD may induce a positive effect even on some ASD comorbidities, such as motor impairment and anxiety, along with cerebellar inflammation and axonal demyelination. BTBR T+ Itpr3tf/J (BTBR) and C57BL/6 (C57) mice were fed with a standard chow diet (CD) or KD for 5 weeks. Modified beam walking (MBW) and open field (OFT) tests were used to examine locomotor activity and anxiety-related behaviors. At the same time, cerebellar pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were evaluated together with g-ratio of myelinated axons, detected by TEM. The levels of different isoforms (21.5, 18.5/17, and 14-kDa) of the myelin basic protein (MBP) were also analyzed. As expected, KD improved motor deficits and anxiety in BTBR mice as displayed by significant increases (P<.001) in the number of peeking and laps during MBW test rather than BTBR treated with CD. Furthermore, reduced path speed and enhanced path length (P<.001) in OFT were reported for the same KD-fed mice strain. Contextually, some pro-inflammatory cytokines (TNF-α and IL-1β) were significantly (P<.05) reduced in the cerebellum of BTBRs exposed to KD. Such ameliorations were correlated to a reduction of g-ratio (P<.001), together with an upregulation (P<.05) of the MBP isoform 18.5/17-kDa. Overall, these findings support a promyelinating and anti-inflammatory action of KD, which very likely determined mitigation of motor disorder and anxiety-like behaviors.
Quercetin (Que), a natural dietary flavonoid, possesses significant antioxidative and immunoregulatory properties. Di(2-ethylhexyl) phthalate (DEHP), a pervasive environmental endocrine-disrupting chemical, triggers oxidative stress (OS) and elicits immunotoxic effects in various species. However, whether Que can target NF-κB to alleviate DEHP-induced OS and PANoptosis in the chicken thymus remains unclear to date. To investigate the mechanism of thymus damage induced by DEHP and the intervention effect of Que, we established an in vivo chicken model treated with DEHP and/or Que. Based on the results of network pharmacology, molecular docking, molecular dynamics simulations, and Cell Thermal Shift Assay, we predicted that NF-κB is the key target for the protective effect of Que. Subsequently, through hematoxylin and eosin staining, CCK-8, immunofluorescence, Western blot, and other techniques, we verified the effects of DEHP and/or Que on OS, the assembly of PANoptosome, and cellular PANoptosis in chicken thymus tissue and chicken lymphocyte cell line (MSB-1). Meanwhile, to clarify the key role of NF-κB in the above regulatory process, we conducted reverse validation experiments by introducing the NF-κB activator Act1 in cellular experiments. The results demonstrated that DEHP exposure markedly induces the upregulation of NF-κB and TNF-α (P<.05), leading to a pronounced burst of reactive oxygen species and consequent OS within the chicken thymus. This process further activates the ZBP1-mediated PANoptosis pathway, ultimately causing damage to chicken thymus tissue. Que intervention effectively suppresses NF-κB activation, blocking the transmission of the NF-κB/TNF-α/ROS signaling axis, thereby reversing DEHP-induced ZBP1-mediated PANoptosis in chicken thymus.
Background/Objectives: Aging is associated with physiological, biochemical, and psychosocial changes that can significantly affect nutritional status and overall health. In Sub-Saharan Africa (SSA), older adults face unique age-related challenges that may compromise healthy aging, yet evidence remains fragmented. This systematic review synthesized the existing literature on the nutritional status, age-related challenges, and strategies to promote healthy aging of older adults in SSA. Methods: A systematic literature search was conducted on PubMed, Scopus, ScienceDirect, and Cochrane Library to identify relevant studies published up to 10 December 2025. Results: Fifty-five studies met the inclusion criteria, with most of the studies coming from South Africa, Ghana, and Nigeria. Amongst community-dwelling populations, approximately 30-65% of the older adults were either malnourished or at risk of malnutrition, while hospital-based studies reported markedly higher burdens, with malnutrition prevalence exceeding 70% in some settings. Undernutrition, micronutrient deficiencies, and the coexistence of overweight and obesity were frequently observed, reflecting the region's ongoing nutrition transition. Frailty emerged as the predominant age-related challenge, with prevalence ranging around 10-60%. Other common challenges included sarcopenia, reduced muscle strength, functional disability, cognitive impairment, and dysphagia, all of which were closely related to poor nutritional status, food insecurity, multimorbidity, and reduced quality of life. Few studies reported on healthy aging strategies, with the limited evidence suggesting that nutrition education, physical activity, and psychosocial interventions may enhance nutritional and functional outcomes. Conclusions: The need for context-specific, nutrition-sensitive interventions, and stronger health and social support systems is warranted to promote healthy aging in SSA older adults.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing global health concern linked to gut microbiota dysbiosis. This study aims to evaluate the therapeutic effects of Bacteroidetes on MAFLD, and to explore their mechanisms. This study investigates the effects of Bacteroides thetaiotaomicron (B. thetaiotaomicron), Bacteroides ovatus (B. ovatus), and their combination on MAFLD progression in a high-fat and high-cholesterol (HFHC) diet-induced mouse model. It was indicated that both individual and combined treatments with B. thetaiotaomicron and B. ovatus effectively reduced body weight and prevented hepatic steatohepatitis and liver injury. Mechanistically, both Bacteroides species induced changes in gut microbiota diversity and composition. Treatments, whether alone or in combination, resulted in a decreased Firmicutes/Bacteroidetes (F/B) ratio, reduced abundance of Ruminococcustorques_group, Ruminococcusgauvreaui_group, and Erysipelatoclostridium, and a significant increase in the fecal abundance of Lachnospiraceae-NK4A136_group, norank_f__Oscillospiraceae, and Colidextribacter. Compared to group M, treated mice exhibited significant changes in fecal short-chain fatty acids (SCFA), decreased levels of serum lipopolysaccharides (LPS), CD163, IL-1β, TNF-α, and reduced liver macrophages. Furthermore, both M-A and M-B treatments led to the downregulation of genes involved in de novo lipogenesis (such as Srebf1, Acaca, Scd1, Fasn) and upregulation of genes related to fatty acid oxidation (such as Ppara). Combination therapy did not exhibit superior efficacy compared to individual treatments. This study provides evidence that B. thetaiotaomicron and B. ovatus can improve MAFLD by regulating the gut-liver axis, combination therapy did not exhibit superior efficacy compared to individual treatments (P>.05).
To date, no study has focused on the combined effects of arsenic and lipid exposure on vascular disorders. Substantial evidence indicates that vascular endothelial dysfunction is a primary driver of vascular diseases. Endothelial progenitor cells (EPCs) exert pivotal roles in repairing dysfunctional vascular endothelial cells. Therefore, elucidating the role of EPCs in endothelial dysfunction induced by combined exposure to arsenic and lipid is of great significance. Our results revealed that 25 mg/L sodium arsenite combined with high-fat diet had the most detrimental effect on vascular endothelial function. Exposure to 30 µmol/L NaAsO2+10 µg/mL oxidized low-density lipoprotein, it significantly reduces the cell viability, intracellular NO content, and NOS activity in both mouse aortic endothelial cells and EPCs. Both in vivo and in vitro, a certain number of EPCs could both repair the damaged endothelial function caused by the combined exposure to arsenic and high-fat diet, or oxidized low-density lipoprotein. Proteomic analysis identified Caveolin-1 (Cav-1) as a candidate molecule whose expression was remarkably altered in EPCs under combined exposure, and under 5 µg/mL Cav-1 recombinant protein intervention, the repair ability of EPCs on the dysfunctional mouse aortic endothelial cells was significantly improved. Moreover, 5 µg/mL Cav-1 recombinant protein has comparable repairing effects on endothelial function as intravenous injection of EPCs. Collectively, our systematic studies provide novel promising measures on the prevention and treatment of vascular diseases induced by chronic arsenic exposure and high lipid.
Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Necroptosis is a controlled, programmed form of cell death, with its core comprising a highly conserved signaling pathway that primarily involves key proteins, including Receptor-interacting protein kinase-1 (RIPK1), RIPK3, and Mixed lineage kinase domain-like protein (MLKL). Diosgenin (DG), classified as a steroidal saponin, exhibits anti-inflammatory, immune-regulating, and lipid-lowering properties, demonstrating efficacy in ameliorating dyslipidemia across multiple metabolic pathologies. However, the exact signaling pathways involved in improving NAFLD and preventing liver damage remain unclear. In our study, the data showed that the administration of diosgenin effectively mitigated hepatic damage and excessive lipid deposition in the high-fat diet (HFD)-induced rat model. Meanwhile, it also significantly downregulates Tumor necrosis factor-α (TNF-α), Tumor necrosis factor receptor-1 (TNFR1), and Tumor necrosis factor receptor-associated death domain protein (TRADD), inhibits upstream signaling of the necroptosis pathway, and suppresses necroptosis by reducing RIPK1, RIPK3, and MLKL phosphorylation. DG decreases cell damage and inhibits the expression of necroptosis-related genes in free fatty acids (FFAs)-induced HepG2 cells, which is consistent with the results of in vivo experiments. We inhibited and overexpressed RIPK1 in vitro for further research. Inhibition of RIPK1 enhances the effect of DG on NAFLD, while overexpression of RIPK1 partially reverses its beneficial effect. In addition, to test whether DG acts independently of upstream TNF-α, we introduced exogenous recombinant TNF-α to amplify upstream signals. In conclusion, DG has a favorable reduction effect on NAFLD through the RIPK1-dependent necroptosis signaling pathway. Also, this study offers further data and a theoretical basis for the use of natural medicines to improve NAFLD.
This systematic review evaluates the current literature on the protective mechanisms of dietary phytochemicals in cellular and animal models of myocardial infarction, with a specific focus on miRNA modulation. A literature search was conducted across three databases (PubMed, Scopus, and Embase) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies published in English between 2014 and 2024 were included based on predefined keywords. Of 432 identified records, 28 articles met the inclusion criteria and were included in the review. The results showed that phytochemicals upregulated 20 different miRNAs (e.g., miR-21, miR-126, and miR-24-3p) and downregulated 10 others (e.g., miR-34a and miR-155-5p). These changes in miRNA expression were associated with reduced ischemia-induced apoptosis (e.g., decreased cleaved caspase-3 or BAX levels), inflammation (e.g., decreased levels of pro-inflammatory interleukins), and oxidative stress (e.g., increased antioxidant enzyme activity). In addition, phytochemicals modulated autophagy (e.g., decreased Beclin-1 and LC3-II levels or increased p62 levels) and activated prosurvival pathways such as PI3K/Akt signaling. Overall, our analysis suggests that targeting miRNA pathways with phytochemicals may mitigate ischemic injury, as shown by increased cell viability and reduced myocardial infarct size. This approach may therefore support the development of new nutritional and therapeutic strategies for myocardial infarction. However, because all included studies were conducted in preclinical models, clinical trials in humans are required to validate these findings.
Long noncoding RNAs (lncRNAs) are important regulators of adipogenesis and energy metabolism, but their roles in visceral fat deposition remain incompletely understood. Here, we investigated the function of the rabbit lncRNA RRP12-AS and evaluated the conservation of its human homolog using in vitro and in vivo gain- and loss-of-function models. RRP12-AS promoted rabbit adipocyte proliferation but inhibited adipogenic differentiation, while in vivo overexpression reduced perirenal fat hypertrophy and improved lipid metabolic parameters. Mechanistically, RRP12-AS interacted with hnRNPA1 and enhanced UCP1 expression by regulating UCP1 mRNA stability and translation efficiency, thereby promoting thermogenesis in adipose tissue. In addition, the human homolog H-RRP12-AS showed similar regulatory effects on cellular lipid metabolism. Together, these findings identify RRP12-AS as a regulator of visceral fat metabolism through the hnRNPA1/UCP1 axis and suggest its potential relevance as a therapeutic target for central obesity.
Carnosic acid (CA), a phenolic diterpene abundant in Rosmarinus officinalis, has emerged as a bioactive compound with multifaceted effects on hepatic cells and liver tissue. The present work aims to critically discuss, from a mechanistic perspective, the molecular and cellular effects induced by CA on the liver, integrating evidence from in vitro and in vivo experimental models. Across hepatocytes, hepatic stellate cells, and hepatocellular carcinoma models, CA consistently modulates redox balance, inflammatory signaling, mitochondrial integrity, metabolic pathways, and cell fate decisions. Mechanistically, CA engages signaling hubs, such as nuclear factor erythroid 2-related factor 2, sirtuin 1 , AMP-activated protein kinase, 66 kDa Src homologous-collagen homologue adaptor protein, nuclear factor-κB, and Akt/mechanistic target of rapamycin, thereby coordinating antioxidant defenses, suppression of inflammation, regulation of lipid and glucose metabolism, and control of apoptosis and autophagy. Importantly, these effects are highly context-dependent, with CA promoting cytoprotection and metabolic homeostasis in non-transformed hepatic cells, while inducing apoptotic or autophagy-related cell death in hepatocellular carcinoma models. Despite this robust mechanistic framework, significant gaps remain regarding CA bioavailability, intracellular distribution, mitochondrial targeting, and the integration of metabolic reprogramming with redox and inflammatory signaling. Collectively, the data position CA as a pleiotropic modulator of hepatic biology and highlight its translational potential, while underscoring the need for more refined mechanistic and pharmacokinetic investigations.
Epidemiological evidence suggests fetal hyperglycemia predisposes the offspring of mothers with gestational diabetes (GDM) to insulin resistance. While breastfeeding is known to improve metabolic outcomes in offspring from GDM mothers, the breast-milk (BM) composition may be significantly altered. How the BM in GDM-induced changes influence insulin signaling and contribute to-or interfere with-these clinical benefits remains unknown. We hypothesized that impaired maternal glucose tolerance (IGT) during gestation alters BM-composition. Using a high-calorie nutritional rodent GDM-model, we investigated whether IGT and its resolution postpartum affect BM-composition, especially in emerging regulators of insulin-sensitivity (IS). Female rats were fed either a high-fat high-sucrose (HFHS) or control standard (CTL) diet during gestation. At delivery, IGT-dams (HFHS group) either switched to standard diet (4HFHS, resolved-IGT postpartum) or remained on HFHS (7HFHS, persistent-IGT) throughout lactation. BM-metabolome and lipidome were analyzed, combined with microRNAs profiles. Colostrum from IGT-dams displayed enrichments in specific lipids, including polyunsaturated-phospholipid-plasmalogens and medium-chain-acylglycerols, a readily useable source of energy for the newborn, as well as sphingolipids with very-long-chain fatty acids, associated with IS, with specificities depending on IGT status postpartum. 4HFHS milk retained elevated glutathione precursors, versus 7HFHS. Additionally, mature 4HFHS milk presented higher abundance of miRNAs linked to β-cell survival and insulin signaling (miR-200b-3p, miR-148a-3p). Resolution of maternal IGT postpartum restored mature milk metabotype, despite specificities in colostrum. Compared with persistent-IGT dams, milk of resolved-IGT dams was enriched in novel BM-candidate bioactive agents, including specific sphingolipids, plasmalogens, miRNAs, and glutathione precursors, that may impact neonatal glucose homeostasis and IS.
The composite dietary antioxidant index (CDAI), a composite score of multiple dietary antioxidants that assesses and reflects the overall impact of dietary antioxidants on health. The state of sleep is one of the major public health issues. The interaction between CDAI combined with physical activity on sleep is currently unclear. Therefore, we aimed to explore the association between CDAI, physical activity, and sleep condition. A total of 23,425 participants were enrolled. Six dietary factors (vitamin A, vitamin C, vitamin E, zinc, selenium, and carotenoids) were selected to score the CDAI. The association between CDAI, physical activity, and sleep condition were analyzed using weighted binary logistic regression. A stratified analysis of sub-groups was also used in this study. Both high levels of CDAI and active physical activity were protective factors for poor sleep condition (P<.05). There was an interaction between CDAI and physical activity (P-interaction=.062). There was a positive association between higher levels of CDAI and good sleep condition among those who were physically active. Compared to the third tertile of CDAI (CDAI T3) and active activity groups, all subgroups except the second tertile CDAI (CDAI T2) and active activity groups had statistically significant (P<.05) increased odds of poor sleep condition. Both low levels of CDAI and physical inactivity were significantly associated with sleep condition. There was an interaction between CDAI and physical activity. Low levels of CDAI combined with physical inactivity may be associated with an increased odds of poor sleep condition.
Anemia is a public health issue affecting people of all ages worldwide. 43% of children under five in Egypt are suffering from anemia. Hemolytic anemia (HA), characterized by the premature destruction of red blood cells, is often associated with oxidative stress. Phenylhydrazine (PHZ) is a chemical substance frequently used to induce HA in experimental animal models. Studies indicate that niacin (nicotinic acid) activates antioxidant pathways through nuclear factor erythroid 2-related factor 2 (Nrf2). This study aimed to evaluate the antianemic effects of niacin in PHZ-induced hemolytic anemia in rats. Twenty-four rats were divided into four groups (n=6). The control group received saline for two days, then 5% CMC. The anemia group received PHZ (40 mg/kg/day, i.p.) for two days, followed by 5% CMC. The low- and high-dose niacin groups received PHZ for two days, then niacin (100 or 360 mg/kg/day, orally) for six days. Niacin-treated groups showed hematological parameters close to normal levels, affected the expression of Nrf2/ARE genes, preserved histological architecture, and reduced caspase-3 protein expression. Niacin protected rats from hemolytic anemia by restoring blood parameters and promoting red blood cell survival. It may serve as a potential treatment by reducing oxidative stress, ferroptosis, and inflammation, while supporting erythropoiesis.
Vitamin A is an essential micronutrient with broad physiological roles. The liver is of central importance in whole-body vitamin A homeostasis, with hepatocytes distributing retinol to the rest of the body by secreting it in complex with RBP4 (Retinol-binding protein 4). The goal of this study was to elucidate homeostatic mechanisms regulating hepatic vitamin A metabolism by specifically blocking retinoic acid (RA) signaling in hepatocytes. Herein, we used Albumin-Cre (AlbCre) mice to conditionally express a dominant negative retinoic acid receptor (Rardn) in hepatocytes, generating AlbCre:Rardn mice. These mice experience a functional block in hepatocyte RA signalling, as evidenced by the suppression of Cyp26a1, a gene that is highly responsive to RA and is exclusively expressed in hepatocytes within the liver. Unexpectedly, we observed increased circulating levels of retinol and RBP4 in AlbCre:Rardn mice, accompanied by increased hepatic expression of RBP4 at the gene and protein level. We then compared the effect of blocking RA signaling in AlbCre:Rardn mice with a more physiological depletion of hepatic retinoid content, using a mouse model of diet-induced vitamin A deficiency. Similar to AlbCre:Rardn mice, hepatic RBP4 protein expression was higher in vitamin A deficient mice. However, this was instead accompanied by no transcriptional change in hepatic Rbp4 and reduced retinol-RBP4 in the plasma, indicating an overall reduction in hepatic retinol-RBP4 secretion. Together, these data provide new insight into factors that modulate circulating retinol-RBP4 levels, and how the liver supplies the rest of the body with vitamin A.
Supranutritional selenium intake, while potentially oncoprotective, paradoxically elevates the risk of type 2 diabetes through metabolic hijacking of the one-carbon pool. Se-detoxification exhausts S-adenosylmethionine (SAM) and its precursor L‑serine, triggering a maladaptive surge in de novo serine synthesis that impairs insulin sensitivity. Identifying a precise nutritional countermeasure to decouple Se-driven metabolic risks from its therapeutic benefits remains a critical challenge. We systematically evaluated the dose-response efficacy of dietary L‑serine (0.7%-3.5% of dietary protein) in C57BL/6J mice under high-Se stress (0.8 mg/kg). Systemic glucose homeostasis, tissue-specific Se distribution, hepatic S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) methylation index (LC-MS/MS), hepatic malondialdehyde (MDA), PI3K-AKT-mTOR signaling, and plasma hepatic and renal function markers were assessed. The pharmacological PHGDH inhibitor NCT503 was included as a mechanistic comparator rather than as an alternative therapeutic strategy. L‑serine supplementation dose-dependently ameliorated high-Se-induced glucose intolerance and insulin resistance, with a functional threshold between 0.7% and 1.4% dietary serine (≈96-182 mg/kg/d). Direct LC-MS/MS quantification demonstrated a dose-dependent increase in the hepatic SAM/SAH methylation index, providing direct biochemical evidence of one-carbon pool replenishment; parallel reduction in hepatic MDA indicated attenuation of oxidative stress. Recovery of PI3K-AKT-mTOR signaling was observed across hepatic, muscular, and pancreatic tissues in a tissue-specific, dose-dependent manner. Plasma ALT, AST, and creatinine did not differ significantly across groups at all doses. NCT503 induced hyperhomocysteinemia and produced the lowest hepatic SAM/SAH ratio, indicating that PHGDH suppression under basal serine availability depletes rather than replenishes the one-carbon pool. Dietary L‑serine supplementation ameliorates high-selenium-induced insulin resistance with a functional threshold between 0.7% and 1.4% dietary serine (≈96-182 mg/kg/d), mechanistically anchored to dose-dependent elevation of the hepatic SAM/SAH methylation index. These findings provide a preclinical framework for precision nutritional interventions in populations chronically exposed to supranutritional selenium environments.