Journal of Nutritional Biochemistry最新文献_第5页

Dietary phospholipids alleviate high fat diet-induced intestinal lipid deposition through ATF4-PPARα-MTTP/SAR1B pathway in yellow catfish 膳食磷脂通过ATF4-PPARα-MTTP/SAR1B途径缓解高脂饮食诱导的肠道脂质沉积。

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2026-01-06 DOI: 10.1016/j.jnutbio.2026.110261

Hua Zheng , Xiao-Ying Tan , Biao Wang , Chong-Chao Zhong , Xiao-Lei Wei , Chang-Chun Song , Zhi Luo

Phospholipids serve as an efficient emulsifier and transport carrier for lipids. However, the regulatory mechanism by which phospholipids ameliorate lipid metabolic disorders induced by high-fat diet (HFD) remains unclear. The study aimed to investigate the effects and regulatory mechanisms of dietary phospholipids and HFD on intestinal lipid metabolism. We found that dietary phospholipids alleviated HFD-induced intestinal lipid deposition by inhibiting sterol regulatory element binding proteins 1 (SREBP1)-dependent lipogenesis and promoting peroxisome proliferator-activated receptor α (PPARα)-dependent lipolysis. Dietary phospholipids alleviated HFD-induced impairment in chylomicrons (CMs) synthesis and secretion by promoting microsomal triglyceride transfer protein (MTTP), apolipoprotein B and secretion-associated, Ras-related GTPase 1b (SAR1B) mRNA and protein expression. Moreover, dietary phospholipids alleviated the reduction in phosphatidylcholine synthesis induced by HFD via promoting cytidine triphosphate: phosphocholine cytidylyltransferase (CCTα) protein expression and mitigated HFD-induced ER stress by inhibiting glucose-regulated protein 78 (GRP78), protein kinase R like endoplasmic reticulum kinase (PERK) and activating transcription factor 4 (ATF4) mRNA and protein expression. Mechanistically, phosphatidylcholine promoted CCTα protein expression to alleviate the obstruction of CMs synthesis and secretion caused by fatty acid (palmitic acid and oleic acid). Moreover, phosphatidylcholine enhanced the transcription of mttp and sar1b genes by PPARα through reducing the interaction between ATF4 and PPARα, thereby promoting the CMs assembly and secretion to alleviate fatty acid-induced lipid deposition in primary intestinal cells of yellow catfish. Overall, this study reveals that phospholipids alleviate HFD-induced intestinal lipid accumulation through the ATF4-PPARα-MTTP/SAR1B pathway, and provides strong basis for phospholipids in the prevention of obesity-related metabolic diseases.

磷脂是一种高效的乳化剂和脂质的运输载体。然而，磷脂改善高脂饮食（HFD）引起的脂质代谢紊乱的调节机制尚不清楚。本研究旨在探讨饲粮中磷脂和HFD对肠道脂质代谢的影响及其调控机制。我们发现，膳食磷脂通过抑制甾醇调节元件结合蛋白1 （SREBP1）依赖的脂肪生成和促进过氧化物酶体增殖因子激活受体α (PPARα)依赖的脂肪分解，减轻了hfd诱导的肠道脂质沉积。膳食磷脂通过促进微粒体甘油三酯转移蛋白（MTTP）、载脂蛋白B和分泌相关的ras相关GTPase 1b (SAR1B) mRNA和蛋白的表达，减轻了hfd诱导的乳糜微粒（CMs）合成和分泌损伤。此外，饲粮磷脂通过促进三磷酸胞苷：磷脂酰转移酶（CCTα）蛋白表达，减轻了HFD诱导的磷脂酰胆碱合成减少，并通过抑制葡萄糖调节蛋白78 （GRP78）、蛋白激酶R样内质网激酶（PERK）和激活转录因子4 (ATF4) mRNA和蛋白表达，减轻了HFD诱导的内质网应激。磷脂酰胆碱通过促进CCTα蛋白的表达，减轻脂肪酸（棕榈酸和油酸）对CMs合成和分泌的阻碍。磷脂酰胆碱通过降低ATF4与PPARα的相互作用，增强PPARα对mttp和sar1b基因的转录，从而促进CMs的组装和分泌，缓解脂肪酸诱导的黄颡鱼原代肠细胞脂质沉积。综上所述，本研究揭示了磷脂通过ATF4-PPARα-MTTP/SAR1B途径缓解hfd诱导的肠道脂质积累，为磷脂预防肥胖相关代谢性疾病提供了强有力的依据。

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引用次数: 0

Association between dairy-derived bioactive peptides and the risk of type 2 diabetes mellitus and cardiovascular diseases: Tehran lipid and glucose study 乳源性生物活性肽与2型糖尿病和心血管疾病风险之间的关系：德黑兰脂质和葡萄糖研究

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2026-01-03 DOI: 10.1016/j.jnutbio.2026.110260

Fatemeh Ghasemi , Farshad Teymoori , Sajjad Roosta , Mitra Kazemi Jahromi , Hossein Farhadnejad , Parvin Mirmiran , Ebrahim Falahi , Fereidoun Azizi

Cardiometabolic diseases, including type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) are escalating globally, posing significant health challenges. While dairy products and their bioactive peptides (BPs) may influence chronic diseases risk, the evidence remains inconsistent. These peptides may act via modulation of gut microbiota, reducing inflammation, and regulating lipid metabolism. The current study aimed to investigate the possible association between dairy-derived BPs (DDBPs) and the risk of T2DM and CVDs in Iranian adult population within the framework of Tehran Lipid and Glucose Study (TLGS). In this population-based cohort study, 5,469 participants (T2DM analysis) and 4,980 participants (CVDs analysis) from the TLGS were followed for a mean follow-up period of 6 years. Dietary intake data were determined using a validated food-frequency-questionnaire. Various types of DDBPs were estimated via in-silico proteolysis simulations. The association of bioactive peptides with T2DM and CVDs risk were determined using Cox proportional hazards regression models. Higher intake of k-casein-derived peptides (HR:1.21;95% CI: 1.01–1.64), Hepta-peptides (HR:1.31;95% CI:1.02–1.67), peptides with glycosylated residues (HR:1.29;95%CI: 1.01–1.65), glycosylated residues (HR:1.39;95% CI: 1.07–1.80), and disulfide bond- containing peptides (HR:1.34;95% CI: 1.05–1.71) was associated with an elevated T2DM risk in the adjusted model. Dairy protein intake (highest vs. lowest tertile: HR:1.29;95% CI: 1.02–1.62) Also increased T2DM risk, while total dairy intake showed no association. No significant associations were found between DDBPs, dairy intake, or dairy protein intake and the risk of CVDs. Our results showed that specific DDBPs particularly k-casein-derived fragments and structurally modified peptides (including hepta-peptides, glycosylated peptides, and peptides with disulfide bonds), were associated with an increased risk of T2DM in Tehranian adults. Further studies are warranted to elucidate these associations.

包括2型糖尿病（T2DM）和心血管疾病（cvd）在内的心脏代谢疾病在全球范围内不断升级，构成了重大的健康挑战。虽然乳制品及其生物活性肽（bp）可能影响慢性疾病的风险，但证据仍然不一致。这些肽可能通过调节肠道微生物群，减少炎症和调节脂质代谢而起作用。本研究旨在在德黑兰脂质和葡萄糖研究（TLGS）的框架内调查伊朗成年人乳制品源性bp （DDBPs）与2型糖尿病和心血管疾病风险之间的可能关联。在这项基于人群的队列研究中，来自TLGS的5469名参与者（T2DM分析）和4980名参与者（心血管疾病分析）被随访，平均随访时间为6年。膳食摄入数据是通过有效的食物频率问卷来确定的。通过硅蛋白水解模拟估计了各种类型的ddbp。采用Cox比例风险回归模型确定生物活性肽与T2DM和cvd风险的关系。在调整后的模型中，摄入k-酪蛋白衍生肽（风险比：1.21;95%CI:1.01-1.64）、七肽（风险比：1.31;95%CI:1.02-1.67）、糖基化残基肽（风险比：1.29;95%CI:1.01-1.65）、糖基化残基肽（风险比：1.39;95%CI:1.07-1.80）和含二硫键肽（风险比：1.34;95%CI:1.05-1.71）与T2DM风险升高相关。乳制品蛋白摄入量（最高与最低比值：HR:1.29;95%CI:1.02-1.62）也增加了2型糖尿病的风险，而乳制品总摄入量没有显示出相关性。没有发现DDBPs、乳制品摄入量或乳制品蛋白摄入量与心血管疾病风险之间存在显著关联。我们的研究结果表明，特定的DDBPs，特别是k-酪蛋白衍生的片段和结构修饰的肽（包括七肽、糖基化肽和具有二硫键的肽），与德黑兰成年人患T2DM的风险增加有关。需要进一步的研究来阐明这些关联。

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引用次数: 0

Natural products as modulators of ferroptosis: Therapeutic implications and molecular mechanisms in disease treatment 作为铁下垂调节剂的天然产物：疾病治疗的治疗意义和分子机制。

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2026-01-03 DOI: 10.1016/j.jnutbio.2026.110259

Weifang Tong , Xupeng Mu , Haitao Xu , Xunzhe Yin

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation and is implicated in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, diabetes, and cardiovascular diseases. Natural products, with their unique chemical scaffolds and multitarget pharmacological effects, have recently been recognized as potent modulators of ferroptosis, offering promising drug-like properties. This review comprehensively summarizes the molecular mechanisms underlying ferroptosis, encompassing iron metabolism, lipid peroxidation, and the SLC7A11-GSH-GPX4 antioxidant axis, and systematically categorizes natural products such as terpenoids, flavonoids, alkaloids, saponins, and polyphenols based on their structural classes and mechanisms of action. These compounds modulate ferroptosis through various pathways, including iron chelation, ROS regulation, and key protein interactions, demonstrating efficacy in both experimental and preliminary clinical settings across a spectrum of diseases. In oncology, natural compounds can sensitize tumors to chemotherapy and overcome drug resistance by activating ferroptotic cell death. Conversely, their antiferroptotic actions protect against tissue injury in nononcological diseases such as neurodegenerative conditions, metabolic disorders, and organ injury. Nevertheless, their application remains limited by restricted availability, compositional complexity, and unstable pharmacokinetic features. Advances in nano-delivery systems and synthetic biology are highlighted as promising strategies to overcome these barriers. Overall, natural products represent a valuable resource for developing novel ferroptosis-targeting therapies, with significant implications for future drug discovery and therapeutic innovation in a wide range of human diseases.

铁死亡是一种受调控的细胞死亡形式，其特征是铁依赖性脂质过氧化积累，与多种疾病的发病机制有关，包括癌症、神经退行性疾病、糖尿病和心血管疾病。天然产物具有独特的化学支架和多靶点药理作用，最近被认为是铁下垂的有效调节剂，具有很好的药物样特性。本文从铁代谢、脂质过氧化、SLC7A11-GSH-GPX4抗氧化轴等方面综述了铁死亡的分子机制，并对萜类、黄酮类、生物碱、皂苷、多酚等天然产物进行了结构分类和作用机制分类。这些化合物通过多种途径调节铁死亡，包括铁螯合、活性氧调节和关键蛋白相互作用，在一系列疾病的实验和初步临床环境中均显示出疗效。在肿瘤学中，天然化合物可以使肿瘤对化疗敏感，并通过激活嗜铁细胞死亡来克服耐药性。相反，它们的抗铁的作用可以防止非肿瘤疾病的组织损伤，如神经退行性疾病、代谢紊乱和器官损伤。然而，它们的应用仍然受到有限的可用性、成分复杂性和不稳定的药代动力学特性的限制。纳米递送系统和合成生物学的进展被强调为克服这些障碍的有希望的策略。总的来说，天然产物是开发新的铁中毒靶向疗法的宝贵资源，对未来广泛的人类疾病的药物发现和治疗创新具有重要意义。

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引用次数: 0

Myeloid monoamine oxidase A protects against glucose intolerance, insulin resistance and weight gain in high-fat diet-fed mice by preventing the hyperactivation of macrophages 髓系单胺氧化酶A通过阻止巨噬细胞的过度激活来防止高脂肪饮食小鼠的葡萄糖耐受不良、胰岛素抵抗和体重增加。

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2026-01-03 DOI: 10.1016/j.jnutbio.2025.110257

Seonwook Kim , Matthew R. Eber , Alessandro G. Salerno , Elena Boudyguina , Reto Asmis

The aim of this study was to determine the role of myeloid monoamine oxidase A (Mao A) in diet-induced obesity (DIO). Ten-week-old male and female LysMCre^tg/tg (CTL) and LysMCre^tg/tgMaoA^fl/fl (Mao A_Myeloid^−/−) mice were fed a high-fat diet for 20 week. Male but not female mice with myeloid Mao A deficiency showed increased weight gain, increased visceral adipose tissue (AT) weight as well as elevated fasting blood glucose and leptin levels. However, both male and female Mao A_Myeloid^−/- mice showed increased insulin resistance of the AT and glucose intolerance. Mao A mRNA levels were reduced by 90% and 94% in bone marrow-derived macrophages (BMDM) from male and female Mao A_Myeloid^−/- mice, respectively, but neither Mao A mRNA expression nor protein levels or Mao A activity in AT were altered by myeloid Mao A deficiency. Targeted gene profiling of M_TNFα+IFNγ and M_IL-4-polarized BMDM from Mao A KO mice and 129S1 strain-matched control mice revealed that Mao A deficiency amplifies the expression of polarization state-specific marker genes in BMDM from male mice but affects only a few selected marker genes in female polarized BMDM. Myeloid Mao A protects male but not female mice from AT inflammation, AT expansion and DIO, possibly by suppressing the polarization of monocyte-derived macrophages recruited into the AT. However, myeloid Mao A deficiency promoted insulin resistance in AT and glucose intolerance in both male and female mice suggesting that macrophage Mao A in other tissues contributes to the maintenance of glucose tolerance and homeostasis.

目的：本研究的目的是确定髓系单胺氧化酶A （Mao A）在饮食性肥胖（DIO）中的作用。方法与结果：10周龄雌雄LysMCretg/tg （CTL）和LysMCretg/tgMaoAfl/fl （Mao AMyeloid-/-）小鼠分别饲喂高脂饲料20周。骨髓性Mao A缺乏的雄性而非雌性小鼠表现出体重增加，内脏脂肪组织（AT）重量增加以及空腹血糖和瘦素水平升高。然而，雄性和雌性毛淀粉样-/-小鼠均表现出胰岛素抵抗和葡萄糖耐受不良的增加。在雄性和雌性Mao AMyeloid-/-小鼠骨髓源性巨噬细胞（BMDM）中，Mao A mRNA水平分别降低90%和94%，但Mao A mRNA表达、蛋白水平和AT中Mao A活性均未因骨髓性Mao A缺乏而改变。对Mao A KO小鼠和129S1株匹配对照小鼠的MTNFα+IFNγ和mil -4极化BMDM的靶向基因谱分析显示，Mao A缺陷增加了雄性小鼠BMDM中极化状态特异性标记基因的表达，而只影响雌性极化BMDM中少数特定标记基因的表达。结论：髓鞘Mao A对雄性小鼠的AT炎症、AT扩张和DIO有保护作用，但对雌性小鼠无保护作用，其机制可能是抑制单核细胞来源的巨噬细胞的极化。然而，骨髓Mao A缺乏促进了雄性和雌性小鼠AT中的胰岛素抵抗和葡萄糖耐受不良，这表明其他组织中的巨噬细胞Mao A有助于维持葡萄糖耐量和体内平衡。

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引用次数: 0

Dietary disodium fumarate relieves high-concentrate diet-induced hepatic injury by inhibiting endoplasmic reticulum stress, mitochondrial dysfunction and autophagy via epigenetic modifications in lactating hu sheep 饲粮富马酸二钠通过表观遗传修饰抑制内质网应激、线粒体功能障碍和自噬，减轻泌乳湖羊高精日粮诱导的肝损伤。

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2026-01-02 DOI: 10.1016/j.jnutbio.2025.110254

Nana Ma, Wan Xie, Huimin Shi, Shendong Zhou, Hongzhu Zhang, Guangjun Chang, Xiangzhen Shen

A high-concentrate diet fed to ruminants induced the release of LPS from the rumen to the liver. Dietary disodium fumarate (DF) fed to ruminants helps restore rumen homeostasis by improving the pH of the rumen fluid. However, the effects of dietary disodium fumarate on hepatic injury induced by high-concentrate diet have not been thoroughly explored. Eighteen lactating Hu sheep with rumen fistula were randomly divided into three groups: the low-concentrate diet group (LC, forage:concentrate=7:3, n=6), the high-concentrate diet group (HC, forage:concentrate=3:7, n=6) and the high-concentrate diet with DF supplementation group (FHC, 10g DF per sheep daily, n=6). After 8 weeks, the rumen fluid, portal vein and hepatic blood and liver tissue were collected for analysis. A high-concentrate diet decreased the pH of the rumen fluid and increased the LPS concentration in portal vein blood, resulting in morphological damage and an inflammatory response. GRP78-regulated unfolded protein response receptors and CHOP were upregulated, indicating ER stress; The imbalance between fusion and fission, mitophagy and PGAM5 upregulation indicated the mitochondrial damage in the liver of the HC group. Dietary DF supplementation relieved these hepatic injuries, accompanied by reduced autophagy. The level of methylation and chromatin compaction of ER stress- and autophagy-related genes were also increased by DF supplementation. These epigenetic modifications were negatively correlated with the mRNA expression of the target genes. Therefore, DF supplementation alleviated the inflammatory response, ER stress, and mitochondrial damage, not only by reducing LPS release but also through epigenetic modifications in the livers of Hu sheep fed a high-concentrate diet.

反刍动物饲喂高精料日粮可诱导LPS从瘤胃向肝脏释放。饲粮中添加富马酸二钠（DF）可通过改善瘤胃液pH值来恢复瘤胃稳态。然而，饲粮中添加富马酸二钠对高精料日粮肝损伤的影响尚未深入研究。选取18只患有瘤胃瘘管的哺乳期湖羊，随机分为3组：低精饲粮组（LC，饲料：精料=7:3,n=6）、高精饲粮组（HC，饲料：精料=3:7,n=6）和高精饲粮加DF组（FHC， 10 g DF /羊，n=6）。8周后采集瘤胃液、门静脉、肝血和肝组织进行分析。高精料饲粮降低了瘤胃液的pH值，增加了门静脉血液中的LPS浓度，导致形态学损伤和炎症反应。grp78调控的未折叠蛋白反应受体和CHOP上调，表明内质网应激；融合与裂变失衡、线粒体自噬及PGAM5上调提示HC组肝脏线粒体损伤。膳食中添加DF可减轻这些肝损伤，并伴有自噬减少。补充DF后，内质网应激和自噬相关基因的甲基化水平和染色质压实水平也增加。这些表观遗传修饰与靶基因mRNA表达呈负相关。因此，饲粮中添加DF不仅可以通过减少LPS的释放，还可以通过表观遗传修饰来减轻高精料饲粮湖羊肝脏的炎症反应、内质网应激和线粒体损伤。

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引用次数: 0

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2026-01-01

引用次数: 0

Chronic theobromine administration attenuates short-term memory decline via neurotrophic, anti-inflammatory and antioxidant mechanisms in senescence-accelerated mouse prone 8 (SAMP8) 慢性可可碱通过神经营养、抗炎和抗氧化机制减轻衰老加速小鼠8 （SAMP8）的短期记忆衰退。

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2025-12-31 DOI: 10.1016/j.jnutbio.2025.110258

Eri Sumiyoshi , Kentaro Matsuzaki , Masanori Katakura , Shadman Nazib , Shahdat Hossain , Sho Maejima , Ying Zhang , Hiroko Kishi , Naotoshi Sugimoto , Osamu Shido

Aging-related cognitive decline is a major concern in aging societies. Theobromine (TB), a cacao-derived methylxanthine, exerts neuroprotective effects through anti-inflammatory, antioxidant, and neurotrophic mechanisms; however, its efficacy in aging models remains unclear. This study investigated the mechanisms underlying neuroprotective effects of chronic TB administration in senescence-accelerated mouse prone 8 (SAMP8), a model of age-related memory impairment. SAMP8 and SAMR1 mice were fed either a control diet or a diet supplemented with 0.05% TB for 50 d. Cognitive performance was evaluated by the novel object recognition (NOR) test. Neurotrophic factors (BDNF and NT-3), synaptic proteins (PSD95 and synaptophysin), and plasticity-related signaling molecules (phosphorylated CREB and TrkB) were analyzed in the prefrontal cortex and hippocampus. Inflammatory cytokines, lipid peroxides, and antioxidant enzymes were quantified. Molecular docking was used to assess TB’s interaction with phosphodiesterase (PDE) enzymes. TB improved short-term memory in SAMP8, increasing discrimination index in the NOR test. This was accompanied by increased BDNF, NT-3, PSD95, and synaptophysin levels and enhanced CREB and TrkB phosphorylation. Furthermore, TB lowered the levels of pro-inflammatory cytokines (IL-1β, TNF-α) and phosphorylated NF-κB, reduced lipid peroxidation, and increased the levels of antioxidant markers (HO-1, GSH). These effects were minimal in SAMR1. No adverse effects on body weight or blood parameters were observed. Molecular docking indicated that TB binds to PDE enzymes with weaker inhibitory activity than selective inhibitors. TB enhances short-term memory and synaptic function in aged mice via neurotrophic, antioxidant, and anti-inflammatory mechanisms, supporting its potential as a safe dietary intervention for age-related cognitive decline.

与衰老相关的认知能力下降是老龄化社会的一个主要问题。可可碱（TB）是一种可可衍生的甲基黄嘌呤，通过抗炎、抗氧化和神经营养机制发挥神经保护作用；然而，其在衰老模型中的功效尚不清楚。本研究探讨了慢性结核治疗对衰老加速小鼠易感8 （SAMP8）的神经保护作用机制，SAMP8是一种与年龄相关的记忆障碍模型。SAMP8和SAMR1小鼠分别饲喂对照饲粮和添加0.05% TB的饲粮，为期50天。通过新目标识别（NOR）测试评估认知能力。神经营养因子（BDNF和NT-3）、突触蛋白（PSD95和synaptophysin）和可塑性相关信号分子（磷酸化的CREB和TrkB）在前额皮质和海马中进行了分析。对炎症细胞因子、脂质过氧化物和抗氧化酶进行定量。分子对接用于评估结核与磷酸二酯酶（PDE）酶的相互作用。结核病改善了SAMP8的短期记忆，增加了NOR测试的辨别指数。同时BDNF、NT-3、PSD95和synaptophysin水平升高，CREB和TrkB磷酸化增强。此外，TB降低促炎细胞因子（IL-1β、TNF-α）和磷酸化NF-κB水平，减少脂质过氧化，提高抗氧化标志物（HO-1、GSH）水平。这些影响在SAMR1中最小。未观察到对体重或血液参数的不良影响。分子对接表明，TB与PDE酶结合，抑制活性弱于选择性抑制剂。结核病通过神经营养、抗氧化和抗炎机制增强老年小鼠的短期记忆和突触功能，支持其作为与年龄相关的认知衰退的安全饮食干预的潜力。

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引用次数: 0

Curcumin alleviates murine ulcerative colitis by modulating Tfh-B cell crosstalk via the CD40/CD40L costimulatory pathway 姜黄素通过CD40/CD40L共刺激通路调节Tfh-B细胞串扰减轻小鼠溃疡性结肠炎

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2025-12-30 DOI: 10.1016/j.jnutbio.2025.110256

Ji Yu , Yazhen Liu , Jiaqi Huang , Xiyan Zhu , Duanyong Liu , Haimei Zhao , Bailing Deng , Youbao Zhong

Ulcerative colitis (UC) progression is closely associated with dysregulated T follicular helper (Tfh)-B cell crosstalk, a process are centrally mediated through the CD40/CD40L costimulatory pathway. This study aimed to investigate whether curcumin (Cur) alleviates UC by regulating Tfh-B cell crosstalk via modulation of this pathway. Mice with dextran sulfate sodium (DSS)-induced UC were administered were treated with Cur for 14 consecutive days. Tfh and B cell subsets were analyzed using flow cytometry, while CD40/CD40L gene and protein expression were assessed via qRT-PCR and WB. Cellular spatial interactions were examined through immunofluorescence. Additionally, molecular docking, molecular dynamics simulations and surface plasmon resonance (SPR) were performed to evaluate Cur's binding to the CD40/CD40L complex. Cur treatment significantly reduced the disease activity index, restored colon length, ameliorated histological damage, and suppressed proinflammatory cytokines (e.g., IL-6, IL-21) as well as IgG levels. Mechanistically, Cur downregulated significantly CD40L⁺ Tfh cells and CD40⁺ B cells, and inhibited significantly key GC transcription factor Bcl-6 and plasma cell differentiation regulator Blimp-1. Molecular simulations confirmed that Cur stably binds to the CD40/CD40L interface through van der Waals forces and electrostatic complementarity, effectively blocking their interaction. The evidence from kinetic and competitive SPR assays demonstrates that Cur not only exhibits strong binding affinity by directly targeting CD40L, but also concentration-dependently blocks its interaction with CD40, resulting in significant functional inhibition of the CD40/CD40L signaling axis. Collectively, these findings demonstrate that Cur ameliorates UC by inhibiting the CD40/CD40L complex, which disrupts pathological Tfh-B cell crosstalk and ultimately restores gut immune homeostasis.

溃疡性结肠炎（UC）的进展与T滤泡辅助细胞(Tfh)-B细胞串扰失调密切相关，这一过程是通过CD40/CD40L共刺激途径中枢介导的。本研究旨在探讨姜黄素（curcumin, Cur）是否通过调节Tfh-B细胞串扰通路来缓解UC。用硫酸葡聚糖钠（DSS）致UC小鼠，连续14天用Cur治疗。流式细胞术检测Tfh和B细胞亚群，qRT-PCR和WB检测CD40/CD40L基因和蛋白表达。通过免疫荧光检测细胞空间相互作用。此外，通过分子对接、分子动力学模拟和表面等离子体共振（SPR）来评估Cur与CD40/CD40L复合物的结合。Cur治疗显著降低了疾病活动性指数，恢复了结肠长度，改善了组织学损伤，抑制了促炎细胞因子（如IL-6、IL-21）和IgG水平。机制上，Cur显著下调CD40L + Tfh细胞和CD40 + B细胞，显著抑制GC关键转录因子Bcl-6和浆细胞分化调节因子Blimp-1。分子模拟证实，Cur通过范德华力和静电互补稳定地结合在CD40/CD40L界面上，有效地阻断了它们的相互作用。动力学和竞争性SPR实验的证据表明，Cur不仅通过直接靶向CD40L表现出很强的结合亲和力，而且还可以浓度依赖性地阻断其与CD40的相互作用，从而显著抑制CD40/CD40L信号轴的功能。总之，这些发现表明，Cur通过抑制CD40/CD40L复合物来改善UC，该复合物破坏病理性Tfh-B细胞串扰，最终恢复肠道免疫稳态。

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引用次数: 0

Schisandrin B alleviates sulfolane-induced liver injury via the APOA1/ROS/NF-κB signaling pathway 五味子素B通过APOA1/ROS/NF-κB信号通路缓解磺胺性肝损伤

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2025-12-29 DOI: 10.1016/j.jnutbio.2025.110255

Yuechen Xing , Bo Zhang , Shuo Jin , Youtong Guo, Yueru Chen, Lili Chen, Yue Wang

Sulfolane is a widely used industrial solvent and emerging groundwater contaminant. Sulfolane has hepatotoxicity, but the molecular mechanisms remain poorly understood. Schisandrin B (Sch B), a bioactive lignan isolated from Schisandra chinensis, has been shown to exert hepatoprotective effects. To elucidate the mechanisms underlying sulfolane-induced liver injury and to determine whether Sch B protects against this toxicity by modulating the APOA1/ROS/NF-κB signaling axis. Male C57BL/6 J mice were administered sulfolane (0, 10, 30 or 300 mg/kg) by oral gavage for 28 d, with or without Sch B (8 mg/kg). Liver injury was assessed using histopathology, serum biochemistry, hepatic lipid deposition, ROS levels, and inflammatory marker expression. Bioinformatic analyses integrating “sulfur compound” and “liver injury” datasets were used to identify candidate pathways. The protective effects of Sch B were investigated through APOA1 gene knockdown, APOA1 overexpression, treatment with the antioxidant NAC, and molecular docking experiments of Sch B with APOA1. Sulfolane caused dose-dependent steatosis, oxidative stress and inflammation in mouse liver and AML12 cells. sulfolane suppressed APOA1, increased ROS and activated NF-κB and downstream cytokines. Sch B restored APOA1 expression, reduced ROS accumulation and NF-κB–dependent cytokine production, and markedly improved biochemical and histological indices of liver injury in vivo and in vitro. Sulfolane-induced hepatotoxicity is mediated by suppression of APOA1 and subsequent activation of the NF-κB signaling pathway in a ROS-dependent manner. Schisandrin B protects the liver against this injury by modulating the APOA1/ROS/NF-κB axis.

背景：亚砜是一种应用广泛的工业溶剂和新兴的地下水污染物。亚砜具有肝毒性，但其分子机制尚不清楚。五味子素B （Schisandrin B, Sch B）是一种从五味子中分离得到的生物活性木脂素，具有保护肝脏的作用。目的：阐明亚砜诱导肝损伤的机制，并确定Sch B是否通过调节APOA1/ROS/NF - κB信号轴来预防这种毒性。方法：雄性C57BL/6J小鼠分别灌胃0、10、30、300 mg/kg的亚砜，加或不加8 mg/kg的Sch B，连续28 d。通过组织病理学、血清生化、肝脂质沉积、ROS水平和炎症标志物表达来评估肝损伤。整合“硫化合物”和“肝损伤”数据集的生物信息学分析用于确定候选途径。通过APOA1的敲除和过表达、ROS清除剂NAC的处理以及Sch B与APOA1的分子对接来探讨APOA1和ROS的作用。结果：亚砜引起小鼠肝脏和AML12细胞的剂量依赖性脂肪变性、氧化应激和炎症。亚砜抑制APOA1，增加ROS，激活NF - κB和下游细胞因子。APOA1过表达或ROS清除会减弱这些变化，而APOA1沉默则会加剧这些变化。Sch B恢复APOA1的表达，减少ROS的积累和NF - κB依赖性细胞因子的产生，显著改善体内和体外肝损伤的生化和组织学指标。结论：磺胺诱导的肝毒性是通过抑制APOA1并随后激活NF-κB信号通路，以ros依赖的方式介导的。五味子素B通过调节APOA1/ROS/NF-κB轴来保护肝脏免受这种损伤。

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引用次数: 0

Complementary mechanisms of high-carbohydrate diets and ketogenic diets restore adult hippocampal neurogenesis and cognitive function in high-fat diet induced obesity in mice 高碳水化合物饮食和生酮饮食在高脂肪饮食诱导的肥胖小鼠中恢复成年海马神经发生和认知功能的互补机制。

IF 4.9 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry

Pub Date : 2025-12-29 DOI: 10.1016/j.jnutbio.2025.110245

Huiyoung Kwon , Dong Soo Seo , Yusra Ahmad , Sungjun Park , Jeongwoo Yoo , Junhyeok Lee , Ho Jung Bae , Younghoon Jang

High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK–ERK–CREB–BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline.

高脂肪饮食（HFD）诱导的肥胖损害认知和海马神经发生，与线粒体脂肪酸β氧化（FAO）和细胞质新生脂肪生成（DNL）之间的代谢灵活性降低有关。目前还不完全清楚，切换到高碳水化合物饮食（HCD）或生酮饮食（KD）是否可以逆转这些hfd诱导的缺陷，或者它们是否通过不同的机制起作用。雄性C57BL/6J小鼠给予HFD 8周诱导肥胖。然后将小鼠维持在HFD上或切换到HCD或KD上再持续8周。我们评估了全身代谢（体重、血清生化）、组织特异性代谢重塑（RNA-seq、组织学、RT-qPCR、Western blot）和认知功能（y迷宫测试、新物体识别测试）。HCD和KD干预均可逆转HFD诱导的全身性异常，包括降低ALT/AST、胆固醇和LDL，以及减轻肝脂肪变性和脂肪细胞肥大。代谢方面，KD显著增加β -羟基丁酸，而HCD显示出明显的甘油三酯谱。两种饮食都改善了海马体依赖的工作记忆和识别记忆。海马RNA - seq揭示了饮食特异性机制。HCD丰富了合成代谢过程，包括葡萄糖转运蛋白（Glut 1,2,3,4）和DNL通路（ACLY-ACC-FASN-SCD1）的上调。相反，KD富集了AMPK信号，增加了酮摄取的单羧酸转运蛋白（Mct 1,2,4），激活了神经营养AMPK- erk - creb - bdnf通路。总之，hfd后切换到HCD或KD通过互补机制恢复海马结构和认知。HCD驱动一个以底物为中心的脂肪生成程序，支持增殖，而KD参与一个以信号为中心的神经营养程序，增强可塑性。代谢灵活性是肥胖相关认知衰退的一个有希望的目标。

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引用次数: 0