Food frontiersPub Date : 2025-08-04DOI: 10.1002/fft2.70088
Yan Mou, Yunhuan Liu, Yanjuan Chen, Ruling Shen, Aoxue Yan, Tongtong Liao, Yanyin Liu, Hejun Su, Zhenming He, Yue Wang, Lin Qi, Huili Zhu, Haiyan Ge
{"title":"Astragalus Polysaccharide Alleviates COPD-Associated Skeletal Muscle Dysfunction Through Suppression of Inflammation and Cellular Senescence","authors":"Yan Mou, Yunhuan Liu, Yanjuan Chen, Ruling Shen, Aoxue Yan, Tongtong Liao, Yanyin Liu, Hejun Su, Zhenming He, Yue Wang, Lin Qi, Huili Zhu, Haiyan Ge","doi":"10.1002/fft2.70088","DOIUrl":"10.1002/fft2.70088","url":null,"abstract":"<p>Astragalus polysaccharide (APS) exhibits various pharmacological properties. However, scientific evidence to support its usage in chronic obstructive pulmonary disease (COPD)-associated skeletal muscle dysfunction is limited. This study aimed to investigate the effects of APS and its underlying mechanisms in cigarette smoke (CS)-induced COPD-associated skeletal muscle dysfunction in mice and CS extract (CSE)-induced atrophy in C2C12 myotubes. In vivo, APS significantly attenuated CS-induced weight loss, pulmonary inflammation, and lung structural damage. APS ameliorated skeletal muscle atrophy, evidenced by restored muscle weight, reduced fibrosis, and improved histoarchitecture. This was accompanied by the downregulation of atrophy markers (<i>Atrogin-1and MuRF-1</i>), pro-inflammatory cytokines (<i>IL-6, TNF-α, CXCL1, CCL2, CXCL2</i> and <i>GM-CSF</i>), and senescence markers (<i>p16</i>, <i>p21</i>and <i>p53</i>) in skeletal muscle. In vitro, APS protected C2C12 myotubes from CSE-induced wasting, preventing reductions in myotube diameter and myogenic factor expression (<i>MyoD</i>, and <i>Myogenin</i>), while suppressing the upregulation of <i>Atrogin-1</i>, <i>MuRF-1</i>, <i>IL-6</i>, <i>TNF-α</i>, β-galactosidase activity and <i>p53</i>). Our findings demonstrated that APS effectively alleviated COPD-associated skeletal muscle dysfunction in both animal and cellular models. This protective effect is mediated through the concurrent suppression of inflammatory cascades and cellular senescence via NF-κB/p53 signaling pathway. This study provides preclinical evidence supporting APS as a promising functional food or supplement to mitigate COPD-associated skeletal muscle dysfunction.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2182-2192"},"PeriodicalIF":6.9,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145037965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dietary Riboflavin Supplementation Suppresses Colorectal Cancer Progression by Restoring the Function Effector of CD8+ T Cells","authors":"Lining Chen, Yao Lu, Peng Xue, Yingying Lin, Zhen Zhang, Yuqi Wang, Yuning Zhang, Heng Quan, Yiran Wang, Huiyuan Guo","doi":"10.1002/fft2.70084","DOIUrl":"10.1002/fft2.70084","url":null,"abstract":"<p>Tumor cells have a competitive edge in nutrient uptake, leading to immune cell nutrient deprivation within the tumor microenvironment (TME) and suppressing anti-tumor immunity. However, the key nutrient deprived by intestinal tumor cells and effective intervention strategies remains unidentified. Using organoid models and metabolomics, we clarified riboflavin as the most preferential nutrient for intestinal tumor cells over normal epithelial cells. After confirming in vitro that riboflavin supplementation did not promote tumor cell proliferation, we found in vivo that drinking water with riboflavin effectively inhibited murine colorectal tumor growth with enhanced intra-tumoral CD8<sup>+</sup> T-cell cytotoxicity. We further demonstrated the indispensable role of adequate riboflavin in maintaining effector CD8<sup>+</sup> T cells and revealed intestinal tumor cells overexpressed the riboflavin transporter SLC52A2, depleting riboflavin from CD8<sup>+</sup> T cells and dampening their cytotoxicity, which can be restored by riboflavin supplementation. Our work clarified the critical nutrient and immune evasion mechanism, suggesting riboflavin supplementation as potential therapy to enhance anti-tumor immunity in colorectal cancer.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2241-2254"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Synergistic Effects of Ginsenoside Rb3 and Rc From Panax notoginseng Leaf on Alleviating Neuroinflammation via PACAP in Depression","authors":"Shu-zhen Ran, Rui Peng, Qin-wan Guo, Li-juan Ma, Jian-bo Wan, Jun-qing Huang, Zi-ying Wang, Gang Chen","doi":"10.1002/fft2.70080","DOIUrl":"10.1002/fft2.70080","url":null,"abstract":"<p><i>Panax notoginseng</i> Leaf (PNL), an edible-medicinal botanical resource, shows potential as functional ingredients for alleviating depression, owing to their unique saponin composition. This study investigates the regulatory effects of PNL-derived saponins on pituitary adenylate cyclase-activating polypeptide (PACAP) and <span>their</span> related antidepressant mechanisms.</p><p>Our findings demonstrate that PNL supplementation significantly alleviates depressive-like behaviors. Mechanistically, PNL upregulates PACAP expression in the hippocampus and activates the downstream CREB and mTOR signaling pathways, leading to increased expression of synaptic plasticity markers, including BDNF and PSD95, while concurrently inhibiting microglial activation and the production of pro-inflammatory cytokines. Among the major saponins in PNL, ginsenosides Rb3 and Rc were found to synergistically enhance PACAP expression in the cultured PC12 cells.</p><p>These results underscore the potential of PNL for novel functional food ingredients, highlighting the antidepressant synergism of its naturally occurring ginsenosides (Rb3/Rc), and provide a natural antidepressant strategy.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2492-2505"},"PeriodicalIF":6.9,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food frontiersPub Date : 2025-07-23DOI: 10.1002/fft2.70081
Philipp Sprengholz, Anna Tabea Feifel, Babett Reich, Antonia Sahler
{"title":"Navigating the Nutri-Score: Inequidistant Perceptions of Front-of-Package Health Information","authors":"Philipp Sprengholz, Anna Tabea Feifel, Babett Reich, Antonia Sahler","doi":"10.1002/fft2.70081","DOIUrl":"10.1002/fft2.70081","url":null,"abstract":"<p>The Nutri-Score is a front-of-package label designed to guide consumers toward healthier food choices, using letters A (indicating <i>high nutritional quality</i>) to E (indicating <i>low nutritional quality</i>). While many studies have assessed the impact on food consumption, little research has explored how the label is perceived. To address this gap, two online studies with representative samples from Germany investigated whether differences between neighboring Nutri-Scores are perceived as equidistant. Study 1 (<i>N</i> = 562) assessed perceived healthiness across the Nutri-Score scale, revealing a middle-of-scale effect, where differences between mid-range scores appeared larger than those at the extremes. Study 2 (<i>N</i> = 319) used a discrete choice experiment with products varying in price and Nutri-Score. While participants were more willing to pay for an improvement from C to B than from B to A, a different pattern emerged at the lower end of the scale, where consumers prioritized avoiding the lowest-rated products. These findings highlight the need for public education on the Nutri-Score's interpretation. They may also inform potential revisions to the label and contribute to broader public health strategies, such as food taxation policies.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2485-2491"},"PeriodicalIF":6.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food frontiersPub Date : 2025-07-21DOI: 10.1002/fft2.70079
Xiuqi Wang, Yiqiao Wang, Yu Wang, Qiao Huang, Yutang He, Jian Sun, Guangchen Zhang, He Liu
{"title":"Insights Into Processing Properties of Germinated Brown Rice: Based on Physicochemical, Non-Volatile, and Volatile Metabolomics","authors":"Xiuqi Wang, Yiqiao Wang, Yu Wang, Qiao Huang, Yutang He, Jian Sun, Guangchen Zhang, He Liu","doi":"10.1002/fft2.70079","DOIUrl":"10.1002/fft2.70079","url":null,"abstract":"<p>Germinated brown rice is increasingly recognized for its physiological benefits. However, the effects of germination on its processing properties, as well as on the composition of its volatile and non-volatile metabolites, have not been systematically elucidated. In this study, the elongation of germination time may represent one of the contributing factors to the decline in brown rice integrity. Prolonged germination was associated with reduced hardness, chewiness, and resilience of the cooked brown rice, likely due to increased water infiltration during the germination process. Furthermore, non-volatile metabolomic analysis revealed the accumulation of 141 non-volatile metabolites in germinated brown rice. Germination significantly promoted γ-aminobutyric acid (GABA) accumulation in the cooked brown rice; however, disruption of the <i>OsBADH2</i> gene significantly suppressed GABA accumulation. Volatile metabolomics analysis revealed that short-duration germination enhanced the formation of aldehydes, esters, and alcohols, while the levels of several undesirable metabolites, such as indole, decreased with prolonged germination time. These findings will contribute to the industrial production and promotion of germinated brown rice.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2470-2484"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Machine Learning for Precise Identification of Royal Jelly From Various Food Sources With Stable Isotope and Physicochemical Properties","authors":"Zhaolong Liu, Xinlei Yu, Xin Yin, Dong Qiao, Hongxia Li, Lanzhen Chen","doi":"10.1002/fft2.70058","DOIUrl":"10.1002/fft2.70058","url":null,"abstract":"<p>Royal jelly (RJ) is highly regarded for its bioactive compounds and salutary effects. However, the traceability and authenticity of royal jelly are significantly challenged due to the considerable variability in its composition, which is influencedby the diverse food sources of bees. This study examines the impact of three food sources—natural foods, sugar-water, and pollen substitutes—on stable carbon (<i>δ</i><sup>13</sup>C) and nitrogen (<i>δ</i><sup>15</sup>N) isotope fractionation in RJ produced during different floral periods. The findings indicate that RJ derived from natural honey and beebread exhibited lower <i>δ</i><sup>13</sup>C values, whereas RJ produced from sugar-water feeding showed higher <i>δ</i><sup>13</sup>C values. Furthermore, a notable degree of variation in <i>δ</i><sup>13</sup>C was observed regarding the diverse beebread sources. A positive correlation was identified between <i>δ</i><sup>15</sup>N in beebreads and RJ, whereas a negative correlation (<i>r</i> = −0.89) was observed between <i>δ</i><sup>15</sup>N in pollen substitutes and RJ. The application of machine learning (ML) models, including artificial neural networks (ANNs) and random forests (RFs), resulted in 100% classification accuracy in the identification of RJ on the basis of feeding sources and floral periods, utilizing calculated fractionation factors. These findings demonstrate that <i>δ</i><sup>13</sup>C and <i>δ</i><sup>15</sup>N are reliable markers for RJ authenticity and highlight the importance of integrating isotopic data with feeding conditions for precise identification. The success of ANN and RF models underscores the potential of combining isotope fractionation with ML for high-precision traceability, offering a framework for food traceability and sustainability in apiculture.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2314-2327"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food frontiersPub Date : 2025-07-21DOI: 10.1002/fft2.70086
Shahad K. Alsaiari, Linzixuan Zhang, Xin Yang, Aranda R. Duan, John L. Daristotle, Aurelien vander Straeten, Shelley B. Weinstock, Robert Langer, Ana Jaklenec
{"title":"Stable Natural Iron Complex Micronutrient Powder for Enhanced Cellular Uptake","authors":"Shahad K. Alsaiari, Linzixuan Zhang, Xin Yang, Aranda R. Duan, John L. Daristotle, Aurelien vander Straeten, Shelley B. Weinstock, Robert Langer, Ana Jaklenec","doi":"10.1002/fft2.70086","DOIUrl":"10.1002/fft2.70086","url":null,"abstract":"<p>Iron deficiency anemia (IDA) is a persistent global health challenge, particularly in low- and middle-income countries, necessitating effective iron fortification strategies. In this study, we developed FeC-4-1, a novel iron complex composed of ferrous sulfate, vitamin C (VC), and histidine, to enhance iron stability, cellular iron uptake, and compatibility with food matrices. FeC-4-1 exhibited high stability across a broad pH range (3–12). Under simulated gastric conditions, FeC-4-1 released nearly 100% of its iron and VC within 10 min, ensuring efficient cellular iron uptake. FeC-4-1 also demonstrated superior oxidation resistance compared to FeSO<sub>4</sub>, exhibiting 2.5-fold lower color change in polyphenol-rich banana milk after 2-h treatment. Long-term storage studies revealed that FeC-4-1 maintained 60% of its initial total iron content with the ferrous iron fraction remaining at ∼80% after 12 months, indicating minimal oxidation over time. Bioaccessibility studies following an established INFOGEST protocol showed that FeC-4-1 provided about 2-fold higher bioaccessible iron compared to FeSO<sub>4</sub> under room temperature conditions. In addition, FeC-4-1 resulted in approximately a 3.2-fold increase in total intracellular iron compared to FeSO<sub>4</sub> in Caco-2 cells. Sensory evaluation results demonstrated that FeC-4-1 fortification at 16 mg per serving (50% RDA of iron) in bouillon soup did not alter flavor or mouthfeel. These findings suggest that FeC-4-1 is a technically feasible and effective iron fortificant, offering enhanced stability, bioaccessibility, and consumer acceptability for in-home iron fortification.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2231-2240"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food frontiersPub Date : 2025-07-15DOI: 10.1002/fft2.70062
Van-Long Truong, Razanamanana H. G. Rarison, Woo-Sik Jeong
{"title":"Curcuma comosa-Derived Diarylheptanoid Ameliorates Ulcerative Colitis by Inhibiting JNK/NF-κB and Activating AMPK/Nrf2 Pathways","authors":"Van-Long Truong, Razanamanana H. G. Rarison, Woo-Sik Jeong","doi":"10.1002/fft2.70062","DOIUrl":"10.1002/fft2.70062","url":null,"abstract":"<p>Ulcerative colitis (UC) is a persistent inflammatory condition affecting the mucosal layer of the colon, with limited treatment options available. Diarylheptanoids, bioactive secondary metabolites found in <i>Curcuma</i> plants, possess diverse anti-inflammatory and antioxidant properties. However, the biological activities of 1,7-diphenyl-(6<i>E</i>)-6-hepten-3-ol (DPHP), a linear diarylheptanoid derived from <i>Curcuma comosa</i> rhizomes, remain largely unexplored. This study was conducted to investigate the antioxidant and anti-inflammatory mechanisms of DPHP in dextran sodium sulfate (DSS)-induced colitis mice and lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. The results showed that DPHP supplementation considerably alleviated the severity of DSS-induced colitis by reducing the disease activity index, minimizing colon damage and neutrophil infiltration, and preventing body weight loss and colon shortening. DPHP inhibited inflammation in both DSS-induced colitis mice and LPS-treated macrophages by suppressing the c-Jun N-terminal kinases/nuclear factor kappa B pathway. Additionally, DPHP treatment effectively reduced reactive oxygen species formation and oxidative damage by upregulating the expression of antioxidant enzymes, likely via regulation of the adenosine monophosphate-activated protein kinase/nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway. Moreover, the antioxidant and anti-inflammatory effects of DPHP were significantly abrogated upon blocking Nrf2/heme oxygenase-1 activation. Overall, these findings shed light on the protective effects of DPHP against oxidative stress and inflammation through coordinated Nrf2 and nuclear factor-kappa B (NF-κB) pathway modulation, underscoring its potential as a therapeutic agent for preventing and treating UC.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2295-2313"},"PeriodicalIF":6.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Improving Activity of ACE Inhibitory Peptide by Sequence-Based Rational Design: Properties, Function on Endothelial Cells, and Potential Antihypertensive Mechanism","authors":"Qingping Liang, Zhemin Liu, Mengshi Xiao, Wei Zhou, Dongxing Yu, Jiaming Liu, Le Wang, Haijin Mou","doi":"10.1002/fft2.70076","DOIUrl":"10.1002/fft2.70076","url":null,"abstract":"<p>The comprehension of the relationship between structure and function and mechanisms of intermolecular interactions within amino acid sequences is essential for developing potent angiotensin-converting enzyme (ACE) inhibitory peptides based on food-derived peptide sequences. This study developed six peptides based on the original ACE inhibitory peptide LYPVK that was derived from <i>Ficus carica</i> by sequence-based rational design and investigated their ACE inhibitory functions. Three of them demonstrated improved activity, among which YWLKP had the strongest activity, with an IC<sub>50</sub> value of 5.02 ± 0.62 µg/mL. They exhibited competitive or noncompetitive action modes and desirable resistance to gastrointestinal environments. Molecular docking analysis revealed that the enhanced hydrogen bonds and hydrophobic interactions contribute to their increased affinity for ACE. Accordingly, the potential sequence regularity was proposed that peptides containing residue composition of X1-X2-Lys-Pro motifs (X1 represents hydrophobic aromatic residues and X2 represents hydrophobic residues with long side chains) may exhibit strong activity against ACE. It was found that these peptides promoted nitric oxide (NO) release and reduced endothelin-1 (ET-1) content to achieve antihypertensive effects on endothelial cells. Additionally, YWLKP might regulate multiple targets and pathways for its antihypertensive function through network pharmacology and real-time fluorescence quantitative PCR (RT-qPCR) analysis. This study provides potential sequence regularity and sequence-designed peptides that can serve as promising multitarget ACE inhibitors.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2376-2393"},"PeriodicalIF":6.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food frontiersPub Date : 2025-07-11DOI: 10.1002/fft2.70059
Yi-San Lee, Catherine Ortega, Tien-Fen Kuo, Greta Yang, Wen-Chin Yang
{"title":"Natural Products Targeting Protein Disulfide Isomerases: New Frontiers for Diabetes, Cancer, and Coagulation","authors":"Yi-San Lee, Catherine Ortega, Tien-Fen Kuo, Greta Yang, Wen-Chin Yang","doi":"10.1002/fft2.70059","DOIUrl":"10.1002/fft2.70059","url":null,"abstract":"<p>The protein disulfide isomerase (PDI) family comprises 21 members that have oxidase, reductase, isomerase, and foldase activities essential for human health and disease. Protein disulfide isomerase A4 (PDIA4) is the largest member in this family. This family is pivotal in various human diseases. This review explores PDIA4 as a representative PDI member and other PDIs from the perspective of their roles in cancer, diabetes, and thrombotic diseases. The natural compounds that target PDIA4 and/or other PDIs are summarized, and a comprehensive overview of their compound screening/identification, functions, mechanisms of action, and therapeutic applications in the diseases is provided. A literature search of studies published between 1990 and 2024 was conducted using PubMed, Web of Science, Google Scholar, SciFinder, and Dictionary of Natural Products databases online. Keywords alone and in combination, such as “PDI,” “PDIA4,” “natural compound,” “inhibitor,” and “disease,” were used to retrieve related publications, followed by manual assessment and selection. The results highlight the functions, mechanisms, and potential interventions of PDIs, with particular focus on PDIA4, in cancer, diabetes, and thrombotic disorders. Nineteen compounds that modulate the enzymatic activity or expression of PDIA4 and/or PDIs and show promising pharmacological functions, unique mechanisms, and novel therapeutic opportunities in managing cancer, metabolic syndromes, and thrombosis are presented. Collectively, the mechanisms for the natural inhibitors of PDIA4 are via disruption of the interaction between PDIA4 and its substrates, leading to activation of executioner procaspases in cancer, inhibition of β-cell reactive oxygen species (ROS) generating pathways in diabetes, and increased displacement of antithrombin by histidine-rich glycoprotein in coagulation.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"6 5","pages":"2165-2181"},"PeriodicalIF":6.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://iadns.onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145037850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}