Pub Date : 2026-02-01Epub Date: 2025-10-04DOI: 10.1016/j.jnutbio.2025.110139
Ligia Soares Lima , Marcia Ribeiro , Ludmila F.M.F. Cardozo , Rudolf Bittner , Marcelo Ribeiro-Alves , Júnia Schultz , Alexandre Soares Rosado , Paulo Emilio Correa Leite , Lia S. Nakao , Leon J. Schurgers , Denise Mafra
Vitamin K insufficiency is common in chronic kidney disease (CKD) and may be associated with gut dysbiosis, which decreases the number of vitamin K-producing bacteria. This insufficient status worsens inflammation, leading to vascular calcification and oxidative stress. This study investigates the correlation between vitamin K status and gut microbiota composition, and its association with inflammation in hemodialysis (HD) patients. In this cross-sectional study, patients were grouped based on dephosphorylated-uncarboxylated matrix gla-protein (dp-ucMGP) levels: adequate (≤500 pmol/L) or inadequate (>500 pmol/L) vitamin K status. Plasma cytokines were analyzed using a multiplex assay, and uremic toxins via reverse-phase high-performance liquid chromatography (RP-HPLC). Gut microbiota composition was assessed in a subgroup using fecal DNA extraction and 16S rRNA gene sequencing on the Illumina NovaSeq PE250 platform. Among 107 patients (53 [interquartile range=16] years and 36 [interquartile range=42] months on HD) completed the study, 70 patients (53 years, BMI, 24.2 Kg/m2) exhibited insufficient vitamin K status, and 37 patients presented adequate status (52.5 years, BMI, 25.6 Kg/m2). Patients with inadequate vitamin K status exhibited significantly higher levels of interleukin (IL)-6, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) compared to patients with adequate status, reflecting elevated inflammatory marker levels in patients with insufficient vitamin K. Additionally, Bacteroides, a key vitamin K2-producing genus, was decreased in patients with inadequate vitamin K status. Gut dysbiosis is a consequence of CKD, which can result in reduced production of vitamin K and subsequent insufficient status. Additionally, inadequate vitamin K status may contribute to the inflammatory state in patients undergoing HD.
{"title":"Association of poor vitamin K status with inflammation and gut microbiota in hemodialysis patients: A cross-sectional study","authors":"Ligia Soares Lima , Marcia Ribeiro , Ludmila F.M.F. Cardozo , Rudolf Bittner , Marcelo Ribeiro-Alves , Júnia Schultz , Alexandre Soares Rosado , Paulo Emilio Correa Leite , Lia S. Nakao , Leon J. Schurgers , Denise Mafra","doi":"10.1016/j.jnutbio.2025.110139","DOIUrl":"10.1016/j.jnutbio.2025.110139","url":null,"abstract":"<div><div>Vitamin K insufficiency is common in chronic kidney disease (CKD) and may be associated with gut dysbiosis, which decreases the number of vitamin K-producing bacteria. This insufficient status worsens inflammation, leading to vascular calcification and oxidative stress. This study investigates the correlation between vitamin K status and gut microbiota composition, and its association with inflammation in hemodialysis (HD) patients. In this cross-sectional study, patients were grouped based on dephosphorylated-uncarboxylated matrix gla-protein (dp-ucMGP) levels: adequate (≤500 pmol/L) or inadequate (>500 pmol/L) vitamin K status. Plasma cytokines were analyzed using a multiplex assay, and uremic toxins <em>via</em> reverse-phase high-performance liquid chromatography (RP-HPLC). Gut microbiota composition was assessed in a subgroup using fecal DNA extraction and 16S rRNA gene sequencing on the Illumina NovaSeq PE250 platform. Among 107 patients (53 [interquartile range=16] years and 36 [interquartile range=42] months on HD) completed the study, 70 patients (53 years, BMI, 24.2 Kg/m<sup>2</sup>) exhibited insufficient vitamin K status, and 37 patients presented adequate status (52.5 years, BMI, 25.6 Kg/m<sup>2</sup>). Patients with inadequate vitamin K status exhibited significantly higher levels of interleukin (IL)-6, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) compared to patients with adequate status, reflecting elevated inflammatory marker levels in patients with insufficient vitamin K. Additionally, <em>Bacteroides</em>, a key vitamin K2-producing genus, was decreased in patients with inadequate vitamin K status. Gut dysbiosis is a consequence of CKD, which can result in reduced production of vitamin K and subsequent insufficient status. Additionally, inadequate vitamin K status may contribute to the inflammatory state in patients undergoing HD.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110139"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238847","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 : 2026-02-01Epub Date: 2025-08-20DOI: 10.1016/j.jnutbio.2025.110082
Shuai Liu , Lixin Wang , Yinyan Yue , DongBo Ma , Xiang Deng , Yuanfang Wang , Dongdong Wu , Yang Wang , Qiuge Wu
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options. This study investigates the therapeutic potential of resveratrol, a natural compound, in treating IPF by targeting IKZF3, a transcription factor upregulated in IPF patients. Using bioinformatics analysis of the GSE110147 dataset, we identified IKZF3 as a key molecule in IPF progression. In vitro experiments with bleomycin (BLM)-treated A549 cells showed that IKZF3 overexpression exacerbated cell death and fibrosis, while its silencing reversed these effects. Resveratrol treatment significantly improved cell viability, reduced fibrosis markers, and inhibited IKZF3′s transcriptional regulation of IL-33, which in turn decreased ILC-2 activation. Molecular docking revealed a strong binding affinity between resveratrol and IKZF3. In vivo validation using a BLM-induced IPF mouse model demonstrated that resveratrol reduced lung fibrosis and downregulated fibrosis-related markers. Our findings suggest that targeting IKZF3 with resveratrol may offer a novel therapeutic strategy for IPF, highlighting the potential of this combination to improve disease outcomes.
{"title":"Resveratrol improves idiopathic pulmonary fibrosis by targeting IKZF3","authors":"Shuai Liu , Lixin Wang , Yinyan Yue , DongBo Ma , Xiang Deng , Yuanfang Wang , Dongdong Wu , Yang Wang , Qiuge Wu","doi":"10.1016/j.jnutbio.2025.110082","DOIUrl":"10.1016/j.jnutbio.2025.110082","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options. This study investigates the therapeutic potential of resveratrol, a natural compound, in treating IPF by targeting IKZF3, a transcription factor upregulated in IPF patients. Using bioinformatics analysis of the GSE110147 dataset, we identified IKZF3 as a key molecule in IPF progression. In vitro experiments with bleomycin (BLM)-treated A549 cells showed that IKZF3 overexpression exacerbated cell death and fibrosis, while its silencing reversed these effects. Resveratrol treatment significantly improved cell viability, reduced fibrosis markers, and inhibited IKZF3′s transcriptional regulation of IL-33, which in turn decreased ILC-2 activation. Molecular docking revealed a strong binding affinity between resveratrol and IKZF3. <em>In vivo</em> validation using a BLM-induced IPF mouse model demonstrated that resveratrol reduced lung fibrosis and downregulated fibrosis-related markers. Our findings suggest that targeting IKZF3 with resveratrol may offer a novel therapeutic strategy for IPF, highlighting the potential of this combination to improve disease outcomes.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110082"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957937","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}
During perinatal period, some women limit caffeine intake to 300mg/day, following the WHO recommendation. Previously, using an animal model of low perinatal caffeine exposure, correspondent to 250mg/day for human, we observed a deleterious effect on thyroid hormone (TH), with low total T3 in dams and weaned male pups and high T3 in adult offspring of both sexes. The hypothesis of the present study is that this phenotype results from alterations in TH synthesis and metabolism. Pregnant Wistar rats received vehicle or caffeine (CAF, 25mg/kg/day) by gavage during gestation and lactation. We evaluated markers of TH synthesis in dams and offspring, such as gland morphology and mRNA expression. Here, at birth, CAF males presented higher total T4 (+96%; P < .05) and unchanged total T3 and TSH. At weaning, CAF dams presented only lower TSH. CAF male offspring presented lower colloid area, CAF female offspring presented greater thyroid epithelial height, and both sexes presented unchanged mRNA expression of TH synthesis markers, such as thyroid stimulating hormone receptor (Tshr), sodium-iodine symporter (Nis), thyroperoxidase (Tpo), dual oxidase (Duox), NADP oxidase 2 (Nox2) and iodothyronine deiodinase 1 (Dio1). Adult CAF males presented greater epithelial area, downregulation of Nis mRNA expression, and higher hepatic Dio1 mRNA expression. However, CAF females presented higher TSH, although genes of TH synthesis were downregulated. Perinatal low caffeine exposure promotes temporal adaptive changes in the pituitary-thyroid axis, thyroid gland and peripheral TH metabolism of offspring, supporting our hypothesis. These modifications contribute to changes in TH levels in an age- and sex-dependent manner.
{"title":"Low perinatal caffeine intake alters offspring thyroid function in a sex- and age-dependent manner","authors":"Luana Lopes de Souza , Rosiane Aparecida Miranda , Iala Milene Bertasso , Beatriz Souza da Silva , Reinaldo Röpke-Junior , Leandro Miranda-Alves , Egberto Gaspar Moura , Patricia Cristina Lisboa","doi":"10.1016/j.jnutbio.2025.110148","DOIUrl":"10.1016/j.jnutbio.2025.110148","url":null,"abstract":"<div><div>During perinatal period, some women limit caffeine intake to 300mg/day, following the WHO recommendation. Previously, using an animal model of low perinatal caffeine exposure, correspondent to 250mg/day for human, we observed a deleterious effect on thyroid hormone (TH), with low total T3 in dams and weaned male pups and high T3 in adult offspring of both sexes. The hypothesis of the present study is that this phenotype results from alterations in TH synthesis and metabolism. Pregnant Wistar rats received vehicle or caffeine (CAF, 25mg/kg/day) by gavage during gestation and lactation. We evaluated markers of TH synthesis in dams and offspring, such as gland morphology and mRNA expression. Here, at birth, CAF males presented higher total T4 (+96%; <em>P</em> < .05) and unchanged total T3 and TSH. At weaning, CAF dams presented only lower TSH. CAF male offspring presented lower colloid area, CAF female offspring presented greater thyroid epithelial height, and both sexes presented unchanged mRNA expression of TH synthesis markers, such as thyroid stimulating hormone receptor (Tshr), sodium-iodine symporter (Nis), thyroperoxidase (Tpo), dual oxidase (Duox), NADP oxidase 2 (Nox2) and iodothyronine deiodinase 1 (Dio1). Adult CAF males presented greater epithelial area, downregulation of <em>Nis</em> mRNA expression, and higher hepatic Dio1 mRNA expression. However, CAF females presented higher TSH, although genes of TH synthesis were downregulated. Perinatal low caffeine exposure promotes temporal adaptive changes in the pituitary-thyroid axis, thyroid gland and peripheral TH metabolism of offspring, supporting our hypothesis. These modifications contribute to changes in TH levels in an age- and sex-dependent manner.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110148"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313118","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 : 2026-02-01Epub Date: 2025-10-15DOI: 10.1016/j.jnutbio.2025.110144
Anne Manson , Sandrius Mirochnikov , Isabel Delgado Poveda , Hiu Yan Chan , Tanja Winter , Harold M. Aukema
Alpha-linolenic acid (ALA) is an essential n-3 fatty acid that can be converted to docosahexaenoic acid (DHA), which by itself can also meet the dietary n-3 fatty acid requirement. However, the amount of dietary DHA that is bioequivalent to ALA remains unknown. The study objective was to estimate the DHA dose that is equivalent to a recently proposed ALA requirement assessment, using non-esterified oxylipins and fatty acids. 168 male and female Sprague-Dawley rats received graded doses of dietary ALA (0.10–2.0 g/100 g diet) or DHA (0.07–1.3 g/100 g diet). All diets contained 2 g of linoleic acid/100 g diet and were based on the AIN93G. Non-esterified fatty acids and oxylipins were analyzed in serum, liver, heart, and brain by HPLC-MS/MS. Using piecewise regression, breakpoints were calculated for ALA diets using DHA/arachidonic acid (ARA) and hydroxy‑DHA/hydroxy‑ARA oxylipins (DHAOH/ARAOH). Breakpoints in serum and liver were highest and deemed most suitable to determine the dietary ALA requirement, with no differences between sexes or whether the DHA/ARA or DHAOH/ARAOH ratio was used. These breakpoints indicated an estimated average dietary ALA requirement of 0.55 g ALA/100 g diet (1.32% energy) 95% CI (0.42, 0.69), which is higher than what is provided by the AIN93G diet. DHA was ∼4–6 (mean ± SE: 4.74±0.22) times more effective than ALA, with 0.12 g DHA/100 g diet (0.28% energy) being equivalent to the 0.55 g ALA/100 g diet that meets the ALA requirement. Hence, dietary DHA is ∼5 times more effective than ALA in meeting the proposed dietary ALA requirement in the growing rat.
{"title":"Bioequivalence of docosahexaenoic acid intake to a novel estimate of the dietary alpha-linolenic acid requirement in growing rats using non-esterified oxylipins and fatty acids","authors":"Anne Manson , Sandrius Mirochnikov , Isabel Delgado Poveda , Hiu Yan Chan , Tanja Winter , Harold M. Aukema","doi":"10.1016/j.jnutbio.2025.110144","DOIUrl":"10.1016/j.jnutbio.2025.110144","url":null,"abstract":"<div><div>Alpha-linolenic acid (ALA) is an essential <em>n</em>-3 fatty acid that can be converted to docosahexaenoic acid (DHA), which by itself can also meet the dietary <em>n</em>-3 fatty acid requirement. However, the amount of dietary DHA that is bioequivalent to ALA remains unknown. The study objective was to estimate the DHA dose that is equivalent to a recently proposed ALA requirement assessment, using non-esterified oxylipins and fatty acids. 168 male and female Sprague-Dawley rats received graded doses of dietary ALA (0.10–2.0 g/100 g diet) or DHA (0.07–1.3 g/100 g diet). All diets contained 2 g of linoleic acid/100 g diet and were based on the AIN93G. Non-esterified fatty acids and oxylipins were analyzed in serum, liver, heart, and brain by HPLC-MS/MS. Using piecewise regression, breakpoints were calculated for ALA diets using DHA/arachidonic acid (ARA) and hydroxy‑DHA/hydroxy‑ARA oxylipins (DHA<sub>OH</sub>/ARA<sub>OH</sub>). Breakpoints in serum and liver were highest and deemed most suitable to determine the dietary ALA requirement, with no differences between sexes or whether the DHA/ARA or DHA<sub>OH</sub>/ARA<sub>OH</sub> ratio was used. These breakpoints indicated an estimated average dietary ALA requirement of 0.55 g ALA/100 g diet (1.32% energy) 95% CI (0.42, 0.69), which is higher than what is provided by the AIN93G diet. DHA was ∼4–6 (mean ± SE: 4.74±0.22) times more effective than ALA, with 0.12 g DHA/100 g diet (0.28% energy) being equivalent to the 0.55 g ALA/100 g diet that meets the ALA requirement. Hence, dietary DHA is ∼5 times more effective than ALA in meeting the proposed dietary ALA requirement in the growing rat.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110144"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313146","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 : 2026-02-01Epub Date: 2025-10-20DOI: 10.1016/j.jnutbio.2025.110152
Jiayu Chen , Haoxin Lian , Ruqin Guo , Kai Chen , Hao Ma , Jiachen Yang , Zhiping Huang , Lijia Chen , Kinon Chen , Jie Liu , Qing’an Zhu , Junhao Liu , Hui Jiang , Zucheng Huang
Spinal cord injury (SCI) initiates secondary pathologies characterized by dysregulated autophagy and neuroinflammation Although the ketogenic diet (KD) has shown potential in promoting functional recovery after SCI, the mechanisms underlying KD-mediated neural repair remain unclear. We employed an integrated multi-omics approach combining 4D proteomics, transcriptomics, and single-cell RNA sequencing in a C5 hemi-contusion mouse model. This was combined with in vitro validation using β-hydroxybutyrate (β-OHB)-treated BV2 microglia cells to investigate KD’s effects on lysosome-mediated autophagy and microglial dynamics. Behavioral assessments and histopathological analyses were conducted over acute to chronic phases, spanning from 0 to 8 weeks post-injury. KD attenuated maladaptive lysosomal activation by downregulating cathepsin B (CTSB) and lysosomal-associated membrane protein 2 (LAMP2). This suppression concurrently reduced pro-inflammatory cytokines levels (IL-1β, TNF-α, IL-6) while facilitating M2 microglia polarization. Proteomic analysis identified 73 proteins responsive to KD that are associated with endoplasmic reticulum stress and chaperone-mediated autophagy. Single-cell transcriptomics revealed co-upregulation of CTSB and LAMP2 in injury-associated microglia subpopulations. Importantly, β-OHB partially replicated the effects of KD in vitro, reducing autophagy hyperactivity and enhancing M2 polarization. By targeting CTSB/LAMP2 axis, KD orchestrates dual neuroprotective mechanisms: lysosomal homeostasis restoration and immunomodulatory reprogramming. This coordinated action reconciles proteostatic regulation with microglial M1/M2 polarization dynamics, establishing KD as a multimodal metabolic intervention capable of simultaneously addressing autophagy dysregulation and neuroinflammation following SCI. These findings hold significant translational potential for neurotrauma management.
{"title":"Multi-omics analysis of ketogenic diet-mediated neural repair in spinal cord injury: Targeting of lysosomal autophagy through CTSB/LAMP2 regulation","authors":"Jiayu Chen , Haoxin Lian , Ruqin Guo , Kai Chen , Hao Ma , Jiachen Yang , Zhiping Huang , Lijia Chen , Kinon Chen , Jie Liu , Qing’an Zhu , Junhao Liu , Hui Jiang , Zucheng Huang","doi":"10.1016/j.jnutbio.2025.110152","DOIUrl":"10.1016/j.jnutbio.2025.110152","url":null,"abstract":"<div><div>Spinal cord injury (SCI) initiates secondary pathologies characterized by dysregulated autophagy and neuroinflammation Although the ketogenic diet (KD) has shown potential in promoting functional recovery after SCI, the mechanisms underlying KD-mediated neural repair remain unclear. We employed an integrated multi-omics approach combining 4D proteomics, transcriptomics, and single-cell RNA sequencing in a C5 hemi-contusion mouse model. This was combined with in vitro validation using β-hydroxybutyrate (β-OHB)-treated BV2 microglia cells to investigate KD’s effects on lysosome-mediated autophagy and microglial dynamics. Behavioral assessments and histopathological analyses were conducted over acute to chronic phases, spanning from 0 to 8 weeks post-injury. KD attenuated maladaptive lysosomal activation by downregulating cathepsin B (CTSB) and lysosomal-associated membrane protein 2 (LAMP2). This suppression concurrently reduced pro-inflammatory cytokines levels (IL-1β, TNF-α, IL-6) while facilitating M2 microglia polarization. Proteomic analysis identified 73 proteins responsive to KD that are associated with endoplasmic reticulum stress and chaperone-mediated autophagy. Single-cell transcriptomics revealed co-upregulation of CTSB and LAMP2 in injury-associated microglia subpopulations. Importantly, β-OHB partially replicated the effects of KD in vitro, reducing autophagy hyperactivity and enhancing M2 polarization. By targeting CTSB/LAMP2 axis, KD orchestrates dual neuroprotective mechanisms: lysosomal homeostasis restoration and immunomodulatory reprogramming. This coordinated action reconciles proteostatic regulation with microglial M1/M2 polarization dynamics, establishing KD as a multimodal metabolic intervention capable of simultaneously addressing autophagy dysregulation and neuroinflammation following SCI. These findings hold significant translational potential for neurotrauma management.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110152"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337155","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 : 2026-02-01Epub Date: 2025-10-10DOI: 10.1016/j.jnutbio.2025.110140
Hui Su , Luyao Liu , Zechen Yan , Jun Dong , Xianze Chen , Lin Wang , Guangxin Huang , WenXuan Guo , Rujie Zhuang , Yu Pan
<div><div>This study aims to investigate the therapeutic effects and underlying mechanisms of astilbin on high-fat diet (HFD)-induced bone loss, focusing on its regulation of the UPP1-Mitogen-Activated Protein Kinase (MAPK) axis, metabolic reprogramming, and gut microbiota modulation. Male C57BL/6 mice were fed an HFD for 10 weeks to induce obesity and bone loss, followed by astilbin intervention at different doses (25, 50, 100 mg/kg/d) for 8 weeks. Body weight, serum biochemical parameters, bone microstructure (via micro-CT), and bone metabolism markers were assessed. Transcriptomic, 16S rRNA sequencing, and serum metabolomics analyses were performed to explore the molecular mechanisms. <em>In vitro</em> experiments using bone marrow-derived mesenchymal stem cells (BMSCs) were conducted to evaluate osteogenic and adipogenic differentiation under palmitic acid and astilbin treatment. Astilbin significantly reduced HFD-induced weight gain, dyslipidemia, and bone loss, as evidenced by improved bone mineral density and trabecular bone structure. It upregulated osteogenic markers (RUNX2, alkaline phosphatase) while downregulating adipogenic markers (PPAR-γ) and inflammatory signals (p38MAPK). Transcriptomic analysis revealed that astilbin restored UPP1 expression, which was downregulated in HFD mice, and modulated the MAPK signaling pathway. Metabolomic analysis showed that astilbin downregulated proinflammatory lipids (<em>e.g.</em>, prostaglandin F2α) and upregulated anti-inflammatory metabolites (<em>e.g.</em>, sphingolipids and 4-hydroxyindole). Gut microbiota analysis demonstrated that astilbin restored microbial diversity, reduced the Firmicutes/Bacteroidetes ratio, and suppressed proinflammatory genera while promoting beneficial bacteria. <em>In vitro</em>, astilbin enhanced osteogenic differentiation and inhibited adipogenic differentiation in bone marrow mesenchymal stem cells by regulating the UPP1-MAPK axis and reducing oxidative stress. Astilbin ameliorates HFD-induced bone loss by targeting the UPP1-MAPK axis, modulating lipid metabolism, reducing inflammation, and restoring gut microbiota homeostasis. These findings provide a comprehensive understanding of the multi-target mechanisms of astilbin in metabolic bone diseases and highlight its potential as a therapeutic agent for osteoporosis. The present study demonstrates significant novelty and innovation by elucidating astilbin’s multi-target therapeutic mechanism in HFD-induced bone loss, integrating for the first time its regulation of the UPP1-MAPK signaling axis with metabolic reprogramming and gut microbiota modulation, which has not been previously reported. Unlike existing literature focusing on isolated pathways, this work reveals astilbin’s unique capacity to simultaneously restore UPP1 expression, downregulate proinflammatory MAPK signaling, reshape gut microbiota composition (reducing Firmicutes/Bacteroidetes ratio), and modulate osteogenic-adipogenic differentiation through
{"title":"UPP1 as a potential target for astilbin in ameliorating high-fat diet-induced bone loss via MAPK signaling: a study incorporating gut microbiota and metabolomics","authors":"Hui Su , Luyao Liu , Zechen Yan , Jun Dong , Xianze Chen , Lin Wang , Guangxin Huang , WenXuan Guo , Rujie Zhuang , Yu Pan","doi":"10.1016/j.jnutbio.2025.110140","DOIUrl":"10.1016/j.jnutbio.2025.110140","url":null,"abstract":"<div><div>This study aims to investigate the therapeutic effects and underlying mechanisms of astilbin on high-fat diet (HFD)-induced bone loss, focusing on its regulation of the UPP1-Mitogen-Activated Protein Kinase (MAPK) axis, metabolic reprogramming, and gut microbiota modulation. Male C57BL/6 mice were fed an HFD for 10 weeks to induce obesity and bone loss, followed by astilbin intervention at different doses (25, 50, 100 mg/kg/d) for 8 weeks. Body weight, serum biochemical parameters, bone microstructure (via micro-CT), and bone metabolism markers were assessed. Transcriptomic, 16S rRNA sequencing, and serum metabolomics analyses were performed to explore the molecular mechanisms. <em>In vitro</em> experiments using bone marrow-derived mesenchymal stem cells (BMSCs) were conducted to evaluate osteogenic and adipogenic differentiation under palmitic acid and astilbin treatment. Astilbin significantly reduced HFD-induced weight gain, dyslipidemia, and bone loss, as evidenced by improved bone mineral density and trabecular bone structure. It upregulated osteogenic markers (RUNX2, alkaline phosphatase) while downregulating adipogenic markers (PPAR-γ) and inflammatory signals (p38MAPK). Transcriptomic analysis revealed that astilbin restored UPP1 expression, which was downregulated in HFD mice, and modulated the MAPK signaling pathway. Metabolomic analysis showed that astilbin downregulated proinflammatory lipids (<em>e.g.</em>, prostaglandin F2α) and upregulated anti-inflammatory metabolites (<em>e.g.</em>, sphingolipids and 4-hydroxyindole). Gut microbiota analysis demonstrated that astilbin restored microbial diversity, reduced the Firmicutes/Bacteroidetes ratio, and suppressed proinflammatory genera while promoting beneficial bacteria. <em>In vitro</em>, astilbin enhanced osteogenic differentiation and inhibited adipogenic differentiation in bone marrow mesenchymal stem cells by regulating the UPP1-MAPK axis and reducing oxidative stress. Astilbin ameliorates HFD-induced bone loss by targeting the UPP1-MAPK axis, modulating lipid metabolism, reducing inflammation, and restoring gut microbiota homeostasis. These findings provide a comprehensive understanding of the multi-target mechanisms of astilbin in metabolic bone diseases and highlight its potential as a therapeutic agent for osteoporosis. The present study demonstrates significant novelty and innovation by elucidating astilbin’s multi-target therapeutic mechanism in HFD-induced bone loss, integrating for the first time its regulation of the UPP1-MAPK signaling axis with metabolic reprogramming and gut microbiota modulation, which has not been previously reported. Unlike existing literature focusing on isolated pathways, this work reveals astilbin’s unique capacity to simultaneously restore UPP1 expression, downregulate proinflammatory MAPK signaling, reshape gut microbiota composition (reducing Firmicutes/Bacteroidetes ratio), and modulate osteogenic-adipogenic differentiation through ","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110140"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274828","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 : 2026-02-01Epub Date: 2025-10-21DOI: 10.1016/j.jnutbio.2025.110154
Gita Erta, Gita Gersone, Antra Jurka, Pēteris Tretjakovs
This review examines the potential mechanisms by which SAA may influence glucose homeostasis and insulin sensitivity, emphasizing that current evidence is largely correlational and requires further investigation to establish causality. Salivary α-amylase (SAA), a key enzyme in the breakdown of dietary starch, has emerged as a potential regulator of glucose homeostasis, insulin secretion, and appetite control. Beyond its primary role in carbohydrate digestion, growing evidence highlights the influence of SAA on metabolic processes through its impact on early glucose release and its interaction with hormonal signaling pathways. This review examines the mechanisms by which SAA may affect insulin secretion and appetite regulation, focusing on its involvement in in incretin and other gut hormone-mediated pathways. Despite challenges posed by interindividual variability in SAA activity, its potential utility as a biomarker for metabolic health remains promising. Future research should prioritize uncovering the mechanistic links between SAA activity and metabolic outcomes, as well as establishing standardized protocols for its evaluation in both clinical and research contexts.
{"title":"Salivary amylase activity: A potential modulator of glucose homeostasis, insulin secretion, and appetite regulation","authors":"Gita Erta, Gita Gersone, Antra Jurka, Pēteris Tretjakovs","doi":"10.1016/j.jnutbio.2025.110154","DOIUrl":"10.1016/j.jnutbio.2025.110154","url":null,"abstract":"<div><div>This review examines the potential mechanisms by which SAA may influence glucose homeostasis and insulin sensitivity, emphasizing that current evidence is largely correlational and requires further investigation to establish causality. Salivary α-amylase (SAA), a key enzyme in the breakdown of dietary starch, has emerged as a potential regulator of glucose homeostasis, insulin secretion, and appetite control. Beyond its primary role in carbohydrate digestion, growing evidence highlights the influence of SAA on metabolic processes through its impact on early glucose release and its interaction with hormonal signaling pathways. This review examines the mechanisms by which SAA may affect insulin secretion and appetite regulation, focusing on its involvement in in incretin and other gut hormone-mediated pathways. Despite challenges posed by interindividual variability in SAA activity, its potential utility as a biomarker for metabolic health remains promising. Future research should prioritize uncovering the mechanistic links between SAA activity and metabolic outcomes, as well as establishing standardized protocols for its evaluation in both clinical and research contexts.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110154"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355049","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 : 2026-02-01Epub Date: 2025-10-10DOI: 10.1016/j.jnutbio.2025.110141
Deyuan Wu , Jiawei Nie , Shijian Zhou , Liudan Liu , Lili Wang , Songfeng Yang , Jie Peng , Chengquan Tan
Pregnant sows suffer from iron deficiency; however, excessive iron supplementation can induce tissue damage through ferroptosis. This study aimed to identify the optimal iron supplementation dose for gestating sows and investigate the mechanisms underlying iron deficiency and overdose, which contribute to reduced reproductive performance in sows. 84 sows with similar farrowing times were selected and stratified by body weight at day 85 of gestation. They were randomly assigned to one of three dietary treatments (n=28 per treatment): basal diet (L-Iron), basal diet supplemented with 0.13% protein iron (N-Iron) or 0.27% protein iron (H-Iron). Obviously, the rate of live-born piglets and placental vascular development in the N-Iron group were significantly higher than those in the l-Iron and H-Iron groups. Further analysis revealed that the expression levels of Transferrin (TF) and Transferrin receptor 1(TFR1) in the placenta of the H-Iron group were significantly reduced, while the expression levels of ferritin and nuclear receptor coactivator 4 were significantly increased. Importantly, the expression levels of lipid peroxidation and inflammatory markers such as lysophosphatidylcholine acyltransferase 3 and tumor necrosis factor-α were also significantly increased in the H-Iron group. In summary, our results indicate that supplementation of iron at an appropriate dose in iron-deficient pregnant sows promotes iron transfer between the sow and piglets and supports placental vascularization. Conversely, excessive iron supplementation leads to iron accumulation in the placenta, causing lipid peroxidation and mitochondrial damage, ultimately reducing the number of liveborn piglets.
{"title":"Iron homeostasis: effects of different levels of protein iron on placental iron handling in sows","authors":"Deyuan Wu , Jiawei Nie , Shijian Zhou , Liudan Liu , Lili Wang , Songfeng Yang , Jie Peng , Chengquan Tan","doi":"10.1016/j.jnutbio.2025.110141","DOIUrl":"10.1016/j.jnutbio.2025.110141","url":null,"abstract":"<div><div>Pregnant sows suffer from iron deficiency; however, excessive iron supplementation can induce tissue damage through ferroptosis. This study aimed to identify the optimal iron supplementation dose for gestating sows and investigate the mechanisms underlying iron deficiency and overdose, which contribute to reduced reproductive performance in sows. 84 sows with similar farrowing times were selected and stratified by body weight at day 85 of gestation. They were randomly assigned to one of three dietary treatments (<em>n</em>=28 per treatment): basal diet (L-Iron), basal diet supplemented with 0.13% protein iron (N-Iron) or 0.27% protein iron (H-Iron). Obviously, the rate of live-born piglets and placental vascular development in the N-Iron group were significantly higher than those in the <span>l</span>-Iron and H-Iron groups. Further analysis revealed that the expression levels of Transferrin (TF) and Transferrin receptor 1(TFR1) in the placenta of the H-Iron group were significantly reduced, while the expression levels of ferritin and nuclear receptor coactivator 4 were significantly increased. Importantly, the expression levels of lipid peroxidation and inflammatory markers such as lysophosphatidylcholine acyltransferase 3 and tumor necrosis factor-α were also significantly increased in the H-Iron group. In summary, our results indicate that supplementation of iron at an appropriate dose in iron-deficient pregnant sows promotes iron transfer between the sow and piglets and supports placental vascularization. Conversely, excessive iron supplementation leads to iron accumulation in the placenta, causing lipid peroxidation and mitochondrial damage, ultimately reducing the number of liveborn piglets.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110141"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280461","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 : 2026-02-01Epub Date: 2025-10-25DOI: 10.1016/j.jnutbio.2025.110157
Saudatu Faruk , Ismail Sulaiman , Kasimu Ghandi Ibrahim , Abdullahi Yahya Abbas , Mustapha Umar Imam
Parental iron deficiency (ID) causes intergenerational health risks. Rapamycin, on the other hand, is known for its antioxidant and lifespan-extending properties, but its effects under ID conditions remain unclear. This study investigated how parental ID and rapamycin intervention affect iron homeostasis, antioxidant defenses, autophagy, and longevity in Drosophila melanogaster. F0-generation flies were fed an iron-deficient diet for 14 d. One group was analyzed immediately. Another group was later switched to either a normal or rapamycin-supplemented diet for analysis and survival testing. A third group produced F1 offspring for post-eclosion analysis. F0 ID flies showed significant reductions (P<.0001) in body weight, iron levels, and antioxidant enzyme activity (SOD, CAT), with increased GSH. Gene expression analysis revealed altered iron storage (increased Fer1HCH) and oxidative stress responses (GPx3 downregulated in F0 but increased in F1 females). Significant (P<.05) generational changes were observed in SOD3, CAT, ATG1, and telomerase-associated genes. A normal diet restored iron levels and improved F0 female survival. Rapamycin enhanced antioxidant defenses but reduced F0 survival, while in F1, it improved antioxidant defenses without affecting survival. Parental ID significantly disrupts metabolism and stress responses across generations. While nutritional rehabilitation was beneficial, rapamycin's effects on lifespan were complex and context-dependent; it enhanced antioxidant capacity but did not consistently improve survival. These findings highlight conserved mechanisms linking iron availability and mTOR signaling to antioxidant defenses and longevity, offering potential translational relevance for understanding the intergenerational effects of ID in higher organisms.
{"title":"Parental iron deficiency modulates antioxidant status, autophagy, and longevity: Insight into the role of Rapamycin and iron homeostasis in Drosophila melanogaster","authors":"Saudatu Faruk , Ismail Sulaiman , Kasimu Ghandi Ibrahim , Abdullahi Yahya Abbas , Mustapha Umar Imam","doi":"10.1016/j.jnutbio.2025.110157","DOIUrl":"10.1016/j.jnutbio.2025.110157","url":null,"abstract":"<div><div>Parental iron deficiency (ID) causes intergenerational health risks. Rapamycin, on the other hand, is known for its antioxidant and lifespan-extending properties, but its effects under ID conditions remain unclear. This study investigated how parental ID and rapamycin intervention affect iron homeostasis, antioxidant defenses, autophagy, and longevity in <em>Drosophila melanogaster</em>. F0-generation flies were fed an iron-deficient diet for 14 d. One group was analyzed immediately. Another group was later switched to either a normal or rapamycin-supplemented diet for analysis and survival testing. A third group produced F1 offspring for post-eclosion analysis. F0 ID flies showed significant reductions (<em>P<</em>.0001) in body weight, iron levels, and antioxidant enzyme activity (SOD, CAT), with increased GSH. Gene expression analysis revealed altered iron storage (increased Fer1HCH) and oxidative stress responses (GPx3 downregulated in F0 but increased in F1 females). Significant (<em>P<</em>.05) generational changes were observed in SOD3, CAT, ATG1, and telomerase-associated genes. A normal diet restored iron levels and improved F0 female survival. Rapamycin enhanced antioxidant defenses but reduced F0 survival, while in F1, it improved antioxidant defenses without affecting survival. Parental ID significantly disrupts metabolism and stress responses across generations. While nutritional rehabilitation was beneficial, rapamycin's effects on lifespan were complex and context-dependent; it enhanced antioxidant capacity but did not consistently improve survival. These findings highlight conserved mechanisms linking iron availability and mTOR signaling to antioxidant defenses and longevity, offering potential translational relevance for understanding the intergenerational effects of ID in higher organisms.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110157"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577090","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 : 2026-02-01Epub Date: 2025-10-25DOI: 10.1016/j.jnutbio.2025.110156
Takuji Kawamura , Guilherme da Silva Rodrigues , Carlos Roberto Bueno Júnior , Yasuyuki Taki , Mitsuru Higuchi
Epigenetic aging, regulated by DNA methylation-based clocks, is a modifiable biological process influenced by environmental and lifestyle-related factors. Nutritional interventions have attracted attention as promising strategies to regulate biological aging. In this short review, we discuss the effects of specific nutrients and dietary patterns on epigenetic age acceleration and highlight the potential roles of diet-induced modulation of gene promoter methylation, a relatively underexplored yet critical mechanism underlying aging. We comprehensively review the observational and interventional studies linking nutrient intake, dietary quality, and polyphenol-rich diets to slow epigenetic aging. Furthermore, we discuss the complementary impacts of nutrition-driven promoter methylation changes, revealing a potential dual pathway involved in the dietary regulation of aging at the global and gene levels. By bridging epigenetic clock-based aging and promoter methylation biology, this review provides novel insights and outlines future research directions for establishing precise nutritional approaches for healthy longevity. In addition, this review highlights the need to consider both global and locus-specific epigenetic markers when developing dietary strategies to modulate biological aging.
{"title":"Dietary regulation of epigenetic aging: Beyond clocks to gene-specific mechanisms","authors":"Takuji Kawamura , Guilherme da Silva Rodrigues , Carlos Roberto Bueno Júnior , Yasuyuki Taki , Mitsuru Higuchi","doi":"10.1016/j.jnutbio.2025.110156","DOIUrl":"10.1016/j.jnutbio.2025.110156","url":null,"abstract":"<div><div>Epigenetic aging, regulated by DNA methylation-based clocks, is a modifiable biological process influenced by environmental and lifestyle-related factors. Nutritional interventions have attracted attention as promising strategies to regulate biological aging. In this short review, we discuss the effects of specific nutrients and dietary patterns on epigenetic age acceleration and highlight the potential roles of diet-induced modulation of gene promoter methylation, a relatively underexplored yet critical mechanism underlying aging. We comprehensively review the observational and interventional studies linking nutrient intake, dietary quality, and polyphenol-rich diets to slow epigenetic aging. Furthermore, we discuss the complementary impacts of nutrition-driven promoter methylation changes, revealing a potential dual pathway involved in the dietary regulation of aging at the global and gene levels. By bridging epigenetic clock-based aging and promoter methylation biology, this review provides novel insights and outlines future research directions for establishing precise nutritional approaches for healthy longevity. In addition, this review highlights the need to consider both global and locus-specific epigenetic markers when developing dietary strategies to modulate biological aging.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"148 ","pages":"Article 110156"},"PeriodicalIF":4.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577092","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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