Pub Date : 2026-03-01Epub Date: 2025-11-20DOI: 10.1016/j.jnutbio.2025.110190
Mohammed Abdo Yahya , Ghedeir M. Alshammari , Samy M. Eleawa , Kawther Amawi , Mahmoud Alkhateeb , Ammar M. AL-Farga , Hisham Alshaikhli , Nora A. AlFaris , Setah Naif Alotaibi
This study investigated the effects of Isoliquiritigenin (ISL) on adiposity in Wistar rats fed a high-fat diet (HFD), positing that ISL mitigates adiposity by inhibiting adipogenesis and promoting lipolysis via AMPK activation. Adult male Wistar rats were divided into six groups (n=8): Control (vehicle), Control + ISL (40 mg/kg), HFD (vehicle), HFD + ISL (20 mg/kg), HFD + ISL (40 mg/kg), and HFD + ISL (40 mg/kg) + Dorsomorphin (0.2 mg/kg) for 12 weeks. In a dose-dependent manner, ISL (thrice a week) significantly attenuated the increase in body weight and adipocyte size, improving glucose and insulin tolerance, HbA1c, and HOMA-IR without affecting food intake in HFD rats. Particularly, the higher dose of ISL (40 mg/kg) significantly increased the phosphorylation of AMPK (+193.3%), resulting in a p-AMPK/AMPK activity ratio increase of 191.0% in the white adipose tissue (WAT) of HFD rats. This dose also reduces body weight (24.6%), weight gain (28.7), fat deposit weight (−39.2% %), HOMA-IR (−67.62%), and serum triglycerides (−62.4%), cholesterol (56.7%), IL-6 (−66.1%) and TNF-α (−79.5%) in these HFD rats. It also increased p-ACC levels (+86.7%), Nrf2 mRNA (+392.7%), and PPARα mRNA (+255.0%), as well as the levels of HSL (+149.7%) and ATGL (139.62%). ISL (40 mg/kg) also decreased WAT levels of IL-6 (−57.86%), TNF-α (−74.96%), mRNA of SREBP1 (−38/8%), FAS (−50%) and NF-kB (58.8%), and levels of PLIN1 (−50.1) in these HFD rats. Dorsomorphin treatment reversed these effects in ISL + HFD rats. In conclusion, ISL demonstrates anti-obesity effects in HFD-induced rats through AMPK activation.
{"title":"Decoding the anti-obesity mechanisms of isoliquiritigenin: AMPK activation modulates adipogenesis, lipolysis, oxidative stress, and inflammation in high-fat diet rat models","authors":"Mohammed Abdo Yahya , Ghedeir M. Alshammari , Samy M. Eleawa , Kawther Amawi , Mahmoud Alkhateeb , Ammar M. AL-Farga , Hisham Alshaikhli , Nora A. AlFaris , Setah Naif Alotaibi","doi":"10.1016/j.jnutbio.2025.110190","DOIUrl":"10.1016/j.jnutbio.2025.110190","url":null,"abstract":"<div><div>This study investigated the effects of Isoliquiritigenin (ISL) on adiposity in Wistar rats fed a high-fat diet (HFD), positing that ISL mitigates adiposity by inhibiting adipogenesis and promoting lipolysis via AMPK activation. Adult male Wistar rats were divided into six groups (<em>n</em>=8): Control (vehicle), Control + ISL (40 mg/kg), HFD (vehicle), HFD + ISL (20 mg/kg), HFD + ISL (40 mg/kg), and HFD + ISL (40 mg/kg) + Dorsomorphin (0.2 mg/kg) for 12 weeks. In a dose-dependent manner, ISL (thrice a week) significantly attenuated the increase in body weight and adipocyte size, improving glucose and insulin tolerance, HbA1c, and HOMA-IR without affecting food intake in HFD rats. Particularly, the higher dose of ISL (40 mg/kg) significantly increased the phosphorylation of AMPK (+193.3%), resulting in a p-AMPK/AMPK activity ratio increase of 191.0% in the white adipose tissue (WAT) of HFD rats. This dose also reduces body weight (24.6%), weight gain (28.7), fat deposit weight (−39.2% %), HOMA-IR (−67.62%), and serum triglycerides (−62.4%), cholesterol (56.7%), IL-6 (−66.1%) and TNF-α (−79.5%) in these HFD rats. It also increased p-ACC levels (+86.7%), Nrf2 mRNA (+392.7%), and PPARα mRNA (+255.0%), as well as the levels of HSL (+149.7%) and ATGL (139.62%). ISL (40 mg/kg) also decreased WAT levels of IL-6 (−57.86%), TNF-α (−74.96%), mRNA of SREBP1 (−38/8%), FAS (−50%) and NF-kB (58.8%), and levels of PLIN1 (−50.1) in these HFD rats. Dorsomorphin treatment reversed these effects in ISL + HFD rats. In conclusion, ISL demonstrates anti-obesity effects in HFD-induced rats through AMPK activation.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110190"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-07DOI: 10.1016/j.jnutbio.2025.110177
Huihua Liang , Yue Yang , Kai Yao , Ling Lin , Bin Wang , Sha Liu , Zhihua Gong , Wenjun Xiao
Heat stress compromises the intestinal mucosal barrier, whereas bifidobacteria preserve its structural integrity. L-theanine (LTA) elevates intestinal Bifidobacterium abundance in heat-stressed mice, thereby alleviating barrier damage. This protection may occur through heat shock factor 1 (Hsf1) regulation, though the precise mechanism requires further elucidation. We investigated the mechanism for the protective effect of L-theanine against heat stress: the LTA protects the intestinal mucosal barrier to alleviate heat stress through Hsf1 and is mediated by Bifidobacterium for Hsf1 regulation. These investigations employed LTA interventions in heat-stressed MODE-K cells, Hsf1-knockout mice, pseudo-germ-free mice, and LTA-Bifidobacterium longum (BL) co-culture experiments. In heat-stressed MODE-K cells, LTA intervention significantly increased cell viability, improved mucosal barrier function, and inhibited Hsf1 and its target proteins Hsp70 and Hsph1. These effects were no longer observed in the Hsf1-inhibited cells but were enhanced in the Hsf1-overexpressing cells. Consistently, LTA failed to protect the intestinal mucosal barrier in heat-stressed Hsf1-knockout mice. In pseudo-germ-free mice and co-culture experiments, BL improved intestinal morphology, protected mucosal barrier function, and suppressed Hsf1 and its target proteins. The effects of L-theanine and BL were superior to those of BL alone. These findings indicate that L-theanine protects the intestinal mucosal barrier in a manner dependent on Bifidobacterium and the Hsf1 signaling pathway.
{"title":"L-theanine mediates Hsf1 protection of intestinal mucosal barrier through Bifidobacterium to alleviate heat stress","authors":"Huihua Liang , Yue Yang , Kai Yao , Ling Lin , Bin Wang , Sha Liu , Zhihua Gong , Wenjun Xiao","doi":"10.1016/j.jnutbio.2025.110177","DOIUrl":"10.1016/j.jnutbio.2025.110177","url":null,"abstract":"<div><div>Heat stress compromises the intestinal mucosal barrier, whereas bifidobacteria preserve its structural integrity. L-theanine (LTA) elevates intestinal <em>Bifidobacterium</em> abundance in heat-stressed mice, thereby alleviating barrier damage. This protection may occur through heat shock factor 1 (Hsf1) regulation, though the precise mechanism requires further elucidation. We investigated the mechanism for the protective effect of L-theanine against heat stress: the LTA protects the intestinal mucosal barrier to alleviate heat stress through Hsf1 and is mediated by <em>Bifidobacterium</em> for Hsf1 regulation. These investigations employed LTA interventions in heat-stressed MODE-K cells, <em>Hsf1</em>-knockout mice, pseudo-germ-free mice, and LTA-<em>Bifidobacterium longum</em> (BL) co-culture experiments. In heat-stressed MODE-K cells, LTA intervention significantly increased cell viability, improved mucosal barrier function, and inhibited Hsf1 and its target proteins Hsp70 and Hsph1. These effects were no longer observed in the Hsf1-inhibited cells but were enhanced in the Hsf1-overexpressing cells. Consistently, LTA failed to protect the intestinal mucosal barrier in heat-stressed <em>Hsf1</em>-knockout mice. In pseudo-germ-free mice and co-culture experiments, BL improved intestinal morphology, protected mucosal barrier function, and suppressed Hsf1 and its target proteins. The effects of L-theanine and BL were superior to those of BL alone. These findings indicate that L-theanine protects the intestinal mucosal barrier in a manner dependent on <em>Bifidobacterium</em> and the Hsf1 signaling pathway.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110177"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-22DOI: 10.1016/j.jnutbio.2025.110187
Tong Pan , Shu-Ying Chen , Ching-Wen Kung , Hsuan-Yu Chen , Pao-Yun Cheng , Hsin-Hsueh Shen , Ing-Luen Shyu , Yen-Mei Lee
Estrogen deficiency caused by menopause leads to obesity in women. In obesity, excessive visceral fat accumulation induces a chronic, low-grade inflammatory response, thereby increasing the risk of cardiovascular disease, insulin resistance, and type 2 diabetes mellitus. Browning of white adipose tissue (WAT) has emerged as a promising strategy to counteract obesity and related metabolic disorders. Coenzyme Q10 (CoQ10) has been reported to reduce oxidative stress, enhance mitochondria function and improve metabolic syndrome in obese and diabetic animals and patients. In this study, we evaluated whether long-term CoQ10 supplementation could induce WAT browning to ameliorate obesity in ovariectomized (OVX) rats fed a high-fat diet (HFD), and explored the underlying mechanisms. Supplementation with CoQ10 (20 and 40 mg/kg, once daily by gavage) for 12 weeks in OVX rats significantly reduced weight gain, excessive visceral fat accumulation, white adipocyte hypertrophy, plasma triglyceride levels, and glucose intolerance, while increasing energy expenditure compared to OVX rats treated with vehicle (P<.05). High dose CoQ10 (40 mg/kg) significantly lowered plasma insulin levels, reduced HIF-1α, MCP-1 and IL-6 protein expression, and increased phosphorylated AKT in retroperitoneal WAT (P<.05). In inguinal WAT (iWAT), CoQ10 enhanced the expression of browning-related proteins including UCP-1, CIDEA, PRDM16, PGC-1α, and phosphorylated AMPK, and elevated plasma irisin levels (P<.05). CoQ10 also regulated mitochondria dynamics of iWAT, as evidenced by increased MFN1, MFN2, and OPA1, and decreased FIS1 protein expression compared with the OVX group (P<.05). In 3T3-L1 adipocytes, CoQ10-induced expression of browning markers (UCP-1, TBX1 and PRDM16) was significantly suppressed by dorsomorphin, an AMPK inhibitor, and by AMPK knockdown (P<.05). In conclusion, long-term CoQ10 supplementation ameliorates weight gain, white adipocyte hypertrophy and inflammation in WAT, and metabolic disorders caused by combined estrogen deficiency and HFD, likely through its WAT browning effect. AMPK activation is suggested to contribute to the browning effect and enhance the expression of proteins involved in mitochondrial dynamics. Therefore, CoQ10 supplementation could be an effective intervention for preventing postmenopausal obesity.
{"title":"Coenzyme Q10 ameliorates obesity by promoting white adipose tissue browning and preserving mitochondrial dynamics in ovariectomized rats fed a high-fat diet","authors":"Tong Pan , Shu-Ying Chen , Ching-Wen Kung , Hsuan-Yu Chen , Pao-Yun Cheng , Hsin-Hsueh Shen , Ing-Luen Shyu , Yen-Mei Lee","doi":"10.1016/j.jnutbio.2025.110187","DOIUrl":"10.1016/j.jnutbio.2025.110187","url":null,"abstract":"<div><div>Estrogen deficiency caused by menopause leads to obesity in women. In obesity, excessive visceral fat accumulation induces a chronic, low-grade inflammatory response, thereby increasing the risk of cardiovascular disease, insulin resistance, and type 2 diabetes mellitus. Browning of white adipose tissue (WAT) has emerged as a promising strategy to counteract obesity and related metabolic disorders. Coenzyme Q10 (CoQ10) has been reported to reduce oxidative stress, enhance mitochondria function and improve metabolic syndrome in obese and diabetic animals and patients. In this study, we evaluated whether long-term CoQ10 supplementation could induce WAT browning to ameliorate obesity in ovariectomized (OVX) rats fed a high-fat diet (HFD), and explored the underlying mechanisms. Supplementation with CoQ10 (20 and 40 mg/kg, once daily by gavage) for 12 weeks in OVX rats significantly reduced weight gain, excessive visceral fat accumulation, white adipocyte hypertrophy, plasma triglyceride levels, and glucose intolerance, while increasing energy expenditure compared to OVX rats treated with vehicle (<em>P</em><.05). High dose CoQ10 (40 mg/kg) significantly lowered plasma insulin levels, reduced HIF-1α, MCP-1 and IL-6 protein expression, and increased phosphorylated AKT in retroperitoneal WAT (<em>P</em><.05). In inguinal WAT (iWAT), CoQ10 enhanced the expression of browning-related proteins including UCP-1, CIDEA, PRDM16, PGC-1α, and phosphorylated AMPK, and elevated plasma irisin levels (<em>P</em><.05). CoQ10 also regulated mitochondria dynamics of iWAT, as evidenced by increased MFN1, MFN2, and OPA1, and decreased FIS1 protein expression compared with the OVX group (<em>P</em><.05). In 3T3-L1 adipocytes, CoQ10-induced expression of browning markers (UCP-1, TBX1 and PRDM16) was significantly suppressed by dorsomorphin, an AMPK inhibitor, and by AMPK knockdown (<em>P</em><.05). In conclusion, long-term CoQ10 supplementation ameliorates weight gain, white adipocyte hypertrophy and inflammation in WAT, and metabolic disorders caused by combined estrogen deficiency and HFD, likely through its WAT browning effect. AMPK activation is suggested to contribute to the browning effect and enhance the expression of proteins involved in mitochondrial dynamics. Therefore, CoQ10 supplementation could be an effective intervention for preventing postmenopausal obesity.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110187"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145587635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-29DOI: 10.1016/j.jnutbio.2025.110205
Jianrong Wang , Xue Zhang , Qin Wang , Feng Han , Xuesong Xiang , Jiaqiang Huang , Cuilan Fang , Yiqun Liu , Zhenwu Huang
Our previous research demonstrated that exogenous serine ameliorates insulin resistance in C57BL/6 mice fed a diet containing 0.8 mg/kg selenium, likely by serving as a methyl donor for SAM biosynthesis. This study aims to investigate whether betaine, an alternative methyl donor, can similarly mitigate high Se-induced IR in mice. Thirty C57BL/6 mice were randomized into three groups fed: (1) 0.1 mg/kg Se (non-IR control group), (2) 0.8 mg/kg Se (IR control group), and (3) 0.8 mg/kg Se with Bet supplementation (IR+Bet intervention group). The experiment was conducted in two phases: a 4-month period of IR induction via high-Se diet, followed by a 1-month Bet intervention period. Plasma Se, insulin, and fasting glucose levels were assessed at baseline, and both before and after Bet intervention. Plasma homocysteine, lipid profiles (HDL, LDL, TCHO, TG), as well as glucose tolerance tests and insulin tolerance tests, were measured before and after intervention. After euthanasia, Se content, selenoprotein levels, and the expression of enzymes related to Ser synthesis and metabolism were measured in various tissues. After 1 month of Bet supplementation, mice in the IR+Bet intervention group exhibited significantly higher insulin sensitivity in ITT (P<.01), and lower expression of PHGDH in liver, skeletal muscle, and pancreas tissues (P<.05), compared to the IR control group. Additionally, plasma lipid profiles were significantly improved in the IR+Bet intervention group (P<.05). This is the first report demonstrating that Bet supplementation, like exogenous Ser, can effectively improve hyperglycemia and insulin resistance in mice fed a high-Se diet.
{"title":"Betaine supplementation attenuates high-Se induced insulin resistance in C57BL/6 mice","authors":"Jianrong Wang , Xue Zhang , Qin Wang , Feng Han , Xuesong Xiang , Jiaqiang Huang , Cuilan Fang , Yiqun Liu , Zhenwu Huang","doi":"10.1016/j.jnutbio.2025.110205","DOIUrl":"10.1016/j.jnutbio.2025.110205","url":null,"abstract":"<div><div>Our previous research demonstrated that exogenous serine ameliorates insulin resistance in C57BL/6 mice fed a diet containing 0.8 mg/kg selenium, likely by serving as a methyl donor for SAM biosynthesis. This study aims to investigate whether betaine, an alternative methyl donor, can similarly mitigate high Se-induced IR in mice. Thirty C57BL/6 mice were randomized into three groups fed: (1) 0.1 mg/kg Se (non-IR control group), (2) 0.8 mg/kg Se (IR control group), and (3) 0.8 mg/kg Se with Bet supplementation (IR+Bet intervention group). The experiment was conducted in two phases: a 4-month period of IR induction via high-Se diet, followed by a 1-month Bet intervention period. Plasma Se, insulin, and fasting glucose levels were assessed at baseline, and both before and after Bet intervention. Plasma homocysteine, lipid profiles (HDL, LDL, TCHO, TG), as well as glucose tolerance tests and insulin tolerance tests, were measured before and after intervention. After euthanasia, Se content, selenoprotein levels, and the expression of enzymes related to Ser synthesis and metabolism were measured in various tissues. After 1 month of Bet supplementation, mice in the IR+Bet intervention group exhibited significantly higher insulin sensitivity in ITT (<em>P</em><.01), and lower expression of <em>PHGDH</em> in liver, skeletal muscle, and pancreas tissues (<em>P</em><.05), compared to the IR control group. Additionally, plasma lipid profiles were significantly improved in the IR+Bet intervention group (<em>P</em><.05). This is the first report demonstrating that Bet supplementation, like exogenous Ser, can effectively improve hyperglycemia and insulin resistance in mice fed a high-Se diet.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110205"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-12DOI: 10.1016/j.jnutbio.2025.110182
Yu Huang, Zhiqing Huang, Gang Jia, Hua Zhao, Xiaoling Chen
Oxidative stress represents a critical driver of impaired muscle integrity and compromised meat quality. This study investigates the protective effects and underlying mechanisms of l-theanine against oxidative stress-induced muscle damage. Our results DEMONSTRATED that diquat exposure triggered significant histopathological lesions, oxidative stress (elevated reactive oxygen species and malondialdehyde, decreased muscle antioxidant capacity), mitochondrial dysfunction (reduced adenosine triphosphate levels, mitochondrial membrane potential and gene expression related to mitochondrial biogenesis and function), calcium dyshomeostasis (cytosolic and mitochondrial Ca²⁺ overload), iron accumulation (increased free Fe²⁺), increased acyl-CoA synthetase long chain family member 4 expression and decreased glutathione peroxidase 4 expression. l-theanine pretreatment effectively reversed these pathological alterations. Collectively, l-theanine alleviated oxidative stress-induced muscle damage by enhancing antioxidant capacity, improving mitochondrial function, maintaining calcium homeostasis, and inhibiting ferroptosis. These findings provide a novel theoretical foundation for developing l-theanine-based nutritional strategies to enhance muscle health.
{"title":"L-theanine alleviates muscle oxidative damage by improving mitochondrial function, maintaining calcium homeostasis, and inhibiting ferroptosis","authors":"Yu Huang, Zhiqing Huang, Gang Jia, Hua Zhao, Xiaoling Chen","doi":"10.1016/j.jnutbio.2025.110182","DOIUrl":"10.1016/j.jnutbio.2025.110182","url":null,"abstract":"<div><div>Oxidative stress represents a critical driver of impaired muscle integrity and compromised meat quality. This study investigates the protective effects and underlying mechanisms of <span>l</span>-theanine against oxidative stress-induced muscle damage. Our results DEMONSTRATED that diquat exposure triggered significant histopathological lesions, oxidative stress (elevated reactive oxygen species and malondialdehyde, decreased muscle antioxidant capacity), mitochondrial dysfunction (reduced adenosine triphosphate levels, mitochondrial membrane potential and gene expression related to mitochondrial biogenesis and function), calcium dyshomeostasis (cytosolic and mitochondrial Ca²⁺ overload), iron accumulation (increased free Fe²⁺), increased acyl-CoA synthetase long chain family member 4 expression and decreased glutathione peroxidase 4 expression. <span>l</span>-theanine pretreatment effectively reversed these pathological alterations. Collectively, <span>l</span>-theanine alleviated oxidative stress-induced muscle damage by enhancing antioxidant capacity, improving mitochondrial function, maintaining calcium homeostasis, and inhibiting ferroptosis. These findings provide a novel theoretical foundation for developing <span>l</span>-theanine-based nutritional strategies to enhance muscle health.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110182"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-11DOI: 10.1016/j.jnutbio.2025.110179
Nannan Sun , Wenyu Liu , Jing Li , Dandan Zhang , Xiuli Liu , Juan Liu , Huiling Hu
The intestinal barrier represents a fundamental defense system against environmental insults, and its disruption is increasingly recognized as a central contributor to the pathogenesis of diverse diseases. This review provides a comprehensive analysis of intestinal barrier function, highlighting its pivotal role in maintaining physiological homeostasis. We delineate the structural components and regulatory mechanisms that safeguard barrier integrity, and examine the factors that precipitate barrier dysfunction and their implications for disease progression. Particular emphasis is placed on the gut-brain, gut-eye, and gut-liver axes, which mediate the systemic consequences of barrier impairment on overall health. Additionally, we critically evaluate current methodologies for assessing intestinal barrier integrity, discussing their respective advantages and limitations. By synthesizing these insights, this review aims to guide the selection of appropriate investigative approaches, thereby facilitating advancements in disease prevention and therapeutic strategies. Ultimately, this work seeks to deepen understanding of intestinal barrier dynamics and to inform future directions in this rapidly evolving field.
{"title":"Composition, function, and detection methods of the intestinal barrier","authors":"Nannan Sun , Wenyu Liu , Jing Li , Dandan Zhang , Xiuli Liu , Juan Liu , Huiling Hu","doi":"10.1016/j.jnutbio.2025.110179","DOIUrl":"10.1016/j.jnutbio.2025.110179","url":null,"abstract":"<div><div>The intestinal barrier represents a fundamental defense system against environmental insults, and its disruption is increasingly recognized as a central contributor to the pathogenesis of diverse diseases. This review provides a comprehensive analysis of intestinal barrier function, highlighting its pivotal role in maintaining physiological homeostasis. We delineate the structural components and regulatory mechanisms that safeguard barrier integrity, and examine the factors that precipitate barrier dysfunction and their implications for disease progression. Particular emphasis is placed on the gut-brain, gut-eye, and gut-liver axes, which mediate the systemic consequences of barrier impairment on overall health. Additionally, we critically evaluate current methodologies for assessing intestinal barrier integrity, discussing their respective advantages and limitations. By synthesizing these insights, this review aims to guide the selection of appropriate investigative approaches, thereby facilitating advancements in disease prevention and therapeutic strategies. Ultimately, this work seeks to deepen understanding of intestinal barrier dynamics and to inform future directions in this rapidly evolving field.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110179"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-12DOI: 10.1016/j.jnutbio.2025.110183
Lene S. Myrmel , Stine Hoff Austgulen , Annette Bernhard , Atabak M. Azad , Even Fjære
This study explored whether erucic acid (EA) intake at levels typical of fatty fish consumption aggravates non-alcoholic fatty liver disease (NAFLD) or affects the benefits of marine n-3 polyunsaturated fatty acids (PUFAs). N-3 PUFAs, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), enhance beta-oxidation and suppress lipogenesis, reducing hepatic triglyceride accumulation.
Sixty-six C57BL/6N mice were fed a chow diet, western diet (WD), or WDs supplemented with EA alone or combined with EPA or DHA for 13 weeks. Dietary EA, EPA, and DHA levels matched average intake from recommended fatty fish consumption. Body weight and food intake were monitored, followed by body composition scans and glucose tolerance testing (GTT). After the feeding trial, hepatic lipid accumulation was analyzed.
EA supplementation did not increase hepatic fat or worsen WD-induced hepatic steatosis. Dietary intake of EPA together with EA preserved protection against elevated liver fat. EA alone reduced glucose tolerance, while fasting glucose was unchanged. However, intake of EA combined with EPA or DHA also elevated fasting and post-glucose blood glucose levels.
In conclusion, EA at levels relevant to fatty fish consumption does not impact hepatic steatosis. And EPA combined with EA prevented liver fat buildup. However, EA alone and in combination with EPA or DHA reduced glucose tolerance, assessed by the area under the curve during the glucose tolerance test, highlighting potential metabolic concerns and the need for further study the role of EA in glucose metabolism.
{"title":"Erucic acid, eicosapentaenoic acid, and docosahexaenoic acid consumption affect hepatic steatosis in mice fed a western diet","authors":"Lene S. Myrmel , Stine Hoff Austgulen , Annette Bernhard , Atabak M. Azad , Even Fjære","doi":"10.1016/j.jnutbio.2025.110183","DOIUrl":"10.1016/j.jnutbio.2025.110183","url":null,"abstract":"<div><div>This study explored whether erucic acid (EA) intake at levels typical of fatty fish consumption aggravates non-alcoholic fatty liver disease (NAFLD) or affects the benefits of marine n-3 polyunsaturated fatty acids (PUFAs). N-3 PUFAs, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), enhance beta-oxidation and suppress lipogenesis, reducing hepatic triglyceride accumulation.</div><div>Sixty-six C57BL/6N mice were fed a chow diet, western diet (WD), or WDs supplemented with EA alone or combined with EPA or DHA for 13 weeks. Dietary EA, EPA, and DHA levels matched average intake from recommended fatty fish consumption. Body weight and food intake were monitored, followed by body composition scans and glucose tolerance testing (GTT). After the feeding trial, hepatic lipid accumulation was analyzed.</div><div>EA supplementation did not increase hepatic fat or worsen WD-induced hepatic steatosis. Dietary intake of EPA together with EA preserved protection against elevated liver fat. EA alone reduced glucose tolerance, while fasting glucose was unchanged. However, intake of EA combined with EPA or DHA also elevated fasting and post-glucose blood glucose levels.</div><div>In conclusion, EA at levels relevant to fatty fish consumption does not impact hepatic steatosis. And EPA combined with EA prevented liver fat buildup. However, EA alone and in combination with EPA or DHA reduced glucose tolerance, assessed by the area under the curve during the glucose tolerance test, highlighting potential metabolic concerns and the need for further study the role of EA in glucose metabolism.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110183"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-11DOI: 10.1016/j.jnutbio.2025.110184
Zi-Jun Hu , Jun-Jie You , Yun-Liang Miao , Hong-Liang Lu , Jia-Ming Zou , Ling Li , Shan He
Accompanied by the increased intake of carbohydrate-rich foods, the utilization of carbohydrate is enhanced across generations of humans, but little is known about its epigenetic mechanism. In this study, zebrafish fed with carbohydrate-rich diets for two months (carbohydrate-programming group, PG), showed the better utilization of carbohydrates than those fed with carbohydrate-normal diets (normal group, NG) in the first and the second high-carbohydrate diet challenge, including the preference for ingesting glucose, and the enhanced carbohydrate absorption and metabolism. The maternal zebrafish were mated with wild type males, and the utilization of carbohydrates was also improved in the offspring from the PG. Through RNA-seq and ATAC-seq of offspring, beside of the higher expression of glut2 gene related to glucose absorption and phip gene related to carbohydrate metabolism, the mRNA level of H3K9me2-specific histone methyltransferase gene ehmt2 was down-regulated, while the demethylase gene kdm4a was significantly up-regulated, and then the protein levels of H3K9me2 was decreased in the PG. Furthermore, the regulatory relationship of H3K9me2 with glut2 and phip was demonstrated by the treatment with the ehmt2 inhibitor BRD4770 in vitro, administration of the kdm4a inhibitor PKF-118-310 in vivo, combining with the methods of dual-luciferase, ChIP and siRNA. Therefore, the improved carbohydrate utilization induced by maternal programming could be inherited through epigenetics, provide new insights into human dietary nutrition plans and therapeutic targets for diabetes.
{"title":"Maternal carbohydrate-programming enhances carbohydrate utilization in zebrafish offspring by histone H3K9 methylation","authors":"Zi-Jun Hu , Jun-Jie You , Yun-Liang Miao , Hong-Liang Lu , Jia-Ming Zou , Ling Li , Shan He","doi":"10.1016/j.jnutbio.2025.110184","DOIUrl":"10.1016/j.jnutbio.2025.110184","url":null,"abstract":"<div><div>Accompanied by the increased intake of carbohydrate-rich foods, the utilization of carbohydrate is enhanced across generations of humans, but little is known about its epigenetic mechanism. In this study, zebrafish fed with carbohydrate-rich diets for two months (carbohydrate-programming group, PG), showed the better utilization of carbohydrates than those fed with carbohydrate-normal diets (normal group, NG) in the first and the second high-carbohydrate diet challenge, including the preference for ingesting glucose, and the enhanced carbohydrate absorption and metabolism. The maternal zebrafish were mated with wild type males, and the utilization of carbohydrates was also improved in the offspring from the PG. Through RNA-seq and ATAC-seq of offspring, beside of the higher expression of <em>glut2</em> gene related to glucose absorption and <em>phip</em> gene related to carbohydrate metabolism, the mRNA level of H3K9me2-specific histone methyltransferase gene <em>ehmt2</em> was down-regulated, while the demethylase gene <em>kdm4a</em> was significantly up-regulated, and then the protein levels of H3K9me2 was decreased in the PG. Furthermore, the regulatory relationship of H3K9me2 with <em>glut2</em> and <em>phip</em> was demonstrated by the treatment with the <em>ehmt2</em> inhibitor BRD4770 <em>in vitro</em>, administration of the <em>kdm4a</em> inhibitor PKF-118-310 <em>in vivo</em>, combining with the methods of dual-luciferase, ChIP and siRNA. Therefore, the improved carbohydrate utilization induced by maternal programming could be inherited through epigenetics, provide new insights into human dietary nutrition plans and therapeutic targets for diabetes.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110184"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-01DOI: 10.1016/j.jnutbio.2025.110214
Changjiang Zhao , Lingling Jia , Ruiyu Luo , He Yan , Zihan Li , Hua Jiang , Yufei Li
Androgenetic alopecia (AGA) is the most common form of progressive hair loss, marked by a multifaceted pathogenesis and a lack of effective pharmacological treatments to arrest its progression. Flavonoids have drawn considerable research attention for their potential in fostering hair regeneration, yet kaempferol (Kae), a well-researched flavone, remains unexplored as a therapeutic agent for AGA. This study delves into the mechanisms and efficacy of Kae in AGA treatment, employing a blend of in vivo and in vitro experiments, complemented by transcriptome sequencing and molecular docking techniques. In vitro, Kae exhibited no significant toxicity to dermal papilla cells (DPCs); instead, it enhanced DPCs proliferation and migration in a dose-dependent manner, and significantly mitigated dihydrotestosterone (DHT)-induced cellular damage. Transcriptomic analysis and RT-qPCR indicated that Kae modulates the Wnt/β-catenin signaling pathway. Molecular docking studies indicated that Kae has binding potential to β-catenin and Cyclin D1, pivotal proteins within this pathway. Subsequent immunofluorescence experiments and Western blot confirmed Kae’s ability to promote β-catenin nuclear translocation and inhibit DHT-induced downregulation of β-catenin and Cyclin D1. In vivo, oral Kae administration substantially promoted hair regeneration in an AGA mouse model, with efficacy on par with oral finasteride. In conclusion, this study presents robust evidence that Kae effectively stimulates hair growth by bolstering DPCs function and counteracting DHT-induced damage, thus holding promising therapeutic potential for AGA sufferers.
{"title":"Kaempferol stimulates dermal papilla cells and upregulates Wnt/β-catenin signaling pathway for androgenetic alopecia treatment","authors":"Changjiang Zhao , Lingling Jia , Ruiyu Luo , He Yan , Zihan Li , Hua Jiang , Yufei Li","doi":"10.1016/j.jnutbio.2025.110214","DOIUrl":"10.1016/j.jnutbio.2025.110214","url":null,"abstract":"<div><div>Androgenetic alopecia (AGA) is the most common form of progressive hair loss, marked by a multifaceted pathogenesis and a lack of effective pharmacological treatments to arrest its progression. Flavonoids have drawn considerable research attention for their potential in fostering hair regeneration, yet kaempferol (Kae), a well-researched flavone, remains unexplored as a therapeutic agent for AGA. This study delves into the mechanisms and efficacy of Kae in AGA treatment, employing a blend of <em>in vivo</em> and in vitro experiments, complemented by transcriptome sequencing and molecular docking techniques. In vitro, Kae exhibited no significant toxicity to dermal papilla cells (DPCs); instead, it enhanced DPCs proliferation and migration in a dose-dependent manner, and significantly mitigated dihydrotestosterone (DHT)-induced cellular damage. Transcriptomic analysis and RT-qPCR indicated that Kae modulates the Wnt/β-catenin signaling pathway. Molecular docking studies indicated that Kae has binding potential to β-catenin and Cyclin D1, pivotal proteins within this pathway. Subsequent immunofluorescence experiments and Western blot confirmed Kae’s ability to promote β-catenin nuclear translocation and inhibit DHT-induced downregulation of β-catenin and Cyclin D1. <em>In vivo</em>, oral Kae administration substantially promoted hair regeneration in an AGA mouse model, with efficacy on par with oral finasteride. In conclusion, this study presents robust evidence that Kae effectively stimulates hair growth by bolstering DPCs function and counteracting DHT-induced damage, thus holding promising therapeutic potential for AGA sufferers.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110214"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-23DOI: 10.1016/j.jnutbio.2025.110193
Ferran S. Fos-Codoner, Jaap Keijer, Melissa Bekkenkamp-Grovenstein, Evert M. van Schothorst
Replacing part of dietary glucose with galactose in the early post-weaning diet of mice, mimicking extended breastfeeding, improves both short- and long-term physiological and metabolic health parameters. As the primary organ for nutrient absorption, the small intestine was hypothesized to play a key role in these effects.
Young, weaned mice underwent a 3 week dietary intervention comparing isocaloric diets with a monosaccharide fraction of galactose+glucose versus glucose. Physiological parameters were assessed in both sexes, while metabolic analyses, transcriptomics, and immunohistochemistry of the proximal small intestine were conducted in fed female mice.
Dietary galactose increased whole-body 24 h fatty acid oxidation (FAO), both absolute and relative to carbohydrate oxidation, without changes in body weight or energy expenditure. Contrasting, the small intestine showed lower expression of transcripts involved in FAO, along with reduced enterocytic lipid droplets. Carbohydrate metabolism remained unaffected, while reduced expression of NADPH-dependent and -independent antioxidant enzymes and the pentose phosphate pathway suggested a shift in local metabolism. Despite these intestinal changes, the liver showed no alterations in lipid catabolism, implicating other organs in the observed systemic FAO increase. In addition, Ppargc1a, central regulator of mitochondrial biogenesis was upregulated, which is in line with the known role of galactose in upregulating mitochondrial oxidative phosphorylation.
In conclusion, replacing half of post-weaning dietary glucose with galactose, mimicking prolonged lactose intake, profoundly affects substrate metabolism at both systemic and intestinal levels. We propose that reduced intestinal FAO redirects fatty acid oxidation to extra-intestinal, extra-hepatic tissues, driving the observed systemic metabolic benefits.
{"title":"Dietary galactose enhances systemic lipid oxidation but decreases intestinal fatty acid oxidation in post-weaning female mice","authors":"Ferran S. Fos-Codoner, Jaap Keijer, Melissa Bekkenkamp-Grovenstein, Evert M. van Schothorst","doi":"10.1016/j.jnutbio.2025.110193","DOIUrl":"10.1016/j.jnutbio.2025.110193","url":null,"abstract":"<div><div>Replacing part of dietary glucose with galactose in the early post-weaning diet of mice, mimicking extended breastfeeding, improves both short- and long-term physiological and metabolic health parameters. As the primary organ for nutrient absorption, the small intestine was hypothesized to play a key role in these effects.</div><div>Young, weaned mice underwent a 3 week dietary intervention comparing isocaloric diets with a monosaccharide fraction of galactose+glucose <em>versus</em> glucose. Physiological parameters were assessed in both sexes, while metabolic analyses, transcriptomics, and immunohistochemistry of the proximal small intestine were conducted in fed female mice.</div><div>Dietary galactose increased whole-body 24 h fatty acid oxidation (FAO), both absolute and relative to carbohydrate oxidation, without changes in body weight or energy expenditure. Contrasting, the small intestine showed lower expression of transcripts involved in FAO, along with reduced enterocytic lipid droplets. Carbohydrate metabolism remained unaffected, while reduced expression of NADPH-dependent and -independent antioxidant enzymes and the pentose phosphate pathway suggested a shift in local metabolism. Despite these intestinal changes, the liver showed no alterations in lipid catabolism, implicating other organs in the observed systemic FAO increase. In addition, <em>Ppargc1a</em>, central regulator of mitochondrial biogenesis was upregulated, which is in line with the known role of galactose in upregulating mitochondrial oxidative phosphorylation.</div><div>In conclusion, replacing half of post-weaning dietary glucose with galactose, mimicking prolonged lactose intake, profoundly affects substrate metabolism at both systemic and intestinal levels. We propose that reduced intestinal FAO redirects fatty acid oxidation to extra-intestinal, extra-hepatic tissues, driving the observed systemic metabolic benefits.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110193"},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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