Pub Date : 2025-11-24DOI: 10.1016/j.jnutbio.2025.110196
Xiaoxia Sun , Yu Qiao , Yu Han , Yufei Hou , Jiongnan Wang , Shangyun Lu , Jia Wang , Fubin Qiu
Vitamin D deficiency (VDD) is a pressing global health concern, with pregnant women being identified as a high-risk population for VDD. Our previous study demonstrated that maternal VDD diet impaired placental development. Here, we aimed to investigate the effects of maternal VDD diet during pregnancy on offspring’s spatial learning and memory ability. Our results showed that maternal VDD diet resulted in a decreased vitamin D levels in dams and their offspring, reduced offspring’s body length and body weight, delayed offspring’s nerve reflex behavior and impaired offspring’s spatial learning and memory ability in Y maze and Morris water maze tests. Moreover, maternal VDD diet caused offspring’s neuronal damage and loss, decreased the expressions of neurotrophic factors. While, maternal vitamin D supplementation during pregnancy has positive improvement on the above indexes, and with the most obvious in first trimester supplement group. Moreover, proteomic analysis of the offspring’s hippocampal tissues was conducted to explore relative molecular mechanisms. Results showed that maternal VDD diet overactivated CaMKK2/AMPK/FoxO3a signaling pathway. While, CaMKK2 inhibitor STO-609 attenuated VDD-induced neuronal apoptosis and necrosis in vitro. Consistantly, maternal vitamin D supplementation during pregnancy also inhibited the overactivation of CaMKK2/AMPK/FoxO3a pathway. In conclusion, the present study provided novel insights into the mechanisms of maternal VDD on offspring’s spatial learning and memory ability.
{"title":"Maternal vitamin D deficiency during pregnancy impaired offspring’s spatial learning and memory ability: Insights into the role of the CaMKK2/AMPK/FoxO3a pathway","authors":"Xiaoxia Sun , Yu Qiao , Yu Han , Yufei Hou , Jiongnan Wang , Shangyun Lu , Jia Wang , Fubin Qiu","doi":"10.1016/j.jnutbio.2025.110196","DOIUrl":"10.1016/j.jnutbio.2025.110196","url":null,"abstract":"<div><div>Vitamin D deficiency (VDD) is a pressing global health concern, with pregnant women being identified as a high-risk population for VDD. Our previous study demonstrated that maternal VDD diet impaired placental development. Here, we aimed to investigate the effects of maternal VDD diet during pregnancy on offspring’s spatial learning and memory ability. Our results showed that maternal VDD diet resulted in a decreased vitamin D levels in dams and their offspring, reduced offspring’s body length and body weight, delayed offspring’s nerve reflex behavior and impaired offspring’s spatial learning and memory ability in Y maze and Morris water maze tests. Moreover, maternal VDD diet caused offspring’s neuronal damage and loss, decreased the expressions of neurotrophic factors. While, maternal vitamin D supplementation during pregnancy has positive improvement on the above indexes, and with the most obvious in first trimester supplement group. Moreover, proteomic analysis of the offspring’s hippocampal tissues was conducted to explore relative molecular mechanisms. Results showed that maternal VDD diet overactivated CaMKK2/AMPK/FoxO3a signaling pathway. While, CaMKK2 inhibitor STO-609 attenuated VDD-induced neuronal apoptosis and necrosis in vitro. Consistantly, maternal vitamin D supplementation during pregnancy also inhibited the overactivation of CaMKK2/AMPK/FoxO3a pathway. In conclusion, the present study provided novel insights into the mechanisms of maternal VDD on offspring’s spatial learning and memory ability.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110196"},"PeriodicalIF":4.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145634773","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 : 2025-11-24DOI: 10.1016/j.jnutbio.2025.110195
Mahmut Bodur , Betül Kocaadam-Bozkurt , Osman Bozkurt , Serkan Aslan , Duygu Ağagündüz
The gut-brain axis represents a complex bidirectional communication network connecting the central nervous and gastrointestinal systems. Fermented foods and their phenolic compounds, which increase their bioavailability due to microbial transformation in their contents, have the potential to affect the gut microbiota and therefore the gut-brain axis positively. Fermented foods such as kefir, yogurt, miso, natto, tempeh, kombucha, and their polyphenols have an effect on the gut microbiota and on the provision of neurological activities through neuroactive components that affect the nervous system. Phenolic compounds appear to have direct or indirect effects on brain tissue through various mechanisms such as reducing neuronal oxidative stress, suppressing microglial activation, supporting synaptic plasticity, and slowing down neurodegenerative processes such as Alzheimer's and Parkinson's. In addition, the polyphenol content enriched in fermented foods has been shown to exhibit psychobiotic effects in depression and anxiety models; it has been shown in clinical studies that it improves systemic inflammation and hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Current data support the inclusion of fermented, polyphenol-rich foods as a noninvasive strategy to enhance neuroprotection and mental health. However, enhanced clinical studies are needed where heterogeneity in the fermentation process and dosage adjustment are standardized. This article reviews the current literature on the effects of fermented foods and polyphenols on brain health via the microbiota and gut-brain axis.
{"title":"Fermented foods and brain health: Gut–brain axis mechanisms and clinical insights","authors":"Mahmut Bodur , Betül Kocaadam-Bozkurt , Osman Bozkurt , Serkan Aslan , Duygu Ağagündüz","doi":"10.1016/j.jnutbio.2025.110195","DOIUrl":"10.1016/j.jnutbio.2025.110195","url":null,"abstract":"<div><div>The gut-brain axis represents a complex bidirectional communication network connecting the central nervous and gastrointestinal systems. Fermented foods and their phenolic compounds, which increase their bioavailability due to microbial transformation in their contents, have the potential to affect the gut microbiota and therefore the gut-brain axis positively. Fermented foods such as kefir, yogurt, miso, natto, tempeh, kombucha, and their polyphenols have an effect on the gut microbiota and on the provision of neurological activities through neuroactive components that affect the nervous system. Phenolic compounds appear to have direct or indirect effects on brain tissue through various mechanisms such as reducing neuronal oxidative stress, suppressing microglial activation, supporting synaptic plasticity, and slowing down neurodegenerative processes such as Alzheimer's and Parkinson's. In addition, the polyphenol content enriched in fermented foods has been shown to exhibit psychobiotic effects in depression and anxiety models; it has been shown in clinical studies that it improves systemic inflammation and hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Current data support the inclusion of fermented, polyphenol-rich foods as a noninvasive strategy to enhance neuroprotection and mental health. However, enhanced clinical studies are needed where heterogeneity in the fermentation process and dosage adjustment are standardized. This article reviews the current literature on the effects of fermented foods and polyphenols on brain health via the microbiota and gut-brain axis.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110195"},"PeriodicalIF":4.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145634720","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 : 2025-11-24DOI: 10.1016/j.jnutbio.2025.110194
Evelyn Fast , Jana Jakobs , Jens Bertram , Inga Weßels , Judith Sailer , Bernhard Michalke , Lothar Rink
Iron overload is a common phenomenon in patients undergoing transfusions or organ transplantation. Clinical studies indicate that iron overload interferes with immune function. Baseless supplementation of iron leads to higher morbidity and mortality. In iron overload T-cell differentiation is skewed towards a Th2 response, with lower levels of interferon (IFN)-γ. Zinc is known for its immune balancing abilities, e.g., by induction of regulatory T cells. This study aims to investigate the interaction of iron and zinc in mixed lymphocyte cultures (MLC). MLC, peripheral blood mononuclear cells (PBMC) stimulation with phytohemagglutinin, ELISA, PCR, and ICP-MS were used as methods. Zn2+ supplementation leads to a significantly lower IFN-γ production in MLC compared with control (P<.03). Fe2+ supplementation lowers the IFN-γ production in MLC (P<.0017), too. However, Fe3+ has a slightly increasing effect on IFN-γ release which differs significantly from Fe2+ (P<.03). In 2,2-Bipyridyl-induced iron deficiency IFN-γ production is lowered (P<.0003), whereas zinc deficiency does not significantly affect IFN-γ production. Examinations of Interleukin (IL)-2 and IL-6 show comparable tendencies. The Fe2+ effect can be imitated by sodium sulfite. Fe3+ treatment increases intracellular free iron in peripheral blood mononuclear cells (PBMC) significantly compared to Fe2+ treatment (P<.02). Iron (II) and zinc both suppress cytokine production in MLC. Fe3+ shows a significantly different effect on IFN-γ production. The underlying mechanism is likely a donation of electrons by Fe2+ or oxidative stress. These findings provide mechanistic insights on how the oxidation state of iron differentially modulates human immune cell function and highlights the importance of iron speciation in nutritional immunology.
{"title":"Zinc, Fe2+, and Fe3+ differentially influence IFN-γ production in human peripheral blood mononuclear cells","authors":"Evelyn Fast , Jana Jakobs , Jens Bertram , Inga Weßels , Judith Sailer , Bernhard Michalke , Lothar Rink","doi":"10.1016/j.jnutbio.2025.110194","DOIUrl":"10.1016/j.jnutbio.2025.110194","url":null,"abstract":"<div><div>Iron overload is a common phenomenon in patients undergoing transfusions or organ transplantation. Clinical studies indicate that iron overload interferes with immune function. Baseless supplementation of iron leads to higher morbidity and mortality. In iron overload T-cell differentiation is skewed towards a Th2 response, with lower levels of interferon (IFN)-γ. Zinc is known for its immune balancing abilities, e.g., by induction of regulatory T cells. This study aims to investigate the interaction of iron and zinc in mixed lymphocyte cultures (MLC). MLC, peripheral blood mononuclear cells (PBMC) stimulation with phytohemagglutinin, ELISA, PCR, and ICP-MS were used as methods. Zn<sup>2+</sup> supplementation leads to a significantly lower IFN-γ production in MLC compared with control (<em>P</em><.03). Fe<sup>2+</sup> supplementation lowers the IFN-γ production in MLC (<em>P</em><.0017), too. However, Fe<sup>3+</sup> has a slightly increasing effect on IFN-γ release which differs significantly from Fe<sup>2+</sup> (<em>P</em><.03). In 2,2-Bipyridyl-induced iron deficiency IFN-γ production is lowered (<em>P</em><.0003), whereas zinc deficiency does not significantly affect IFN-γ production. Examinations of Interleukin (IL)-2 and IL-6 show comparable tendencies. The Fe<sup>2+</sup> effect can be imitated by sodium sulfite. Fe<sup>3+</sup> treatment increases intracellular free iron in peripheral blood mononuclear cells (PBMC) significantly compared to Fe<sup>2+</sup> treatment (<em>P</em><.02). Iron (II) and zinc both suppress cytokine production in MLC. Fe<sup>3+</sup> shows a significantly different effect on IFN-γ production. The underlying mechanism is likely a donation of electrons by Fe<sup>2+</sup> or oxidative stress. These findings provide mechanistic insights on how the oxidation state of iron differentially modulates human immune cell function and highlights the importance of iron speciation in nutritional immunology.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110194"},"PeriodicalIF":4.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145634797","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 : 2025-11-23DOI: 10.1016/j.jnutbio.2025.110192
Sarah Ruth Parsons , Irma Magaly Rivas-Serna , Peter Odion Isesele , Md Monirujjaman , Abha Dunichand-Hoedl , Aducio Leonel Thiesen , Michael Thomas Clandinin , Vera Christine Mazurak
Combination chemotherapy, irinotecan+5-fluorouracil, treats advanced colorectal cancer but causes intestinal toxicity mediated by cytokines and oxylipins. The objective of this study is to determine the effect of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cytokines and the balance of oxylipins in colon tissue after chemotherapy. Ward colon tumors were implanted into female Fischer 344 rats (13–14 weeks old, n=56) and grew for 2 weeks before initiating chemotherapy (day 0). Subsequently, rats were maintained on the control diet (n=32) or switched to the EPA+DHA diet (n=24), an isocaloric diet that differed mainly in EPA and DHA content. Rats were euthanized on day 0 (baseline), 2, 4 and 8. The reference (no tumor, n=8) and baseline D0 (with tumor, n=8) groups did not receive chemotherapy. Cytokines, phospholipid fatty acids, and oxylipins in colon tissue were compared between the diets and over days post-chemotherapy. Feeding EPA+DHA resulted in a 9- and 2-fold increase in colon phospholipid by day 8 mirrored by a 10- and 2-fold increase in total oxylipins derived from EPA and DHA, respectively. Incorporation of EPA and DHA by day 2 prevented an increase in pro-inflammatory arachidonic acid (AA)-derived oxylipins after chemotherapy, including prostaglandin (PG) D2, PGE2, 6-keto-PGF1α, thromboxane B2, and 5-hydroxyeicosatetraenoic acid. Displacement of AA by EPA and DHA in colonic membrane attenuates early inflammatory lipid oxylipins. Dietary EPA+DHA may mitigate intestinal perturbations in colorectal cancer patients receiving irinotecan+5-fluorouracil.
{"title":"Dietary eicosapentaenoic and docosahexaenoic acids reduce oxylipins that provide early mediators of colonic inflammation induced by chemotherapy","authors":"Sarah Ruth Parsons , Irma Magaly Rivas-Serna , Peter Odion Isesele , Md Monirujjaman , Abha Dunichand-Hoedl , Aducio Leonel Thiesen , Michael Thomas Clandinin , Vera Christine Mazurak","doi":"10.1016/j.jnutbio.2025.110192","DOIUrl":"10.1016/j.jnutbio.2025.110192","url":null,"abstract":"<div><div>Combination chemotherapy, irinotecan+5-fluorouracil, treats advanced colorectal cancer but causes intestinal toxicity mediated by cytokines and oxylipins. The objective of this study is to determine the effect of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cytokines and the balance of oxylipins in colon tissue after chemotherapy. Ward colon tumors were implanted into female Fischer 344 rats (13–14 weeks old, n=56) and grew for 2 weeks before initiating chemotherapy (day 0). Subsequently, rats were maintained on the control diet (n=32) or switched to the EPA+DHA diet (n=24), an isocaloric diet that differed mainly in EPA and DHA content. Rats were euthanized on day 0 (baseline), 2, 4 and 8. The reference (no tumor, n=8) and baseline D0 (with tumor, n=8) groups did not receive chemotherapy. Cytokines, phospholipid fatty acids, and oxylipins in colon tissue were compared between the diets and over days post-chemotherapy. Feeding EPA+DHA resulted in a 9- and 2-fold increase in colon phospholipid by day 8 mirrored by a 10- and 2-fold increase in total oxylipins derived from EPA and DHA, respectively. Incorporation of EPA and DHA by day 2 prevented an increase in pro-inflammatory arachidonic acid (AA)-derived oxylipins after chemotherapy, including prostaglandin (PG) D<sub>2</sub>, PGE<sub>2</sub>, 6-keto-PGF<sub>1α</sub>, thromboxane B<sub>2</sub>, and 5-hydroxyeicosatetraenoic acid. Displacement of AA by EPA and DHA in colonic membrane attenuates early inflammatory lipid oxylipins. Dietary EPA+DHA may mitigate intestinal perturbations in colorectal cancer patients receiving irinotecan+5-fluorouracil.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110192"},"PeriodicalIF":4.9,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604641","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 : 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":"2025-11-23","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}
Pub 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":"2025-11-22","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 : 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":"2025-11-20","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 : 2025-11-18DOI: 10.1016/j.jnutbio.2025.110188
Flora Bahrami , Elija Buetler , Katrin Freiburghaus , Patcharamon Seubnooch , Lia Bally , Jonathan Maurer , Christa E Flück , Reiner Wiest , Mojgan Masoodi
The ketogenic diet (KD) has shown therapeutic potential for epilepsy, neuroprotective effects, and, more recently, metabolic complications. In this study, we explored the impact of the KD on the promotion of ketometabolism and the improvement of dyslipidemia. To this end, we investigated the outcomes of two different diets, eucaloric KD and low-calorie diet (LCD), on ketogenesis, circulating intact lipids, bile acids, and neuro and pancreatic peptides. Based on our results, the concentration of ketone bodies, namely 3-hydroxybutyric acid, increased significantly by an average of ten and two times for KD and LCD, respectively. Additionally, the concentration of several triglyceride (TAG) species decreased up to 98.3% and 99.1% for KD and LCD, respectively, while these reductions were only significant for LCD. Moreover, our results showed that 3 d of KD led to an increase in the baseline concentration of pancreatic polypeptide 3-36, which suggests that short-term KD has the potential to suppress the appetite. Finally, no significant change in the baseline and kinetic postprandial concentration of bile acid species was observed during the KD. In conclusion, our findings suggest that the ketogenic diet, being less restrictive than the low-calorie diet, has a greater impact on ketometabolism. However, while KD reduces TAG species, this reduction is not statistically significant, unlike the significant decrease observed with LCD.
{"title":"Short-term effect of Ketogenic diet and Low-calorie diet on Ketometabolism and lipid metabolism","authors":"Flora Bahrami , Elija Buetler , Katrin Freiburghaus , Patcharamon Seubnooch , Lia Bally , Jonathan Maurer , Christa E Flück , Reiner Wiest , Mojgan Masoodi","doi":"10.1016/j.jnutbio.2025.110188","DOIUrl":"10.1016/j.jnutbio.2025.110188","url":null,"abstract":"<div><div>The ketogenic diet (KD) has shown therapeutic potential for epilepsy, neuroprotective effects, and, more recently, metabolic complications. In this study, we explored the impact of the KD on the promotion of ketometabolism and the improvement of dyslipidemia. To this end, we investigated the outcomes of two different diets, eucaloric KD and low-calorie diet (LCD), on ketogenesis, circulating intact lipids, bile acids, and neuro and pancreatic peptides. Based on our results, the concentration of ketone bodies, namely 3-hydroxybutyric acid, increased significantly by an average of ten and two times for KD and LCD, respectively. Additionally, the concentration of several triglyceride (TAG) species decreased up to 98.3% and 99.1% for KD and LCD, respectively, while these reductions were only significant for LCD. Moreover, our results showed that 3 d of KD led to an increase in the baseline concentration of pancreatic polypeptide 3-36, which suggests that short-term KD has the potential to suppress the appetite. Finally, no significant change in the baseline and kinetic postprandial concentration of bile acid species was observed during the KD. In conclusion, our findings suggest that the ketogenic diet, being less restrictive than the low-calorie diet, has a greater impact on ketometabolism. However, while KD reduces TAG species, this reduction is not statistically significant, unlike the significant decrease observed with LCD.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110188"},"PeriodicalIF":4.9,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564174","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 : 2025-11-17DOI: 10.1016/j.jnutbio.2025.110189
Hiroshi Shimada , Johann Urschitz , Theresa L Powell , Thomas Jansson , Fredrick J Rosario
Folate deficiency in pregnancy is strongly associated with fetal growth restriction (FGR). Fetal folate availability is determined by maternal folate intake and the capacity of the placenta to transport folate. However, the mechanisms regulating placental folate transport remain poorly understood. The mechanistic target of rapamycin (mTOR) regulates placental function and fetal growth, but it is unknown if mTOR regulates folate transport in vivo. We hypothesized that trophoblast-specific mTOR knockdown inhibits placental folate transport in mice. We generated transgenic mice with a doxycycline-inducible, trophoblast-specific Mtor knockdown using PiggyBac transposase-enhanced pronuclear injection. Doxycycline administration on embryonic day (E) 14.5 induced placental-specific Mtor knockdown, resulting in reduced fetal weight, placental weight, and fetal-to-placental weight ratio. Functionally, mTOR knockdown reduced folate uptake in isolated trophoblast plasma membranes (TPM), decreased the TPM protein expression of the three main placental folate transporters (FRα, RFC, and PCFT) without affecting protein expression of theses transporters in placental homogenates, and lowered fetal plasma folate concentration. In conclusion, mTOR signaling is a positive regulator of the three main placental folate transporters in vivo mediated by posttranslational mechanisms, likely involving effects of plasma membrane trafficking. Trophoblast mTOR signaling is essential for maintaining adequate fetal folate supply and we propose that the inhibition of placental mTOR signaling reported in FGR contributes to fetal folate deficiency and decreased fetal growth in this pregnancy complication. Our data supports the potential to target placental mTOR signaling as a novel intervention in pregnancies affected by abnormal fetal growth.
{"title":"Inducible trophoblast-specific knockdown of mechanistic target of rapamycin impairs placental folate transport in mice","authors":"Hiroshi Shimada , Johann Urschitz , Theresa L Powell , Thomas Jansson , Fredrick J Rosario","doi":"10.1016/j.jnutbio.2025.110189","DOIUrl":"10.1016/j.jnutbio.2025.110189","url":null,"abstract":"<div><div>Folate deficiency in pregnancy is strongly associated with fetal growth restriction (FGR). Fetal folate availability is determined by maternal folate intake and the capacity of the placenta to transport folate. However, the mechanisms regulating placental folate transport remain poorly understood. The mechanistic target of rapamycin (mTOR) regulates placental function and fetal growth, but it is unknown if mTOR regulates folate transport <em>in vivo.</em> We hypothesized that trophoblast-specific mTOR knockdown inhibits placental folate transport in mice. We generated transgenic mice with a doxycycline-inducible, trophoblast-specific <em>Mtor</em> knockdown using PiggyBac transposase-enhanced pronuclear injection. Doxycycline administration on embryonic day (E) 14.5 induced placental-specific <em>Mtor</em> knockdown, resulting in reduced fetal weight, placental weight, and fetal-to-placental weight ratio. Functionally, mTOR knockdown reduced folate uptake in isolated trophoblast plasma membranes (TPM), decreased the TPM protein expression of the three main placental folate transporters (FRα, RFC, and PCFT) without affecting protein expression of theses transporters in placental homogenates, and lowered fetal plasma folate concentration. In conclusion, mTOR signaling is a positive regulator of the three main placental folate transporters <em>in vivo</em> mediated by posttranslational mechanisms, likely involving effects of plasma membrane trafficking. Trophoblast mTOR signaling is essential for maintaining adequate fetal folate supply and we propose that the inhibition of placental mTOR signaling reported in FGR contributes to fetal folate deficiency and decreased fetal growth in this pregnancy complication. Our data supports the potential to target placental mTOR signaling as a novel intervention in pregnancies affected by abnormal fetal growth.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110189"},"PeriodicalIF":4.9,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557089","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}
Chronic ultraviolet (UV) radiation induces cutaneous inflammation and immunosuppression, driving photoaging and skin carcinogenesis. n - 3 polyunsaturated fatty acids (PUFAs) have shown clinical efficacy in mitigating various inflammatory cutaneous diseases and neoplastic diseases via dietary supplementation. However, the precise molecular mechanisms by which n - 3 PUFAs prevent photoaging and carcinogenesis remain incompletely defined. In this study, transcriptomic analysis revealed that n - 3 PUFAs exert antiphotoaging effects by sustaining skin homeostasis through coordinated immunomodulation and anti-inflammatory actions. Multitimepoint sampling in murine models was employed to dynamically characterize stage-specific effects of n - 3 PUFAs during photoaging progression. Mechanistically, n - 3 PUFAs were noted to restore balanced M1/M2 ratios in both early and advanced stage of photoaged murine skin, thereby maintaining microenvironmental homeostasis. Moreover, n - 3 PUFAs were shown to counteract UV-induced immunosuppression by diminishing immunosuppressive cell accumulation. Overall, our findings highlight the crucial role of G protein-coupled receptor 120 (GPR120) as the pivotal mediator: its activation inhibits TAK1/NF-κB signaling and directs M2 macrophage skewing after UV exposure. This study elucidates the mechanism through which n - 3 PUFAs reverse photoaging, and lays the groundwork for enhancing the clinical applications of n - 3 PUFAs.
{"title":"Dietary supplementation of n - 3 PUFAs ameliorates UV-induced photoaging and skin tumor via GPR120 activation","authors":"Shuzhan Shen, Qihang Chang, Yiting Zhao, Xidie Yin, Zhi Cao, Huan Xue, Qingyu Zeng, Xiuli Wang, Peiru Wang","doi":"10.1016/j.jnutbio.2025.110186","DOIUrl":"10.1016/j.jnutbio.2025.110186","url":null,"abstract":"<div><div>Chronic ultraviolet (UV) radiation induces cutaneous inflammation and immunosuppression, driving photoaging and skin carcinogenesis. <em>n</em> - 3 polyunsaturated fatty acids (PUFAs) have shown clinical efficacy in mitigating various inflammatory cutaneous diseases and neoplastic diseases via dietary supplementation. However, the precise molecular mechanisms by which <em>n</em> - 3 PUFAs prevent photoaging and carcinogenesis remain incompletely defined. In this study, transcriptomic analysis revealed that <em>n</em> - 3 PUFAs exert antiphotoaging effects by sustaining skin homeostasis through coordinated immunomodulation and anti-inflammatory actions. Multitimepoint sampling in murine models was employed to dynamically characterize stage-specific effects of <em>n</em> - 3 PUFAs during photoaging progression. Mechanistically, <em>n</em> - 3 PUFAs were noted to restore balanced M1/M2 ratios in both early and advanced stage of photoaged murine skin, thereby maintaining microenvironmental homeostasis. Moreover, <em>n</em> - 3 PUFAs were shown to counteract UV-induced immunosuppression by diminishing immunosuppressive cell accumulation. Overall, our findings highlight the crucial role of G protein-coupled receptor 120 (GPR120) as the pivotal mediator: its activation inhibits TAK1/NF-κB signaling and directs M2 macrophage skewing after UV exposure. This study elucidates the mechanism through which <em>n</em> - 3 PUFAs reverse photoaging, and lays the groundwork for enhancing the clinical applications of <em>n</em> - 3 PUFAs.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"149 ","pages":"Article 110186"},"PeriodicalIF":4.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534750","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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