Pub Date : 2026-03-06DOI: 10.1016/j.jare.2026.02.055
Xinyi Han, Lingwei Ma, Jiahui Dai, Dong Gao, Wei Wang
Background
Precancerous lesions are pivotal intermediates in tumorigenesis, creating critical windows for early detection and intervention. However, research has been hindered by limited clinical samples, pronounced molecular heterogeneity, and the absence of models that faithfully mirror in vivo pathology. Organoids have emerged as a powerful solution, preserving patient-specific genetic, phenotypic, and microenvironmental features while enabling long-term culture and functional interrogation.
Aim of review
This review aims to systematically synthesize recent advances in organoid-based modeling of precancerous lesions. We summarize the latest progress in organoid construction strategies, validation frameworks, and multidimensional applications, including mechanistic dissection of precancerous evolution, biomarker discovery for early detection, and therapeutic screening for precision prevention. Furthermore, we highlight integrative approaches that combine CRISPR-mediated genome editing and single-cell multi-omics to enhance the fidelity, scalability, and clinical relevance of organoid systems in precancer research.
Key scientific concepts of review
Organoid technology is reshaping paradigms in precancer research by bridging fundamental biology with clinical translation, providing unprecedented tools for early detection, risk stratification, and personalized cancer prevention.
{"title":"Organoids revolutionizing precancer research","authors":"Xinyi Han, Lingwei Ma, Jiahui Dai, Dong Gao, Wei Wang","doi":"10.1016/j.jare.2026.02.055","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.055","url":null,"abstract":"<h3>Background</h3>Precancerous lesions are pivotal intermediates in tumorigenesis, creating critical windows for early detection and intervention. However, research has been hindered by limited clinical samples, pronounced molecular heterogeneity, and the absence of models that faithfully mirror <em>in vivo</em> pathology. Organoids have emerged as a powerful solution, preserving patient-specific genetic, phenotypic, and microenvironmental features while enabling long-term culture and functional interrogation.<h3>Aim of review</h3>This review aims to systematically synthesize recent advances in organoid-based modeling of precancerous lesions. We summarize the latest progress in organoid construction strategies, validation frameworks, and multidimensional applications, including mechanistic dissection of precancerous evolution, biomarker discovery for early detection, and therapeutic screening for precision prevention. Furthermore, we highlight integrative approaches that combine CRISPR-mediated genome editing and single-cell multi-omics to enhance the fidelity, scalability, and clinical relevance of organoid systems in precancer research.<h3>Key scientific concepts of review</h3>Organoid technology is reshaping paradigms in precancer research by bridging fundamental biology with clinical translation, providing unprecedented tools for early detection, risk stratification, and personalized cancer prevention.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"407 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1016/j.jare.2026.02.054
Kai Zhu, Hongyan Liu, Kun Zhou, Tao Cheng, Liyuan Mo, Peng-Fei Xu, Yan Li
Introduction
Folate (vitamin B9) is a fundamental cofactor in one-carbon metabolism, essential for embryonic development. While maternal folate deficiency is a well-established risk factor for neural tube and congenital heart defects, its specific impact on early embryogenesis, particularly during early post-blastula stages, and the underlying molecular mechanisms remain insufficiently characterized.
Objectives
This study aimed to establish a vertebrate model to facilitate real-time visualization and mechanistic dissection of how folate deficiency drives diverse developmental defects.
Methods and results
We used CRISPR/Cas9 to generate a folrΔ1 zebrafish line harboring a one-nucleotide deletion in the folate receptor gene (folr), resulting in maternal folate deficiency. Embryos derived from folrΔ1 homozygote females exhibited embryonic lethality and defective dorsoventral patterning. Untargeted metabolomics analysis revealed that folate deficiency disrupts nucleotide biosynthesis and mitochondrial homeostasis. Specifically, maternal folate deficiency impaired embryonic DNA synthesis, exacerbated DNA damage, and induced G1/S phase cell cycle arrest. It also compromised mitochondrial integrity, triggering compensatory mitophagy. Notably, suppression of p53 activation in folr mutants improved dorsoventral patterning and alleviated cell cycle arrest. However, it did not mitigate the extent of DNA damage or mitophagy, suggesting p53 acts downstream of these metabolic stresses.
Conclusion
We have established a robust zebrafish model of maternal folate deficiency that recapitulates key metabolic and developmental features of the human condition. Our findings demonstrated that folate deficiency disrupts metabolism, leading to DNA damage and mitochondrial dysfunction. Crucially, this pathology activates p53, which drives G1/S cell cycle arrest and severe embryonic defects, including impaired body axis formation. This model provides a powerful platform for further delineating the precise roles of folate in vertebrate development and in the pathogenesis of congenital anomalies.
{"title":"A novel zebrafish model unveils folate deficiency disrupts embryonic development via p53-driven cell cycle arrest","authors":"Kai Zhu, Hongyan Liu, Kun Zhou, Tao Cheng, Liyuan Mo, Peng-Fei Xu, Yan Li","doi":"10.1016/j.jare.2026.02.054","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.054","url":null,"abstract":"<h3>Introduction</h3>Folate (vitamin B9) is a fundamental cofactor in one-carbon metabolism, essential for embryonic development. While maternal folate deficiency is a well-established risk factor for neural tube and congenital heart defects, its specific impact on early embryogenesis, particularly during early post-blastula stages, and the underlying molecular mechanisms remain insufficiently characterized.<h3>Objectives</h3>This study aimed to establish a vertebrate model to facilitate real-time visualization and mechanistic dissection of how folate deficiency drives diverse developmental defects.<h3>Methods and results</h3>We used CRISPR/Cas9 to generate a <em>folr</em>Δ1 zebrafish line harboring a one-nucleotide deletion in the folate receptor gene (<em>folr</em>), resulting in maternal folate deficiency. Embryos derived from <em>folr</em>Δ1 homozygote females exhibited embryonic lethality and defective dorsoventral patterning. Untargeted metabolomics analysis revealed that folate deficiency disrupts nucleotide biosynthesis and mitochondrial homeostasis. Specifically, maternal folate deficiency impaired embryonic DNA synthesis, exacerbated DNA damage, and induced G1/S phase cell cycle arrest. It also compromised mitochondrial integrity, triggering compensatory mitophagy. Notably, suppression of p53 activation in <em>folr</em> mutants improved dorsoventral patterning and alleviated cell cycle arrest. However, it did not mitigate the extent of DNA damage or mitophagy, suggesting p53 acts downstream of these metabolic stresses.<h3>Conclusion</h3>We have established a robust zebrafish model of maternal folate deficiency that recapitulates key metabolic and developmental features of the human condition. Our findings demonstrated that folate deficiency disrupts metabolism, leading to DNA damage and mitochondrial dysfunction. Crucially, this pathology activates p53, which drives G1/S cell cycle arrest and severe embryonic defects, including impaired body axis formation. This model provides a powerful platform for further delineating the precise roles of folate in vertebrate development and in the pathogenesis of congenital anomalies.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"48 14 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147361107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-05-21DOI: 10.1016/j.jare.2025.05.041
Shiqian Liu , Ruiyang Ding , Linyuan Huang , Jianong Lv , Zhiwei Sun , Xiaoxiao Wang , Junchao Duan
Introduction
Urban particulate matter (UPM) is a major air pollutant affecting public health, with maternal exposure potentially leading to cardiac developmental disorders in offspring. However, the exact mechanisms underlying the intergenerational effects of UPM remain unclear.
Objective
This study aimed to investigate the molecular mechanisms involved in cardiac developmental defects caused by maternal UPM exposure in offspring zebrafish.
Methods and results
Female zebrafish were exposed to UPM for 21 days to examine intergenerational effects. The results indicated that maternal zebrafish in the exposed group exhibited ovarian damage and a reduced number of embryos and fertilization rates. Zebrafish offspring exhibited abnormal cardiac development, including pericardial edema and pathological heart injury. Mechanistically, transcriptomic analysis of the offspring indicated that UPM exposure induced significant modifications in the mitochondrial biogenesis pathway, with altered expression of mitochondrial function-related genes. Maternal UPM exposure impaired respiration in zebrafish embryos and increased angiopoietin-like 4 (ANGPTL4) expression in offspring hearts. In vitro, Angptl4 knockdown alleviated UPM-induced mitochondrial membrane potential reduction and mitochondrial reactive oxygen species overproduction in cardiomyocytes, whereas Angptl4 overexpression exacerbated UPM-induced mitochondrial toxicity.
Conclusion
These findings show that maternal UPM exposure disrupts mitochondrial homeostasis by upregulating ANGPTL4 expression, leading to abnormal cardiac development in zebrafish offspring.
{"title":"Maternal exposure to urban particulate matter induces cardiac developmental toxicity in zebrafish offspring by disrupting mitochondrial homeostasis","authors":"Shiqian Liu , Ruiyang Ding , Linyuan Huang , Jianong Lv , Zhiwei Sun , Xiaoxiao Wang , Junchao Duan","doi":"10.1016/j.jare.2025.05.041","DOIUrl":"10.1016/j.jare.2025.05.041","url":null,"abstract":"<div><h3>Introduction</h3><div>Urban particulate matter (UPM) is a major air pollutant affecting public health, with maternal exposure potentially leading to cardiac developmental disorders in offspring. However, the exact mechanisms underlying the intergenerational effects of UPM remain unclear.</div></div><div><h3>Objective</h3><div>This study aimed to investigate the molecular mechanisms involved in cardiac developmental defects caused by maternal UPM exposure in offspring zebrafish.</div></div><div><h3>Methods and results</h3><div>Female zebrafish were exposed to UPM for 21 days to examine intergenerational effects. The results indicated that maternal zebrafish in the exposed group exhibited ovarian damage and a reduced number of embryos and fertilization rates. Zebrafish offspring exhibited abnormal cardiac development, including pericardial edema and pathological heart injury. Mechanistically, transcriptomic analysis of the offspring indicated that UPM exposure induced significant modifications in the mitochondrial biogenesis pathway, with altered expression of mitochondrial function-related genes. Maternal UPM exposure impaired respiration in zebrafish embryos and increased angiopoietin-like 4 (ANGPTL4) expression in offspring hearts. <em>In vitro</em>, <em>Angptl4</em> knockdown alleviated UPM-induced mitochondrial membrane potential reduction and mitochondrial reactive oxygen species overproduction in cardiomyocytes, whereas <em>Angptl4</em> overexpression exacerbated UPM-induced mitochondrial toxicity.</div></div><div><h3>Conclusion</h3><div>These findings show that maternal UPM exposure disrupts mitochondrial homeostasis by upregulating ANGPTL4 expression, leading to abnormal cardiac development in zebrafish offspring.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 143-155"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-05-20DOI: 10.1016/j.jare.2025.05.044
Yuming Wei , Ya-Ya Yu , Yuan-Chao Li , Xiao-Yu Zhong , Chun Zou , Jingming Ning , Wen-Jiang Dong , Kegang Wu , Yong-Quan Xu
Introduction
Tea (Camellia sinensis) is globally consumed for its pleasant flavor, with sweetness being a key factor in evaluating tea quality. While taste compounds contribute to this sweetness, aroma also plays a significant role, but its contribution is not well understood in tea infusion.
Objectives
This study aimed to identify aroma compounds that enhance sweetness in tea infusion using a sensomics approach, and explore their synergistic effects through molecular docking.
Results
The aroma increased the sweetness of the tea infusion by more than 24.0 %. Eighteen aroma-active compounds linked to sweetness were identified, among which (E)-β-damascenone (apple-like), linalool (citrus-like), geraniol (citrus-like), dimethyl sulfide (corn-like), (E,E)-2,4-heptadienal (floral), (E,Z)-2,6-nonadienal (cucumber-like), (E)-linalool oxide (furanoid) (floral), dihydroactinidiolide (fruity), γ-nonalactone (coconut-like), and (E)-β-ionone (floral) had higher sweetness similarity and significantly increased the sweet intensity of sucrose (p < 0.05). They likely enhance sweetness by reducing the binding energy of sucrose to sweet taste receptors, forming new hydrogen bonds and hydrophobic interactions.
Conclusion
This study provides new insights into the role of aroma compounds in tea sweetness and suggests a potential mechanism for their sweetening effect. These compounds could be used as flavour enhancers or additives to improve the sweetness of tea beverages.
{"title":"Aroma compounds with enhanced sweet perception in tea infusions: Screening, characterization, and sweetening mechanism","authors":"Yuming Wei , Ya-Ya Yu , Yuan-Chao Li , Xiao-Yu Zhong , Chun Zou , Jingming Ning , Wen-Jiang Dong , Kegang Wu , Yong-Quan Xu","doi":"10.1016/j.jare.2025.05.044","DOIUrl":"10.1016/j.jare.2025.05.044","url":null,"abstract":"<div><h3>Introduction</h3><div>Tea (<em>Camellia sinensis</em>) is globally consumed for its pleasant flavor, with sweetness being a key factor in evaluating tea quality. While taste compounds contribute to this sweetness, aroma also plays a significant role, but its contribution is not well understood in tea infusion.</div></div><div><h3>Objectives</h3><div>This study aimed to identify aroma compounds that enhance sweetness in tea infusion using a sensomics approach, and explore their synergistic effects through molecular docking.</div></div><div><h3>Results</h3><div>The aroma increased the sweetness of the tea infusion by more than 24.0 %. Eighteen aroma-active compounds linked to sweetness were identified, among which (<em>E</em>)-<em>β</em>-damascenone (apple-like), linalool (citrus-like), geraniol (citrus-like), dimethyl sulfide (corn-like), (<em>E,E</em>)-2,4-heptadienal (floral), (<em>E,Z</em>)-2,6-nonadienal (cucumber-like), (<em>E</em>)-linalool oxide (furanoid) (floral), dihydroactinidiolide (fruity), <em>γ</em>-nonalactone (coconut-like), and (<em>E</em>)-<em>β</em>-ionone (floral) had higher sweetness similarity and significantly increased the sweet intensity of sucrose (<em>p</em> < 0.05). They likely enhance sweetness by reducing the binding energy of sucrose to sweet taste receptors, forming new hydrogen bonds and hydrophobic interactions.</div></div><div><h3>Conclusion</h3><div>This study provides new insights into the role of aroma compounds in tea sweetness and suggests a potential mechanism for their sweetening effect. These compounds could be used as flavour enhancers or additives to improve the sweetness of tea beverages.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 1-12"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-05-25DOI: 10.1016/j.jare.2025.05.048
Jiahong Sun , Yongliang Zhu , Danyi Huang , Liuqing Li , Mengna Pan , Fei Li , Chuanwei Ma
Introduction
Female diseases pose significant challenges in South Asia and Sub-Saharan Africa, particularly among adolescent girls and young women, who often receive insufficient attention.
Objectives
To report patterns and trends of female diseases among adolescent girls and young females aged 10–24 years in South Asia and Sub-Saharan Africa from 1990 to 2021.
Methods
We used data from the Global Burden of Disease Study 2021 for 51 countries in South Asia and Sub-Saharan Africa between 1990 and 2021. Joinpoint Regression was used to calculate annual average percentage changes and 95 % confidence intervals to quantify temporal trends.
Results
In 2021, South Asia and Sub-Saharan Africa had high mortality rates of maternal disorders of 6.04 (95 % uncertainty intervals 5.02, 7.39) and 17.69 (14.37, 21.78) per 100,000 population, respectively. The mortality rates for female cancers were approximately 0.98 in both regions, and the incidence rates for gynecological diseases were 16472.83 and 14480.99, per 100,000 population, respectively. From 1990 to 2021, there was an increasing trend in the number of maternal disorder deaths in Sub-Saharan Africa, as well as in all metric rates for most female cancers in both regions, and disability-adjusted life years, prevalence, and incidence rates for gynecological diseases in South Asia. Several female diseases varied across countries and were increasingly affecting younger adolescents aged 10–14 years in both regions. Although countries with lower Socio-demographic Index had a heavier burden of female diseases, no significant association was observed between the Universal Health Coverage effective coverage index and death rates for female cancers or gynecological diseases.
Conclusions
The burden of female diseases remains high among young females in South Asia and Sub-Saharan Africa, with younger adolescents being particularly affected. This underscores the urgent need for targeted interventions and increased investment in healthcare infrastructure to reduce the burden of female diseases in these regions.
{"title":"Burden of female diseases among adolescents and young adults aged 10–24 years in South Asia and Sub-Saharan Africa, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021","authors":"Jiahong Sun , Yongliang Zhu , Danyi Huang , Liuqing Li , Mengna Pan , Fei Li , Chuanwei Ma","doi":"10.1016/j.jare.2025.05.048","DOIUrl":"10.1016/j.jare.2025.05.048","url":null,"abstract":"<div><h3>Introduction</h3><div>Female diseases pose significant challenges in South Asia and Sub-Saharan Africa, particularly among adolescent girls and young women, who often receive insufficient attention.</div></div><div><h3>Objectives</h3><div>To report patterns and trends of female diseases among adolescent girls and young females aged 10–24 years in South Asia and Sub-Saharan Africa from 1990 to 2021.</div></div><div><h3>Methods</h3><div>We used data from the Global Burden of Disease Study 2021 for 51 countries in South Asia and Sub-Saharan Africa between 1990 and 2021. Joinpoint Regression was used to calculate annual average percentage changes and 95 % confidence intervals to quantify temporal trends.</div></div><div><h3>Results</h3><div>In 2021, South Asia and Sub-Saharan Africa had high mortality rates of maternal disorders of 6.04 (95 % uncertainty intervals 5.02, 7.39) and 17.69 (14.37, 21.78) per 100,000 population, respectively. The mortality rates for female cancers were approximately 0.98 in both regions, and the incidence rates for gynecological diseases were 16472.83 and 14480.99, per 100,000 population, respectively. From 1990 to 2021, there was an increasing trend in the number of maternal disorder deaths in Sub-Saharan Africa, as well as in all metric rates for most female cancers in both regions, and disability-adjusted life years, prevalence, and incidence rates for gynecological diseases in South Asia. Several female diseases varied across countries and were increasingly affecting younger adolescents aged 10–14 years in both regions. Although countries with lower Socio-demographic Index had a heavier burden of female diseases, no significant association was observed between the Universal Health Coverage effective coverage index and death rates for female cancers or gynecological diseases.</div></div><div><h3>Conclusions</h3><div>The burden of female diseases remains high among young females in South Asia and Sub-Saharan Africa, with younger adolescents being particularly affected. This underscores the urgent need for targeted interventions and increased investment in healthcare infrastructure to reduce the burden of female diseases in these regions.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 535-550"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-05-30DOI: 10.1016/j.jare.2025.05.051
Ying He , Chen Ding , Bo Zhang , Bingkun Bao , Yantong Liu , Duo Yun , Xia Chen , Rui Guo , Yongbo She , Zhigang Liu
Introduction
Maternal immune activation (MIA) impairs gut immune function in offspring, with maternal microbiota and their metabolites influencing intestinal development. Indole-3-propionic acid (IPA), a microbial metabolite derived from tryptophan, promotes gut health by enhancing epithelial proliferation. However, the impact of prenatal IPA supplementation on offspring gut outcomes remains unclear.
Objectives
This study investigated whether prenatal IPA supplementation could mitigate the susceptibility of MIA offspring to colitis.
Methods
Pregnant mice received oral IPA (20 mg/kg body weight) from embryonic day 5.5 (E5.5) until delivery, with MIA induced at E12.5. Female offspring (7–8 weeks old) were exposed to 3.5 % dextran sulfate sodium (DSS)-induced colitis. IPA levels were measured in maternal serum and amniotic fluid at E14.5 to assess maternal-fetal transfer and potential effects on fetal gut development.
Results
Prenatal IPA supplementation attenuated colitis severity in MIA offspring, as evidenced by reduced body weight loss, milder diarrhea, lower disease activity index, and diminished colonic damage, along with alleviation of anxiety-like behavior. Moreover, prenatal IPA supplementation decreased serum and colonic proinflammatory factor levels and improved colonic barrier function following DSS-induced colitis. Additionally, prenatal IPA supplementation enhanced the proportion of beneficial gut microbiota, such as Bifidobacterium, Lactobacillus, Limosilactobacillus, Allobaculum, and Faecalibaculum, which contributed to intestinal epithelial cell growth and helped preserve barrier integrity. Notably, IPA can be transferred from the mother to the fetus through blood and amniotic fluid, facilitating the mRNA expression of Mdr1b, Ctnnb1, and Lgr5, which are involved in gut cell proliferation and differentiation.
Conclusion
Prenatal IPA is transferred to the fetus and promotes gut development, conferring long-term protection against colitis in MIA offspring. These findings underscore the enduring impact of maternal interventions on offspring intestinal health.
{"title":"Prenatal supplementation with the gut-derived tryptophan metabolite indole-3-propionic acid alleviates colitis susceptibility in maternal immune-activated offspring mice","authors":"Ying He , Chen Ding , Bo Zhang , Bingkun Bao , Yantong Liu , Duo Yun , Xia Chen , Rui Guo , Yongbo She , Zhigang Liu","doi":"10.1016/j.jare.2025.05.051","DOIUrl":"10.1016/j.jare.2025.05.051","url":null,"abstract":"<div><h3>Introduction</h3><div>Maternal immune activation (MIA) impairs gut immune function in offspring, with maternal microbiota and their metabolites influencing intestinal development. Indole-3-propionic acid (IPA), a microbial metabolite derived from tryptophan, promotes gut health by enhancing epithelial proliferation. However, the impact of prenatal IPA supplementation on offspring gut outcomes remains unclear.</div></div><div><h3>Objectives</h3><div>This study investigated whether prenatal IPA supplementation could mitigate the susceptibility of MIA offspring to colitis.</div></div><div><h3>Methods</h3><div>Pregnant mice received oral IPA (20 mg/kg body weight) from embryonic day 5.5 (E5.5) until delivery, with MIA induced at E12.5. Female offspring (7–8 weeks old) were exposed to 3.5 % dextran sulfate sodium (DSS)-induced colitis. IPA levels were measured in maternal serum and amniotic fluid at E14.5 to assess maternal-fetal transfer and potential effects on fetal gut development.</div></div><div><h3>Results</h3><div>Prenatal IPA supplementation attenuated colitis severity in MIA offspring, as evidenced by reduced body weight loss, milder diarrhea, lower disease activity index, and diminished colonic damage, along with alleviation of anxiety-like behavior. Moreover, prenatal IPA supplementation decreased serum and colonic proinflammatory factor levels and improved colonic barrier function following DSS-induced colitis. Additionally, prenatal IPA supplementation enhanced the proportion of beneficial gut microbiota, such as <em>Bifidobacterium</em>, <em>Lactobacillus</em>, <em>Limosilactobacillus</em>, <em>Allobaculum</em>, and <em>Faecalibaculum</em>, which contributed to intestinal epithelial cell growth and helped preserve barrier integrity. Notably, IPA can be transferred from the mother to the fetus through blood and amniotic fluid, facilitating the mRNA expression of <em>Mdr1b</em>, <em>Ctnnb1</em>, and <em>Lgr5</em>, which are involved in gut cell proliferation and differentiation.</div></div><div><h3>Conclusion</h3><div>Prenatal IPA is transferred to the fetus and promotes gut development, conferring long-term protection against colitis in MIA offspring. These findings underscore the enduring impact of maternal interventions on offspring intestinal health.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 211-222"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-01DOI: 10.1016/j.jare.2025.05.064
Yanyan Zhu , Wenwen Zhao , Wan Li , Jinhua Wang , Hexun Chen , Zhihong Wang , Xin Wang , Xiuping Chen
Introduction
Paraquat (PQ), a widely used herbicide, causes lethal lung injury through unresolved mechanisms, posing urgent clinical challenges due to the lack of effective antidotes.
Objectives
This study aimed to define the role of squalene epoxidase (SQLE) in PQ-induced ferroptosis and endoplasmic reticulum (ER) stress, and to evaluate the therapeutic efficacy of the SQLE inhibitor liranaftate (LNT).
Methods
Cytotoxicity was assessed via CCK-8, ATP assays, and PI staining. Labile iron levels and lipid peroxidation were quantified using flow cytometry. ER morphology was visualized with ER-Tracker Green, mitochondrial swelling with MitoTracker Green, and ferrous iron localization with FerroOrange Live Cell Dye. Iron donors (FeSO4, FeCl3, ferric ammonium citrate) were used to modulate ferroptosis. In vivo therapeutic effects of LNT were evaluated in PQ-induced acute lung injury (ALI) mouse models.
Results
PQ triggered ferroptosis via ER stress-dependent PERK/eIF2α activation, with SQLE identified as a key mediator. LNT suppressed PQ-induced cytotoxicity by reducing labile iron, lipid peroxidation, and ER/mitochondrial damage. Iron supplementation exacerbated ferroptosis, while LNT restored GPX4 and SLC7A11 expression. In vivo, LNT treatment significantly improved survival rates from 45% in the PQ model group to 95%, while attenuating ALI severity by blocking the PERK signaling pathway and upregulating the ferroptosis-related proteins GPX4 and SLC7A11.
Conclusion
These findings highlight the potential role of ferroptosis and SQLE in mediating PQ toxicity and provide therapeutic strategies to combat PQ toxicity by inhibiting ferroptosis and/or targeting SQLE. Repurposing LNT may be a potential antidote for PQ-induced ALI.
{"title":"Squalene epoxidase promotes paraquat-induced pulmonary toxicity through endoplasmic reticulum-mediated ferroptosis","authors":"Yanyan Zhu , Wenwen Zhao , Wan Li , Jinhua Wang , Hexun Chen , Zhihong Wang , Xin Wang , Xiuping Chen","doi":"10.1016/j.jare.2025.05.064","DOIUrl":"10.1016/j.jare.2025.05.064","url":null,"abstract":"<div><h3>Introduction</h3><div>Paraquat (PQ), a widely used herbicide, causes lethal lung injury through unresolved mechanisms, posing urgent clinical challenges due to the lack of effective antidotes.</div></div><div><h3>Objectives</h3><div>This study aimed to define the role of squalene epoxidase (SQLE) in PQ-induced ferroptosis and endoplasmic reticulum (ER) stress, and to evaluate the therapeutic efficacy of the SQLE inhibitor liranaftate (LNT).</div></div><div><h3>Methods</h3><div>Cytotoxicity was assessed via CCK-8, ATP assays, and PI staining. Labile iron levels and lipid peroxidation were quantified using flow cytometry. ER morphology was visualized with ER-Tracker Green, mitochondrial swelling with MitoTracker Green, and ferrous iron localization with FerroOrange Live Cell Dye. Iron donors (FeSO<sub>4</sub>, FeCl<sub>3</sub>, ferric ammonium citrate) were used to modulate ferroptosis. In vivo therapeutic effects of LNT were evaluated in PQ-induced acute lung injury (ALI) mouse models.</div></div><div><h3>Results</h3><div>PQ triggered ferroptosis via ER stress-dependent PERK/eIF2α activation, with SQLE identified as a key mediator. LNT suppressed PQ-induced cytotoxicity by reducing labile iron, lipid peroxidation, and ER/mitochondrial damage. Iron supplementation exacerbated ferroptosis, while LNT restored GPX4 and SLC7A11 expression. In vivo, LNT treatment significantly improved survival rates from 45% in the PQ model group to 95%, while attenuating ALI severity by blocking the PERK signaling pathway and upregulating the ferroptosis-related proteins GPX4 and SLC7A11.</div></div><div><h3>Conclusion</h3><div>These findings highlight the potential role of ferroptosis and SQLE in mediating PQ toxicity and provide therapeutic strategies to combat PQ toxicity by inhibiting ferroptosis and/or targeting SQLE. Repurposing LNT may be a potential antidote for PQ-induced ALI.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 673-687"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-13DOI: 10.1016/j.jare.2025.06.020
Hui Kong , Juanjuan Han , Liang Guo , Xin-an Zhang
Background
Bone metabolic diseases constitute a group of disorders characterized by abnormal alterations in bone mass and skeletal metabolism, often resulting from oxidative stress, nutritional deficiencies, and various other etiological factors. Post-translational modification (PTM), a critical mechanism of protein regulation, plays a pivotal role in the pathogenesis of bone metabolic diseases. While previous reviews have primarily focused on the individual regulatory functions of common PTMs, such as phosphorylation, methylation, and ubiquitination, they have largely overlooked the dynamic interactions and cross talk among different PTMs. In recent years, an increasing number of novel PTMs have been implicated in the progression of bone metabolic diseases; however, comprehensive analyses of their underlying mechanisms and interrelationships remain limited. Therefore, a systematic and updated review of the roles and interplay of PTMs in bone metabolic diseases is warranted.
Aim of review
This review systematically introduced the basic processes of different types of PTMs, including phosphorylation, methylation, ubiquitination, glycosylation, acetylation, SUMOylation, succinylation, palmitoylation, lactylation, ADP-ribosylation, sulfhydration, carbonylation, hydroxylation, citrullination, and farnesylation, and summarized underlying mechanisms and cross talks among these PTMs in regulating the development of bone metabolic diseases.
Key scientific concepts of review
This review focuses on three key concepts. First, it highlights PTMs that have been implicated in the pathological process of bone metabolic diseases. Second, it examines the regulatory mechanisms and cross talks among different PTMs in bone metabolic diseases. Third, it discusses how aberrant PTMs can disrupt bone metabolic homeostasis by regulating various signaling pathways, leading to cellular dysfunction involved in the onset and development of osteoarthritis, osteoporosis, osteosarcoma, and rheumatoid arthritis. Therefore, an in-depth study of the PTM mechanisms in bone metabolic diseases may facilitate the identification of novel regulatory targets and provide a theoretical foundation for the development of more effective therapeutic strategies.
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