Journal of Nutritional Biochemistry最新文献

Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), has emerged as one of the leading causes of cirrhosis and hepatocellular carcinoma. Currently, no specific pharmacological treatment is available for MASLD/MASH patients. Sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial metabolism, antioxidant defenses, and the maintenance of cellular homeostasis.

Objective: To investigate the effects of SIRT3 overexpression on inflammation, oxidative stress, and fibrosis in mice.

Methods: Mice were injected an SIRT3 overexpressed adeno-associated virus (AAV-SIRT3) vector or a control vector (AAV-GFP) by intravenous tail vein injection.6-week-old mice were randomly assigned to four groups: CD-GFP, CD-SIRT3, HFD-GFP, and HFD-SIRT3. Mice received tail vein injections according to the group assignment, followed by a 12-week feeding regimen with either a chow diet (CD) or a high-fat diet (HFD). 11-week-old mice were randomly divided into four groups: MCS-GFP, MCS-SIRT3, MCD-GFP, and MCD-SIRT3 groups. Tail vein injections were administered prior to a 4-week dietary intervention using either a methionine-choline-sufficient diet (MCS) or a methionine-choline-deficient diet (MCD).

Results: In both HFD-and MCD diet-fed mice, SIRT3 overexpression improved serum ALT and AST levels, decreased hepatic TG levels, reduced macrophage infiltration, and decreased inflammatory signals and cytokines. In addition, hepatic SIRT3 overexpression reduced ROS production and increased antioxidative protein levels, such as HO-1, NQO1, and NRF2, as well as increased Mitochondrial SOD2 deacetylation. Furthermore, SIRT3 overexpression decreased the levels of fibrogenic genes including Col1α1, Col3α1, and α-SMA.

Conclusion: SIRT3 overexpression significantly reduced hepatic lipid accumulation, inflammation, oxidative stress, and fibrosis in HFD-and MCD diet-fed mice.

Against the backdrop of generally reduced fluoride exposure levels in the current environment, the immune barrier function, as the core of the body's defense system, has attracted significant attention for its role in immune regulation under fluoride exposure. The kidneys, serving as a key target organ for Tregs-mediated immune homeostasis, rely on Foxp3 acetylation as a core regulatory mechanism. However, the role of Tregs in fluoride-induced renal injury remains unclear. In this cross-sectional study, we collected data from 336 residents in areas with low-to-moderate fluoride exposure (water fluoride concentration: 0.89-2.66 mg/L). We measured the following parameters: urinary fluoride, urinary creatinine (Ucr), microalbumin (MALB), and N-acetyl-β-D-glucosaminidase (NAG) levels. In addition, we assessed the proportions of CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺ T cells and regulatory T cells (Tregs) in peripheral blood mononuclear cells, and measured the expression of silent information regulator 1 (SIRT1) in Tregs. Furthermore, a rat model of fluorosis was established by administering fluoride in drinking water at concentrations of 5, 10, 25, and 50 mg/L for 12 weeks. We measured urinary fluoride levels, examined the changes in Tregs within peripheral blood and kidney tissues, and quantified the expression of SIRT1 and histone acetyltransferase (P300) in Tregs. Subsequently, in vitro-prepared rat Tregs were administered via tail vein injection to evaluate their therapeutic effect on renal injury induced by low-dose fluoride exposure. Multivariate logistic regression analysis indicated that among the population with low water fluoride exposure (<1.5 mg/L), elevated urinary fluoride levels were associated with an increased risk of abnormal MALB and NAG levels. Multivariate linear regression demonstrated that elevated urinary fluoride levels led to decreased proportions of CD3⁺, CD3⁺CD4⁺, and CD3⁺CD8⁺ cells, while increasing the proportion of Tregs. Tregs adoptive transfer effectively alleviated fluoride-induced renal inflammation and improved pathological damage in both glomeruli and tubules. Simultaneously, low fluoride exposure reduced IL-2 expression levels in Tregs in both peripheral blood and kidney tissues. Furthermore, low fluoride exposure inhibited SIRT1 in human peripheral Tregs and decreased SIRT1 and P300 levels in rat peripheral and renal Tregs. These findings demonstrate that Tregs mediate renal dysfunction induced by low-level fluoride exposure, potentially through acetylation-mediated regulation. The suppression of IL-2 levels may thereby affect Tregs activation.

Interesterified fat (IF) has replaced partially hydrogenated fats because it does not generate trans isomers, but it may affect lipid metabolism due to structural changes in triacylglycerols (TAGs). Since chemical interesterification alters TAG configuration and influences digestion and absorption, methodological approaches capable of tracking lipid metabolites are needed. In this study, we investigated the absorption kinetics and systemic distribution of IF metabolites using a radiolabeling strategy. Eight-week-old Swiss mice received via gavage: PA group - 3.7 MBq of ^99mTc-palmitic acid (^99mTc-PA); 2-PG group - 3.7 MBq of ^99mTc-2-palmitoylglycerol (^99mTc-2PG); and TC group - 3.7 MBq of free technetium (^99mTcO₄-). Scintigraphic imaging was performed in vivo at 1-, 3-, and 6-hours post-administration to verify complex stability, while ex vivo imaging assessed absorption kinetics and biodistribution. The data indicated that radiolabeling was sTable and efficient. Compared with PA, 2-PG exhibited shorter digestion time, faster intestinal transit until fecal excretion, and more efficient absorption. Once absorbed, 2-PG reached the systemic circulation and was preferentially detected in organs such as mesenteric lymph nodes, spleen, heart, liver, kidneys, and the brain, where it remained detecTable throughout the experimental period. Beyond these findings, the use of technetium radiolabeling represents a methodological innovation, providing a powerful tool to track the metabolic fate of lipid molecules. This approach adds a new dimension to the study of lipid bioavailability and supports future investigations into the biological relevance of sn-2 monoacylglycerols.

Proper fetal development depends on maternal nutrition. We investigated the placental morphofunctional adaptations to a low-protein diet, and their impact on fetal and newborn outcomes. Swiss mice were fed either normal (NPD, 20% crude protein, n=29) or low protein (LPD, 8% crude protein, n=26) diets two weeks before and throughout pregnancy. Dams were euthanized at gestational days (GD) 7.5 and 17.5 for morphological and molecular evaluations. No biometrical or histological alterations were observed in embryonic sites in both GDs. However, LPD placentae exhibited 14.2% increase in maternal sinusoid and 8% reduction in fetal vessel proportions (P<0.05), without significant changes in cellular proliferation, or apoptosis. Placental gene expression analysis varied according to uterine location: LPD placentae near the ovary exhibited downregulation of Fatp4, Mtor, and Kiss1, while Stat3 was upregulated (P<0.05); in the middle third of the uterine horn, Snat1 and Kiss1 were upregulated, while Snat4 was downregulated (P<0.05); and close to the uterine body, Igf2r was downregulated, whereas Snat1 and Kiss1r were upregulated (P<0.05), suggesting region-specific compensatory mechanisms. LPD placentae and fetuses were lighter and exhibited higher brain-to-liver weight ratio in both genders (P<0.05). Maternal LPD intake disproportionately affected male fetuses, which presented higher placental efficiency (P<0.05), yet failed to reach their full growth potential. At birth, although newborn size was not affected by LPD, liver weights were lower and brain-to-liver weight ratios remained higher (P<0.05), particularly in males. Maternal LPD induces region-specific placental adaptations that partially compensate for nutrient restriction, yet still impair fetal growth, particularly in male offspring.

The aim of the study is to analyse the possible neuroprotective effect of two types of olive oils, one with a high content of alcoholic phenols (POO) and the other with a high content of alcoholic phenols and triterpenes (PTOO), in an experimental model of diabetes mellitus. We also aimed to assess the participation of triterpenes, alone or in association with hydroxytyrosol, in the neuroprotective effect of these olive oils. We administered 0.5 mL/kg/day of both oils to type 1 diabetic animals and performed a hypoxia-reoxygenation model in brain slices. Both oils reduced cell death in this experimental model: 38.3% with POO and 57.2% with PTOO. Both oils reduced brain oxidative stress in this model, with PTOO showing a greater effect than POO in increasing brain antioxidant variables. In in vitro experiments in the hypoxia-reoxygenation model, both hydroxytyrosol and triterpene compounds reduced cell death (IC₅₀ 17.7±0.5 µmol/L for triterpenes and 58.7±1.1 µmol/L for hydroxytyrosol. They also showed an antioxidant effect in the experimental model. When associating both types of compounds in proportion to their concentrations in POO and PTOO, a greater neuroprotective and antioxidant effect was quantified, mainly in the inhibition of lipid peroxidation and in the increase of antioxidant variables. It is concluded that the administration of PTOO exerts a greater neuroprotective effect, possibly due to a positive interaction between the content of triterpenes and alcoholic phenols present in olive oils.

Branched-chain α-amino acids (BCAAs) support protein synthesis and their oxidation is restrained by branched-chain α-keto acid dehydrogenase kinase (BCKDK). We previously observed that in the brains of Bckdk knockout (KO) mice, BCAAs fall while glutamate is preserved and other amino acids rise. We asked why this profile emerges and how it affects skeletal muscle versus brain during nutrient stress. Motor behavior, protein synthesis and nutrient signaling were compared in the skeletal muscle and brains of wildtype (WT) and Bckdk KO male mice. In addition, nitrogen delivery into brain from BCAAs was assessed using stable isotope tracing and mass spectrometry imaging. Bckdk KO showed normal grip strength but poor beam traversal and reduced wheel running during protein restriction. In skeletal muscle, leucine or protein-feeding stimulated and fasting suppressed mechanistic target of rapamycin complex 1 (mTORC1) signaling in both genotypes. Fasting reduced muscle protein synthesis in both strains without activating the integrated-stress response (ISR). In contrast, Bckdk KO brains exhibited ISR activation during fasting, and up-regulation of Atf4 and its target genes, including Slc7a5 mRNA. Tracer studies revealed lower serum [¹⁵N]-BCAA enrichment and diminished incorporation of BCAA-derived nitrogen into brain glutamate in Bckdk KO mice, despite unchanged total glutamate. Thus, in the nongrowing adult constitutive BCKDH activation limits BCAA-derived nitrogen delivery to brain and alters AA transporters as part of an adaptive ISR during nutrient scarcity. This creates a vulnerability in brain not observed in skeletal muscle. These data provide a metabolic basis for poor motor performance in Bckdk KO mice.

The aim of this study was to explore the association between copper intake from foods and mortality of respiratory disease among US adults. NHANES 1999-2018 data were linked to National Death Index Mortality Data. A multivariable Cox proportional hazard model and sensitivity analysis were adopted. Restricted cubic splines (RCS) were used to evaluate the potential non-linear relationship. During 500,324 person-years of follow-up (median 9.5 years [IQR 5.1-14.3 years]) between 1999 and 2018, we documented 580 respiratory disease deaths. Compared with individuals in the lowest tertile of dietary copper intake (<0.88 mg/d), those in the middle (≥0.88 and <1.34 mg/d) and highest tertile (>1.34 mg/day) had an adjusted hazard ratio (HR) of 0.68 (95% CI, 0.53, 0.88) and 0.62 (0.40, 0.95) for respiratory disease mortality, respectively. RCS analysis revealed an L-shaped association with a threshold at 1.07 mg/day of copper intake. When copper intake was <1.07 mg/d, each incremental increase in intake was associated with a reduced risk of respiratory disease mortality, with an adjusted HR of 0.48 (95% CI 0.26-0.90, P = 0.022). However, when copper intake >1.07 mg/day, the risk of respiratory disease mortality showed no significant reduction, with an adjusted HR of 0.98 (95% CI: 0.76-1.27; P = 0.886) for each incremental increase in intake. In conclusion, in US adults from the NHANES, an L-shaped association between dietary copper intake and respiratory disease mortality was detected, suggesting that maintaining an optimal level of copper intake may be associated with decreased risk of respiratory disease mortality.

Consumption of a high-fat diet (HFD) can lead to cognitive dysfunction and neuroinflammation in the hippocampus, particularly the CA3 region, which is vital for associative memory. Cholinergic input from the basal forebrain to the hippocampus is critical for regulating excitability, plasticity, and overall cognitive function in this area. Neuroinflammation may disrupt the expression of the α7 nicotinic acetylcholine receptor (α7nAChR), essential for the anti-inflammatory cholinergic pathway. We sought to assess the effects of brief HFD exposure on hippocampal cholinergic function and neurobehavior. Adult Swiss male mice were fed either a standard chow diet (Control; CTR) or a 60% HFD for three days. The Open Field (OF) and Novel Object Recognition (NOR) tests were used to evaluate anxiety-like behavior and memory performance, respectively. Following testing, the CA3 region of the hippocampus was analyzed using Western Blotting, PCR, and immunofluorescence techniques. Additionally, HFD-fed mice treated intracerebroventricularly with the α7nAChR-selective agonist PNU-282987 and α7nAChR knockout (Chrna7-/-) mice were evaluated to elucidate the role of cholinergic signaling in cognition. Results showed that HFD-fed mice performed worse on the NOR test compared to CTR mice and exhibited reduced α7nAChR expression and increased acetylcholinesterase (AChE) levels, along with signs of neuroinflammation in the CA3 area. Treatment with PNU-282987 for three days mitigated memory impairments and neuroinflammation. In contrast, Chrna7^-/- mice fed a HFD displayed poorer performance on the NOR test. Our findings suggest that short-term HFD intake is linked to cholinergic impairment and inflammation in the CA3 region, indicating that targeted agonist therapy may help alleviate HFD-induced memory deficits. These results highlight the critical role of α7nAChR activation in memory regulation during neuroinflammatory episodes.

Oxidative stress impairs intestinal health in animals. As a potential antioxidant, l-theanine exerts anti-inflammatory and antioxidant effects. However, its biological functions and underlying mechanisms in intestinal oxidative damage remain unclear. This study aimed to investigate the protective effect of l-theanine against diquat-induced intestinal oxidative damage in mice and explore its potential molecular mechanisms. The results showed that dietary l-theanine supplementation significantly enhanced intestinal antioxidant capacity (reducing the levels of reactive oxygen species, malondialdehyde and hydrogen peroxide and elevating the activities of antioxidant enzymes), alleviated inflammation (downregulating pro-inflammatory cytokine levels and upregulating interleukin-10 mRNA expression), improved intestinal integrity (enhancing morphology, reducing permeability and upregulating tight junction-related genes), and boosted mitochondrial function (increasing mitochondrial membrane potential, adenosine triphosphate content and mitochondrial function-related gene expression) in oxidatively stressed mice. Concomitantly, l-theanine attenuated intestinal iron overload (inhibiting Fe²⁺ accumulation and upregulated ferritin heavy chain 1 expression) and suppressed the ferroptosis pathway (upregulating nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 expression). In conclusion, l-theanine alleviates intestinal oxidative damage in oxidatively stressed mice by enhancing intestinal antioxidant capacity and inhibiting ferroptosis, a protective effect that may be mediated by the activation of the Nrf2/GPX4 signaling pathway.

In today's fast-paced modern lifestyle, sleep disorders have become a pervasive challenge for many individuals. Conventional treatments often rely on pharmacological interventions, which carry risks of dependency and adverse effects. In recent years, the gut microbiota has gained increasing recognition as a "second brain," engaging in bidirectional communication with the central nervous system via the microbiota-gut-brain axis (MGB axis). Tea polyphenols (TP), the primary bioactive compounds derived from tea, show considerable potential in improving sleep quality through this microbial-gut-brain circuitry. This review systematically elucidates how TP reshape the gut microbiota by selectively enriching beneficial bacteria such as Lactobacillus and Bifidobacterium, while suppressing pathogenic species. These structural changes are accompanied by functional benefits, including enhanced intestinal barrier integrity and attenuated systemic inflammation. Furthermore, gut microbiota metabolize TP into bioactive small molecules that enter systemic circulation, cross the blood-brain barrier (BBB), and modulate central neurotransmitters, notably serotonin (5-HT) and γ-aminobutyric acid (GABA). By delineating this gut-mediated neuromodulatory network, our study provides a novel theoretical foundation for the use of TP as a dietary strategy to ameliorate sleep disorders.