Pub Date : 2025-11-17DOI: 10.1016/j.jare.2025.11.029
Xiaxuan Huang, Cun Li, Piaorong Zeng, Yitong Ling, Shanyuan Tan, Zihong Bai, Si Shen, Shengting Chen, Biao Nie, Hao Wang, Jun Lyu
Background
Non-traditional lipid parameters demonstrate cardiovascular predictive value, yet their interaction with inflammatory markers in stroke risk assessment remains understudied. This research investigated their independent and combined effects on stroke risk in a nationally representative cohort, while comparing their predictive capability with traditional lipid parameters.
Methods
The study cohort comprised 9,236 individuals aged ≥45 years, derived from the China Health and Retirement Longitudinal Study (CHARLS), with self-reported stroke as the primary outcome. Non-traditional lipid parameters were combined with High-sensitivity C-reactive protein (hs-CRP) to create lipid-inflammatory indices. Cox proportional hazards models and restricted cubic spline regression assessed stroke risk associations. Mediation analysis examined relationships between hs-CRP, lipid parameters, and stroke.
Results
During the 7-year follow-up, 664 participants developed stroke. The incidence of stroke increased with increasing quartiles of non-traditional lipid parameters. In fully adjusted models, participants with higher baseline and cumulative levels of non-traditional lipid parameters had the highest risk of stroke, with consistent results across non-traditional lipid inflammation parameters, especially in AIP-CRP (HR = 1.98, 95 % CI: 1.56–2.50). Non-traditional lipid inflammation parameters showed better predictive ability compared with individual parameters, and the results remained robust in subgroup and sensitivity analyses. Mediation analysis established bidirectional mediating effects between non-traditional lipid parameters, hs-CRP, and stroke risk.
Conclusions
Non-traditional lipid parameters are significantly associated with increased stroke risk in middle-aged and older Chinese adults, with combined lipid-inflammatory markers demonstrating superior predictive value. These findings underscore the importance of integrating both non-traditional lipid parameters and inflammatory markers for comprehensive stroke risk assessment.
{"title":"Non-traditional lipid-inflammatory parameters estimate the risk of stroke in middle-aged and older Chinese adults: a nationwide prospective cohort study","authors":"Xiaxuan Huang, Cun Li, Piaorong Zeng, Yitong Ling, Shanyuan Tan, Zihong Bai, Si Shen, Shengting Chen, Biao Nie, Hao Wang, Jun Lyu","doi":"10.1016/j.jare.2025.11.029","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.029","url":null,"abstract":"<h3>Background</h3>Non-traditional lipid parameters demonstrate cardiovascular predictive value, yet their interaction with inflammatory markers in stroke risk assessment remains understudied. This research investigated their independent and combined effects on stroke risk in a nationally representative cohort, while comparing their predictive capability with traditional lipid parameters.<h3>Methods</h3>The study cohort comprised 9,236 individuals aged ≥45 years, derived from the China Health and Retirement Longitudinal Study (CHARLS), with self-reported stroke as the primary outcome. Non-traditional lipid parameters were combined with High-sensitivity C-reactive protein (hs-CRP) to create lipid-inflammatory indices. Cox proportional hazards models and restricted cubic spline regression assessed stroke risk associations. Mediation analysis examined relationships between hs-CRP, lipid parameters, and stroke.<h3>Results</h3>During the 7-year follow-up, 664 participants developed stroke. The incidence of stroke increased with increasing quartiles of non-traditional lipid parameters. In fully adjusted models, participants with higher baseline and cumulative levels of non-traditional lipid parameters had the highest risk of stroke, with consistent results across non-traditional lipid inflammation parameters, especially in AIP-CRP (HR = 1.98, 95 % CI: 1.56–2.50). Non-traditional lipid inflammation parameters showed better predictive ability compared with individual parameters, and the results remained robust in subgroup and sensitivity analyses. Mediation analysis established bidirectional mediating effects between non-traditional lipid parameters, hs-CRP, and stroke risk.<h3>Conclusions</h3>Non-traditional lipid parameters are significantly associated with increased stroke risk in middle-aged and older Chinese adults, with combined lipid-inflammatory markers demonstrating superior predictive value. These findings underscore the importance of integrating both non-traditional lipid parameters and inflammatory markers for comprehensive stroke risk assessment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"7 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531898","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}
Cervical carcinoma (CC) mortality remains high due to chemoresistance. Targeting glycolytic reprogramming is promising since CC cells depend on enhanced glycolysis for proliferation and chemoresistance. However, clinical translation faces two barriers: the lack of spatially resolved validation of glycolytic vulnerability in CC specimens, and absence of CC-specific delivery systems for lonidamine (LND), a potent glycolytic inhibitor with poor bioavailability and hepatotoxicity.
Objectives
Here, we aim to establish spatially resolved validation of tumor-associated glycolytic reprogramming and identify differentially enriched receptors within malignant regions in clinical CC specimens. Leveraging these findings, we will design a tumor-targeted nanoplatform for the precise delivery of a glycolytic inhibitor to CC cells, to achieve tumor suppression and reverse chemoresistance.
Methods
Spatial metabolomics and spatial transcriptomics analyses were employed to validate tumor-associated glycolytic reprogramming and identify specifically overexpressed receptors within malignant regions of clinical CC specimens.
Results
Through spatial multi-omics analysis, we demonstrated upregulated glycolysis in malignant regions of CC and identified solute carrier family 1 member 5 (ASCT2), a glutamine transporter, as a superior CC-specific surface marker compared to the pan-cancer nanocarrier targets like CD44. These findings were corroborated through multi-platform validation spanning single-cell RNA-seq dataset, TCGA cohorts, paired patient specimens, matched murine samples, and multiple CC cell lines. In this context, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression to enable CC-selective accumulation of LND. Our findings reveal that this nanoagonist significantly impedes CC growth by disrupting ATP supply and inducing ROS-mediated cellular damage. Moreover, this nanoagonist effectively reverses cisplatin (DDP)-induced chemoresistance in CC by inhibiting MRP2-mediated DDP efflux and blocking ribose-5-phosphate-mediated DNA repair.
Conclusion
By integrating spatial multi-omics with rational nanocarrier design, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression for tumor-selective accumulation of LND. Our findings revealed that this nanoagonist achieves significant CC suppression and chemoresistance reversal.
{"title":"Spatial multi-omics guides ASCT2-targeted delivery of glycolysis inhibitor for cervical cancer suppression and chemoresistance reversal","authors":"Xiaojiao Li, Xiangchuan Qin, Xiejun Zhao, Yufeng Liu, Ling Wang, Kefeng Li, Jinqiu Li, Jia Ma, Liangliang Dai, Ayshamgul Hasim","doi":"10.1016/j.jare.2025.11.035","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.035","url":null,"abstract":"<h3>Introduction</h3>Cervical carcinoma (CC) mortality remains high due to chemoresistance. Targeting glycolytic reprogramming is promising since CC cells depend on enhanced glycolysis for proliferation and chemoresistance. However, clinical translation faces two barriers: the lack of spatially resolved validation of glycolytic vulnerability in CC specimens, and absence of CC-specific delivery systems for lonidamine (LND), a potent glycolytic inhibitor with poor bioavailability and hepatotoxicity.<h3>Objectives</h3>Here, we aim to establish spatially resolved validation of tumor-associated glycolytic reprogramming and identify differentially enriched receptors within malignant regions in clinical CC specimens. Leveraging these findings, we will design a tumor-targeted nanoplatform for the precise delivery of a glycolytic inhibitor to CC cells, to achieve tumor suppression and reverse chemoresistance.<h3>Methods</h3>Spatial metabolomics and spatial transcriptomics analyses were employed to validate tumor-associated glycolytic reprogramming and identify specifically overexpressed receptors within malignant regions of clinical CC specimens.<h3>Results</h3>Through spatial multi-omics analysis, we demonstrated upregulated glycolysis in malignant regions of CC and identified solute carrier family 1 member 5 (ASCT2), a glutamine transporter, as a superior CC-specific surface marker compared to the pan-cancer nanocarrier targets like CD44. These findings were corroborated through multi-platform validation spanning single-cell RNA-seq dataset, TCGA cohorts, paired patient specimens, matched murine samples, and multiple CC cell lines. In this context, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression to enable CC-selective accumulation of LND. Our findings reveal that this nanoagonist significantly impedes CC growth by disrupting ATP supply and inducing ROS-mediated cellular damage. Moreover, this nanoagonist effectively reverses cisplatin (DDP)-induced chemoresistance in CC by inhibiting MRP2-mediated DDP efflux and blocking ribose-5-phosphate-mediated DNA repair.<h3>Conclusion</h3>By integrating spatial multi-omics with rational nanocarrier design, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression for tumor-selective accumulation of LND. Our findings revealed that this nanoagonist achieves significant CC suppression and chemoresistance reversal.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"7 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525247","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 : 2025-11-16DOI: 10.1016/j.jare.2025.11.034
Li Ding, Jia-Ying Xu, Li-Li Zhang, Yan Liu, Kai-Tian Gu, Yan-Zi Liang, Khemayanto Hidayat, Zhongxiao Wan, Guo-Chong Chen, Li-Qiang Qin
Introduction
Lactoferrin (LF), a multifunctional glycoprotein, has been implicated in the regulation of glucose and lipid metabolism.
Objectives and methods
This study employed in vivo and in vitro models to investigate the direct effects of LF on non-alcoholic steatohepatitis (NASH) and to elucidate its underlying mechanisms.
Results
LF intervention alleviated hepatic lipid metabolic disorders and liver injury in high-fat, high-cholesterol cholate-containing diet (HFCCD)-fed mice by mitigating oxidative stress, suppressing the inflammatory cGAS/STING pathway, and reducing M1 proinflammatory macrophage polarization. These effects were validated in free fatty acid (FFA)-treated HepG2 cells and AML12 cells. Furthermore, LF ameliorated HFCCD-induced gut microbiota dysbiosis and increased short-chain fatty acid levels. The critical role of gut microbiota in mediating the hepatoprotective effects of LF was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation. Mechanistically, LF modulated gut-liver serotonin signaling and promoted fatty acid β-oxidation through the HTR2A-PPARα-CPT-1A pathway, an effect abolished by the HTR2A agonist DOI. In a co-culture system, LF treatment of the Caco-2/HT29 monolayer alleviated lipid accumulation and regulated the HTR2A-PPARα-CPT-1A pathway in FFA-treated HepG2 cells.
Conclusions
These findings indicate that LF attenuates NASH by remodeling gut microbiota to modulate microbiota-derived serotonin signaling and enhance fatty acid oxidation.
{"title":"Lactoferrin alleviates non-alcoholic steatohepatitis via remodeling gut microbiota to regulate serotonin-related pathways","authors":"Li Ding, Jia-Ying Xu, Li-Li Zhang, Yan Liu, Kai-Tian Gu, Yan-Zi Liang, Khemayanto Hidayat, Zhongxiao Wan, Guo-Chong Chen, Li-Qiang Qin","doi":"10.1016/j.jare.2025.11.034","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.034","url":null,"abstract":"<h3>Introduction</h3>Lactoferrin (LF), a multifunctional glycoprotein, has been implicated in the regulation of glucose and lipid metabolism.<h3>Objectives and methods</h3>This study employed in vivo and in vitro models to investigate the direct effects of LF on non-alcoholic steatohepatitis (NASH) and to elucidate its underlying mechanisms.<h3>Results</h3>LF intervention alleviated hepatic lipid metabolic disorders and liver injury in high-fat, high-cholesterol cholate-containing diet (HFCCD)-fed mice by mitigating oxidative stress, suppressing the inflammatory cGAS/STING pathway, and reducing M1 proinflammatory macrophage polarization. These effects were validated in free fatty acid (FFA)-treated HepG2 cells and AML12 cells. Furthermore, LF ameliorated HFCCD-induced gut microbiota dysbiosis and increased short-chain fatty acid levels. The critical role of gut microbiota in mediating the hepatoprotective effects of LF was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation. Mechanistically, LF modulated gut-liver serotonin signaling and promoted fatty acid β-oxidation through the HTR2A-PPARα-CPT-1A pathway, an effect abolished by the HTR2A agonist DOI. In a co-culture system, LF treatment of the Caco-2/HT29 monolayer alleviated lipid accumulation and regulated the HTR2A-PPARα-CPT-1A pathway in FFA-treated HepG2 cells.<h3>Conclusions</h3>These findings indicate that LF attenuates NASH by remodeling gut microbiota to modulate microbiota-derived serotonin signaling and enhance fatty acid oxidation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"120 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531900","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 : 2025-11-16DOI: 10.1016/j.jare.2025.11.024
Shao-Ji Li, Chun-Min Yang, Shiyi Ou
Background
Trichothecenes are a family of structurally related mycotoxins typically found in cereal crops, thus threatening the health of human digestive tract. In colonic epithelial cells (CECs), trichothecenes inhibit protein synthesis and cell proliferation, induce oxidative stress, DNA damage, ribotoxic stress response (RSR), endoplasmic reticulum stress (ERS), unfolded protein response (UPR), inflammation, and apoptosis, destruct cell junctions, and alter mucus composition. Although recent studies have enhanced the understanding on the molecular mechanisms of these toxic effects, interconnections between these toxic effects were poorly established.
Aim of review
This review comprehensively summarizes the influence of trichothecenes on CECs. This review emphasizes the elucidation of molecular mechanisms and signaling pathways underlying trichothecene toxicity, in an attempt to integrate diverse toxic effects into a unified mechanistic framework.
Key scientific concepts of review
Trichothecenes inhibit protein synthesis by binding to the ribosomal A-site, thus triggering ribotoxic stress response to activate MAPKs via PKR or ZAKα. Trichothecenes induce ERS and UPR, mediated by PERK/eIF2/ATF4 and Ire1α/XBP1 signaling, which potentially activate CHOP, MAPKs, p53, and NF-κB. Trichothecenes disturb the mitochondrial electron transport chain to overproduce ROS, further activating NF-κB. Trichothecenes induce nitric oxide overproduction via inducible nitric oxide synthase, which is transcriptionally activated by NF-κB. Trichothecenes may cause DNA damage by direct interaction or by oxidative stress, thereby activating ATM/p53 signaling. Trichothecenes modulate inflammation via MAPKs, NF-κB, JAK/STAT, and UPR pathways. The cytotoxicity of trichothecenes depends on molecular structure, exposure dose, and cell differentiation status. Trichothecenes suppress cell proliferation via Wnt and/or JAK/STAT pathways, and induce apoptosis via mitochondrial and Fas pathways by regulating p53, CHOP, and BCL-2 family proteins. Trichothecenes impair epithelial integrity by reducing cell junction proteins through MAPK, Wnt and JAK/STAT pathways, and by inhibiting tight junction assembly through inactivating PKA. Trichothecenes reduce mucin production through MAPKs and IRE1β signaling
{"title":"Impacts of trichothecene mycotoxins on human colonic epithelial cells: molecular mechanisms and signaling pathways","authors":"Shao-Ji Li, Chun-Min Yang, Shiyi Ou","doi":"10.1016/j.jare.2025.11.024","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.024","url":null,"abstract":"<h3>Background</h3>Trichothecenes are a family of structurally related mycotoxins typically found in cereal crops, thus threatening the health of human digestive tract. In colonic epithelial cells (CECs), trichothecenes inhibit protein synthesis and cell proliferation, induce oxidative stress, DNA damage, ribotoxic stress response (RSR), endoplasmic reticulum stress (ERS), unfolded protein response (UPR), inflammation, and apoptosis, destruct cell junctions, and alter mucus composition. Although recent studies have enhanced the understanding on the molecular mechanisms of these toxic effects, interconnections between these toxic effects were poorly established.<h3>Aim of review</h3>This review comprehensively summarizes the influence of trichothecenes on CECs. This review emphasizes the elucidation of molecular mechanisms and signaling pathways underlying trichothecene toxicity, in an attempt to integrate diverse toxic effects into a unified mechanistic framework.<h3>Key scientific concepts of review</h3>Trichothecenes inhibit protein synthesis by binding to the ribosomal A-site, thus triggering ribotoxic stress response to activate MAPKs via PKR or ZAKα. Trichothecenes induce ERS and UPR, mediated by PERK/eIF2/ATF4 and Ire1α/XBP1 signaling, which potentially activate CHOP, MAPKs, p53, and NF-κB. Trichothecenes disturb the mitochondrial electron transport chain to overproduce ROS, further activating NF-κB. Trichothecenes induce nitric oxide overproduction via inducible nitric oxide synthase, which is transcriptionally activated by NF-κB. Trichothecenes may cause DNA damage by direct interaction or by oxidative stress, thereby activating ATM/p53 signaling. Trichothecenes modulate inflammation via MAPKs, NF-κB, JAK/STAT, and UPR pathways. The cytotoxicity of trichothecenes depends on molecular structure, exposure dose, and cell differentiation status. Trichothecenes suppress cell proliferation via Wnt and/or JAK/STAT pathways, and induce apoptosis via mitochondrial and Fas pathways by regulating p53, CHOP, and BCL-2 family proteins. Trichothecenes impair epithelial integrity by reducing cell junction proteins through MAPK, Wnt and JAK/STAT pathways, and by inhibiting tight junction assembly through inactivating PKA. Trichothecenes reduce mucin production through MAPKs and IRE1β signaling","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"62 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531507","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}
Olaparib resistance limits its therapeutic efficacy in triple-negative breast cancer (TNBC). Exploring the mechanisms underlying olaparib resistance and developing combination strategies are of great clinical significance for improving the long-term therapeutic benefit in TNBC.
Objectives
This study aimed to determine whether ZUP1 is associated with olaparib resistance in TNBC patients and to elucidate the underlying mechanisms involved.
Methods
We established an olaparib-resistant TNBC cell model and integrated transcriptomic profiling with public datasets to DUBs linked to resistance. Candidate function was assessed by drug sensitivity assay, clonogenic assay, apoptosis assay, HR/NHEJ reporter assays and comet assays. Mechanistic studies used co-immunoprecipitation, chromatin fractionation, and PARylation assays. In vitro co-culture assays and flow cytometry analysis were used to evaluated immune infiltration. High-throughput virtual screening (HTVS), biolayer interferometry (BLI), and deubiquitination assays nominated small molecule inhibitors and assessed therapeutic synergy with olaparib.
Results
We identified ZUP1, a recently uncovered deubiquitinase, as significantly upregulated in TNBC patients who did not respond to olaparib. Mechanistically, ZUP1 stabilized PARP1 by removing its polyubiquitin chains at lysine 425, resulting in increased PARylation and enhanced chromatin retention of SSRP1 and SPT16, thereby promoting DNA repair. ZUP1 deficiency significantly increased olaparib-induced DNA damage, facilitates cytosolic dsDNA release to activate STING signalling, and enhanced CD8+T cell infiltration into tumors. High-throughput virtual screening identified procyanidin C1 as a potential ZUP1 inhibitor. Combination treatment with procyanidin C1 and olaparib significantly suppressed tumor growth in olaparib −resistant TNBC models.
Conclusion
ZUP1 facilitates olaparib resistance in TNBC by stabilizing PARP1 and enhancing DNA damage repair. Pharmacological inhibition of ZUP1 with procyanidin C1 represents a promising therapeutic strategy to overcome olaparib resistance in TNBC.
{"title":"ZUP1 promotes DNA repair and immune evasion to drive olaparib resistance in triple-negative breast cancer","authors":"Shanshan Huang, Yu Qiu, Linyu Wu, Yi Xie, Zhiting He, Yingqing Li, Xinhua Xie","doi":"10.1016/j.jare.2025.11.038","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.038","url":null,"abstract":"<h3>Introduction</h3>Olaparib resistance limits its therapeutic efficacy in triple-negative breast cancer (TNBC). Exploring the mechanisms underlying olaparib resistance and developing combination strategies are of great clinical significance for improving the long-term therapeutic benefit in TNBC.<h3>Objectives</h3>This study aimed to determine whether ZUP1 is associated with olaparib resistance in TNBC patients and to elucidate the underlying mechanisms involved.<h3>Methods</h3>We established an olaparib-resistant TNBC cell model and integrated transcriptomic profiling with public datasets to DUBs linked to resistance. Candidate function was assessed by drug sensitivity assay, clonogenic assay, apoptosis assay, HR/NHEJ reporter assays and comet assays. Mechanistic studies used co-immunoprecipitation, chromatin fractionation, and PARylation assays. In vitro co-culture assays and flow cytometry analysis were used to evaluated immune infiltration. High-throughput virtual screening (HTVS), biolayer interferometry (BLI), and deubiquitination assays nominated small molecule inhibitors and assessed therapeutic synergy with olaparib.<h3>Results</h3>We identified ZUP1, a recently uncovered deubiquitinase, as significantly upregulated in TNBC patients who did not respond to olaparib. Mechanistically, ZUP1 stabilized PARP1 by removing its polyubiquitin chains at lysine 425, resulting in increased PARylation and enhanced chromatin retention of SSRP1 and SPT16, thereby promoting DNA repair. ZUP1 deficiency significantly increased olaparib-induced DNA damage, facilitates cytosolic dsDNA release to activate STING signalling, and enhanced CD8<sup>+</sup>T cell infiltration into tumors. High-throughput virtual screening identified procyanidin C1 as a potential ZUP1 inhibitor. Combination treatment with procyanidin C1 and olaparib significantly suppressed tumor growth in olaparib −resistant TNBC models.<h3>Conclusion</h3>ZUP1 facilitates olaparib resistance in TNBC by stabilizing PARP1 and enhancing DNA damage repair. Pharmacological inhibition of ZUP1 with procyanidin C1 represents a promising therapeutic strategy to overcome olaparib resistance in TNBC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"50 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531901","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}
Bone marrow mesenchymal stem cells (BMSCs) are a critical cell type for stem cell-based bone regenerative therapy. Promoting osteogenic differentiation of BMSCs is important for the promotion of bone formation. Interferon regulatory factor 1 (IRF1) was discovered as an essential factor in immune responses and the differentiation of several cell lines. Nevertheless, the potential of IRF1 as a therapeutic target for the modulation of BMSCs in the context of bone regeneration strategies remains unexplored. Here, we investigated the role of IRF1 in BMSC fate determination and demonstrated IRF1 as a promising target for osteoporosis.
Methods
Irf1-overexpressing and Irf1-knockdown murine BMSCs (mBMSCs) were established by plasmid and lentivirus transfection, and the expression efficiency was verified. The role of IRF1 in regulating the proliferation, migration, apoptosis, and osteogenic differentiation of mBMSCs in vitro was investigated using gain- and loss-of-function experiments. In addition, Irf1-overexpressing mBMSCs were implanted subcutaneously with scaffold material into the backs of nude mice to evaluate the ectopic osteogenesis capability in vivo. Irf1-overexpressing mBMSCs were injected into the tail vein of ovariectomized and aging-related osteoporosis mouse models to evaluate their therapeutic effects. In addition, the underlying mechanisms were explored by RNA sequencing and validated through real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting (WB) analysis.
Results
Overexpression of Irf1 promoted the proliferation, migration, and osteogenic differentiation of mBMSCs, and suppressed apoptosis in vitro, while Irf1 knockdown had the opposite effects. Irf1-overexpressing mBMSCs also promoted ectopic bone formation and alleviated osteoporosis compared to controls in vivo. IRF1 may regulate the fate of mBMSCs through activation of the PI3K/AKT signaling pathway.
Conclusion
This study suggested that overexpression of Irf1 promotes osteogenic differentiation of BMSCs and has a therapeutic effect on osteoporosis. IRF1 could play dual roles as a biomarker for bone formation and a target for osteoporosis treatment.
{"title":"IRF1 regulates apoptosis and osteogenic differentiation of bone marrow mesenchymal stem cells and ameliorates osteoporosis by activating the PI3K/AKT signaling pathway","authors":"Menglong Hu, Erfan Wei, Likun Wu, Xingtong Pan, Qiyue Zhu, Xiuyun Xu, Xinyi Dong, Weiliang Wu, Hao Liu, Yunsong Liu","doi":"10.1016/j.jare.2025.11.037","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.037","url":null,"abstract":"<h3>Background</h3>Bone marrow mesenchymal stem cells (BMSCs) are a critical cell type for stem cell-based bone regenerative therapy. Promoting osteogenic differentiation of BMSCs is important for the promotion of bone formation. Interferon regulatory factor 1 (IRF1) was discovered as an essential factor in immune responses and the differentiation of several cell lines. Nevertheless, the potential of IRF1 as a therapeutic target for the modulation of BMSCs in the context of bone regeneration strategies remains unexplored. Here, we investigated the role of IRF1 in BMSC fate determination and demonstrated IRF1 as a promising target for osteoporosis.<h3>Methods</h3><em>Irf1</em>-overexpressing and <em>Irf1</em>-knockdown murine BMSCs (mBMSCs) were established by plasmid and lentivirus transfection, and the expression efficiency was verified. The role of IRF1 in regulating the proliferation, migration, apoptosis, and osteogenic differentiation of mBMSCs <em>in vitro</em> was investigated using gain- and loss-of-function experiments. In addition, <em>Irf1</em>-overexpressing mBMSCs were implanted subcutaneously with scaffold material into the backs of nude mice to evaluate the ectopic osteogenesis capability <em>in vivo</em>. <em>Irf1</em>-overexpressing mBMSCs were injected into the tail vein of ovariectomized and aging-related osteoporosis mouse models to evaluate their therapeutic effects. In addition, the underlying mechanisms were explored by RNA sequencing and validated through real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting (WB) analysis.<h3>Results</h3>Overexpression of <em>Irf1</em> promoted the proliferation, migration, and osteogenic differentiation of mBMSCs, and suppressed apoptosis <em>in vitro</em>, while <em>Irf1</em> knockdown had the opposite effects. <em>Irf1</em>-overexpressing mBMSCs also promoted ectopic bone formation and alleviated osteoporosis compared to controls <em>in vivo</em>. IRF1 may regulate the fate of mBMSCs through activation of the PI3K/AKT signaling pathway.<h3>Conclusion</h3>This study suggested that overexpression of <em>Irf1</em> promotes osteogenic differentiation of BMSCs and has a therapeutic effect on osteoporosis. IRF1 could play dual roles as a biomarker for bone formation and a target for osteoporosis treatment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"19 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531902","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 : 2025-11-16DOI: 10.1016/j.jare.2025.11.020
Zihan Wang, Le Luo Guan, Jianping Wu
Introduction
The bioactive peptide IRW lowers blood pressure in spontaneously hypertensive rats (SHRs) by upregulating angiotensin-converting enzyme 2 (ACE2), but the underlying mechanisms remain unclear.
Objectives
This study aimed to elucidate the mechanisms underlying IRW-mediated ACE2 upregulation through integrated transcriptomic and metabolomic analyses.
Methods
Mesenteric arteries from IRW-treated SHRs underwent transcriptomic and metabolomic analyses. Weighted gene co-expression network analysis (WGCNA) and transcription factor prediction were performed to identify ACE2-associated regulators. Subsequent validation was conducted both in vitro with EA.hy926 endothelial cells and in vivo via receptor blocker infusion in SHRs.
Results
WGCNA of transcriptomic data identified 651 genes co-expressed with ACE2, including 17 predicted transcription factors, notably nuclear receptor 4A1 (Nr4a1). Metabolomic analysis revealed a significant increase in dopamine after IRW treatment, and its abundance correlated with ACE2 expression. Ingenuity pathway analysis indicated that dopamine may activate Nr4a1 via the dopamine D1 receptor (D1R). In vitro, dopamine (1 μM) upregulated protein levels of ACE2 and Nr4a1, effects blocked by the D1R antagonist SCH23390 (10 μM). Additionally, Nr4a1 knockdown reduced dopamine-induced ACE2 upregulation. In SHRs, D1R blockade abolished IRW’s antihypertensive effects and ACE2 upregulation.
Conclusion
IRW-driven ACE2 upregulation in vivo relies on the dopamine/D1R signaling pathway, highlighting the therapeutic potential of this pathway for ACE2-related conditions.
{"title":"Peptide IRW upregulates ACE2 in spontaneously hypertensive rats via dopamine/D1R signaling pathway","authors":"Zihan Wang, Le Luo Guan, Jianping Wu","doi":"10.1016/j.jare.2025.11.020","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.020","url":null,"abstract":"<h3>Introduction</h3>The bioactive peptide IRW lowers blood pressure in spontaneously hypertensive rats (SHRs) by upregulating angiotensin-converting enzyme 2 (ACE2), but the underlying mechanisms remain unclear.<h3>Objectives</h3>This study aimed to elucidate the mechanisms underlying IRW-mediated ACE2 upregulation through integrated transcriptomic and metabolomic analyses.<h3>Methods</h3>Mesenteric arteries from IRW-treated SHRs underwent transcriptomic and metabolomic analyses. Weighted gene co-expression network analysis (WGCNA) and transcription factor prediction were performed to identify ACE2-associated regulators. Subsequent validation was conducted both <em>in vitro</em> with EA.hy926 endothelial cells and <em>in vivo</em> via receptor blocker infusion in SHRs.<h3>Results</h3>WGCNA of transcriptomic data identified 651 genes co-expressed with ACE2, including 17 predicted transcription factors, notably nuclear receptor 4A1 (Nr4a1). Metabolomic analysis revealed a significant increase in dopamine after IRW treatment, and its abundance correlated with ACE2 expression. Ingenuity pathway analysis indicated that dopamine may activate Nr4a1 via the dopamine D1 receptor (D1R). <em>In vitro</em>, dopamine (1 μM) upregulated protein levels of ACE2 and Nr4a1, effects blocked by the D1R antagonist SCH23390 (10 μM). Additionally, Nr4a1 knockdown reduced dopamine-induced ACE2 upregulation. In SHRs, D1R blockade abolished IRW’s antihypertensive effects and ACE2 upregulation.<h3>Conclusion</h3>IRW-driven ACE2 upregulation <em>in vivo</em> relies on the dopamine/D1R signaling pathway, highlighting the therapeutic potential of this pathway for ACE2-related conditions.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"4 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531506","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}
Glycyrrhetinic acid (GA) and its magnesium salt, magnesium isoglycyrrhizinate, exhibit promising anti-obesity effects through mechanisms that are not fully understood.
Objective
This study aims to investigate whether GA mitigated diet-induced obesity and white adipose tissue remodeling by enhancing lipid catabolism.
Methods
The high-fat diet (HFD)-induced obesity is utilized to investigate GA’s lipid-lowering effects. The changes in lipid catabolism are validated in vitro and in vivo through secretion rates of glycerol and free fatty acid (FFA), and immunoblotting of lipases. Mice receive GPCR-activation based sensor rAAV-EF1α-DIO-NE1h to visualize simultaneously the norepinephrine (NE) release in adipose tissue. Whole-mount immunostaining of monoamine oxidase A (MAOA) highlights the whole-3D imaging of intra-adipose macrophages location surrounding sympathetic nerve fibers. RNA sequencing (RNA-Seq) of sorted adipose tissue macrophages (ATMs) was used to study GA’s mechanisms in regulating obesity progression. And molecular docking identifies a targeting pattern of GA action, which is assayed by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS).
Results
GA indirectly promoted adipocyte lipolysis and thermogenesis by modulating catecholamine pathways. This modulation is facilitated by increased sympathetic innervation within adipose tissue and a reduction in the protein expression of MAOA, which degrades NE. In situ visualization of MAOA uncovered ATMs as key mediators of catecholamine degradation within adipose tissues. RNA-Seq of sorted ATMs identified that GA reduced pro-inflammatory shifts and altered macrophage polarity, thereby preventing activation of the Toll-like receptor 4 (TLR4) signaling pathway, as supported by molecular docking analysis and binding assays. Moreover, the anti-obesity effects of GA were abolished in TLR4-deficient mice, likely due to the dysfunction of mitophagy-dependent MAOA degradation in ATMs.
Conclusions
Our findings suggest that GA targets macrophage-sympathetic neuron crosstalk in adipose tissues, offering a promising therapeutic approach for obesity.
{"title":"Glycyrrhetinic acid augments lipid catabolism via immune-neural modulation in adipose tissue","authors":"Wenjiao Jiang, Sasa Zhang, Xinyuan Sun, Shun Wang, Jinwei Zhu, Ziao Liu, Wanting Zhang, Huijie Guo, Hanwen Li, Hao Xie, Kun Hao","doi":"10.1016/j.jare.2025.11.019","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.019","url":null,"abstract":"<h3>Introduction</h3>Glycyrrhetinic acid (GA) and its magnesium salt, magnesium isoglycyrrhizinate, exhibit promising anti-obesity effects through mechanisms that are not fully understood.<h3>Objective</h3>This study aims to investigate whether GA mitigated diet-induced obesity and white adipose tissue remodeling by enhancing lipid catabolism.<h3>Methods</h3>The high-fat diet (HFD)-induced obesity is utilized to investigate GA’s lipid-lowering effects. The changes in lipid catabolism are validated <em>in vitro</em> and <em>in vivo</em> through secretion rates of glycerol and free fatty acid (FFA), and immunoblotting of lipases. Mice receive GPCR-activation based sensor rAAV-EF1α-DIO-NE1h to visualize simultaneously the norepinephrine (NE) release in adipose tissue. Whole-mount immunostaining of monoamine oxidase A (MAOA) highlights the whole-3D imaging of intra-adipose macrophages location surrounding sympathetic nerve fibers. RNA sequencing (RNA-Seq) of sorted adipose tissue macrophages (ATMs) was used to study GA’s mechanisms in regulating obesity progression. And molecular docking identifies a targeting pattern of GA action, which is assayed by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS).<h3>Results</h3>GA indirectly promoted adipocyte lipolysis and thermogenesis by modulating catecholamine pathways. This modulation is facilitated by increased sympathetic innervation within adipose tissue and a reduction in the protein expression of MAOA, which degrades NE. <em>In situ</em> visualization of MAOA uncovered ATMs as key mediators of catecholamine degradation within adipose tissues. RNA-Seq of sorted ATMs identified that GA reduced pro-inflammatory shifts and altered macrophage polarity, thereby preventing activation of the Toll-like receptor 4 (TLR4) signaling pathway, as supported by molecular docking analysis and binding assays. Moreover, the anti-obesity effects of GA were abolished in TLR4-deficient mice, likely due to the dysfunction of mitophagy-dependent MAOA degradation in ATMs.<h3>Conclusions</h3>Our findings suggest that GA targets macrophage-sympathetic neuron crosstalk in adipose tissues, offering a promising therapeutic approach for obesity.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"30 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516145","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 : 2025-11-15DOI: 10.1016/j.jare.2025.11.018
Mingzhe Sun, Shihao Li, Yuan Liu, Fuhua Li
Introduction
The evolution of lymphoid organs is a complex topic in the animal kingdom. A presumptive invertebrate lymphoid organ (Oka) was previously reported in shrimp based on its morphological and histological observations. However, whether it truly functions as a lymphoid organ akin to those in vertebrates remains uncertain.
Objective
This study aims to characterize the cell composition of Oka at single-cell resolution and its function similarity with vertebrate lymphoid organs.
Methods
Single-nucleus RNA-seq and cross-species analysis were conducted to identify the major cell types in Oka of the whiteleg shrimp L. vannamei. The spatial expressions of the key genes were detected by in-situ hybridization and immunohistochemical analyses. Cytotoxic activity against heterologous cells was examined using fluorescence microscopy and flow cytometry.
Results
Oka comprised diverse cell types including ECM-producing cells, macrophage-like cells, lymphocyte precursor-like cells, capsular cells, hemocytes, SLC-rich cells, epithelial cells and progenitors. Notably, typical vertebrate macrophage markers (NLRP3, LAMP2 and LGMN) and ZAP-70, a marker of T lymphocytes/natural killer (NK) cells were expressed in the macrophage-like cells. The lymphocyte precursor-like cells, characterized by the expression of YBX3 and SOX4, were further distinguished by the up-regulated expression of CD39, CD49d, and CD133 homologues following WSSV infection. These two cell types were observed to migrate into the lymphoid organ spheroid during structural remodeling of the Oka following WSSV infection. Functionally, Oka cells of shrimp also exhibited cytotoxic activity against heterologous cells.
Conclusion
The presence and WSSV infection-induced aggregation of ZAP-70 positive cells in Oka of shrimp and its cytotoxic activity against heterologous cells suggest that shrimp Oka might perform similar function as the lymphoid organ in vertebrates. The present results will not only provide evidence to confirm the function of Oka in shrimp, but also greatly widen the knowledge about the origin and evolution of lymphoid organ in the animal kingdom
{"title":"Single-nucleus RNA sequencing illuminates a functional analog of lymphoid organ in crustacean","authors":"Mingzhe Sun, Shihao Li, Yuan Liu, Fuhua Li","doi":"10.1016/j.jare.2025.11.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.018","url":null,"abstract":"<h3>Introduction</h3>The evolution of lymphoid organs is a complex topic in the animal kingdom. A presumptive invertebrate lymphoid organ (Oka) was previously reported in shrimp based on its morphological and histological observations. However, whether it truly functions as a lymphoid organ akin to those in vertebrates remains uncertain.<h3>Objective</h3>This study aims to characterize the cell composition of Oka at single-cell resolution and its function similarity with vertebrate lymphoid organs.<h3>Methods</h3>Single-nucleus RNA-seq and cross-species analysis were conducted to identify the major cell types in Oka of the whiteleg shrimp <em>L. vannamei</em>. The spatial expressions of the key genes were detected by <em>in-situ</em> hybridization and immunohistochemical analyses. Cytotoxic activity against heterologous cells was examined using fluorescence microscopy and flow cytometry.<h3>Results</h3>Oka comprised diverse cell types including ECM-producing cells, macrophage-like cells, lymphocyte precursor-like cells, capsular cells, hemocytes, SLC-rich cells, epithelial cells and progenitors. Notably, typical vertebrate macrophage markers (NLRP3, LAMP2 and LGMN) and ZAP-70, a marker of T lymphocytes/natural killer (NK) cells were expressed in the macrophage-like cells. The lymphocyte precursor-like cells, characterized by the expression of YBX3 and SOX4, were further distinguished by the up-regulated expression of CD39, CD49d, and CD133 homologues following WSSV infection. These two cell types were observed to migrate into the lymphoid organ spheroid during structural remodeling of the Oka following WSSV infection. Functionally, Oka cells of shrimp also exhibited cytotoxic activity against heterologous cells.<h3>Conclusion</h3>The presence and WSSV infection-induced aggregation of ZAP-70 positive cells in Oka of shrimp and its cytotoxic activity against heterologous cells suggest that shrimp Oka might perform similar function as the lymphoid organ in vertebrates. The present results will not only provide evidence to confirm the function of Oka in shrimp, but also greatly widen the knowledge about the origin and evolution of lymphoid organ in the animal kingdom","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"11 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516144","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}
Increasing epidemiological studies suggested that maternal exposure to fine particulate matter (PM2.5) was associated with congenital heart defects (CHD) in fetuses, while the exact mechanisms were still unclear.
Objective
This study aimed to investigate PM2.5-induced effects on cardiac development and elucidate the implicated mechanisms.
Methods and results
In the present study, we first identified that angiopoietin-like 4 (ANGPTL4), sirtuin 3 (SIRT3), and D2-hydroxyglutarate (D2-HG) may be potential biomarkers for PM2.5-related cardiac defects in human umbilical cord serum samples. Moreover, in utero exposure to PM2.5 resulted in increased left ventricular wall thickness, mitochondrial dysfunction, and metabolic changes in the hearts of the offspring mice, while knockout of ANGPTL4 could attenuate PM2.5-induced pathological changes. Furthermore, in vitro investigations revealed that ANGPTL4 may directly bind to a mitochondria-located deacetylase SIRT3 and inhibit its deacetylation capacity. Reduced SIRT3 subsequently enhanced the acetylation of lon peptidase 1 (LONP1), a quality-control protease that was indispensable in maintaining mitochondrial function. More importantly, mitochondrial dysfunction caused by loss of LONP1 further reduced the expression of D2-hydroxyglutarate dehydrogenase (D2HGDH), which disrupted the conversion of D2HG to α-ketoglutarate (α-KG) and impeded energy generation in mitochondria.
Conclusion
These findings suggested that PM2.5 may impair cardiac development through ANGPTL4-mediated mitochondrial dysfunction, which provided a mechanistic basis for further investigation and prevention of PM2.5-related birth defects
{"title":"Gestational exposure to PM2.5 impaired cardiac development through ANGPTL4-mediated mitochondrial metabolic dysfunction","authors":"Jianong Lv, Ruiyang Ding, Chen Liang, Li Tian, Zhiru Liu, Shiqian liu, Zhiqin Xiong, Ruixia Liu, Zhiwei Sun, Chenghong Yin, Junchao Duan","doi":"10.1016/j.jare.2025.11.022","DOIUrl":"https://doi.org/10.1016/j.jare.2025.11.022","url":null,"abstract":"<h3>Introduction</h3>Increasing epidemiological studies suggested that maternal exposure to fine particulate matter (PM<sub>2.5</sub>) was associated with congenital heart defects (CHD) in fetuses, while the exact mechanisms were still unclear.<h3>Objective</h3>This study aimed to investigate PM<sub>2.5</sub>-induced effects on cardiac development and elucidate the implicated mechanisms.<h3>Methods and results</h3>In the present study, we first identified that angiopoietin-like 4 (ANGPTL4), sirtuin 3 (SIRT3), and D2-hydroxyglutarate (D2-HG) may be potential biomarkers for PM<sub>2.5</sub>-related cardiac defects in human umbilical cord serum samples. Moreover, in utero exposure to PM<sub>2.5</sub> resulted in increased left ventricular wall thickness, mitochondrial dysfunction, and metabolic changes in the hearts of the offspring mice, while knockout of <em>ANGPTL4</em> could attenuate PM<sub>2.5</sub>-induced pathological changes. Furthermore, <em>in vitro</em> investigations revealed that ANGPTL4 may directly bind to a mitochondria-located deacetylase SIRT3 and inhibit its deacetylation capacity. Reduced SIRT3 subsequently enhanced the acetylation of lon peptidase 1 (LONP1), a quality-control protease that was indispensable in maintaining mitochondrial function. More importantly, mitochondrial dysfunction caused by loss of LONP1 further reduced the expression of D2-hydroxyglutarate dehydrogenase (D2HGDH), which disrupted the conversion of D2HG to α-ketoglutarate (α-KG) and impeded energy generation in mitochondria.<h3>Conclusion</h3>These findings suggested that PM<sub>2.5</sub> may impair cardiac development through ANGPTL4-mediated mitochondrial dysfunction, which provided a mechanistic basis for further investigation and prevention of PM<sub>2.5</sub>-related birth defects","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"27 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525251","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}
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