Pub Date : 2025-02-19DOI: 10.1016/j.jare.2025.02.017
Zihe Qi, Juanjuan Cao, Jianghua Liu, Jian Chen, Shasha Chen, Luyao Zhang, Jingwen Xu, Di Wu, Yongning Wu, Guoliang Li
Introduction
Alzheimer’s disease (AD) is the primary cause of dementia and is emerging as a global threat to human health. Increased availability of processed food is identified as a crucial environmental risk factor underlying the prevalence of Alzheimer’s disease. Carbon polymers (CPs), as neo-formed substances and ubiquitous in thermally processed foods, the relationship between them and AD onset is remains unclear.
Objectives
The effect of CPs on AD onset was examined and the toxicological mechanisms of prolonged exposure to CPs derived from thermal processed foods on AD progression were comprehensively investigated using a scopolamine-induced neuroinflammatory cell models and the transgenic APPswe/PSEN1dE9 (APP/PS1) AD mouse.
Methods
The CPs were extracted from thermally processed foods and the effects of CPs exposure on oxidative stress in neuroinflammatory cells were evaluated using scopolamine-induced PC12 cells as a neuroinflammation model. Furthermore, APP/PS1 AD mice were used to validate the potential adverse impacts of prolonged exposure to CPs on AD progression through the Morris water maze and open field test. In addition, histopathological examination, including immunofluorescence, immunohistochemistry, Nissl staining, and H&E, of the brain tissue in AD mice after chronic CPs treatment was performed to elucidate the underlying risk of dietary exposure to CPs on AD progression.
Results
Exposure to CPs enhanced oxidative damage in neuroinflammatory cells, as demonstrated by impaired mitochondrial function and activated NF-κB/MAPK signaling pathways. Further results from electron spin resonance substantiated the catalytic properties of CPs, which accelerated oxidative damage through promoting free radical generation. Using transgenic AD mice model, our findings also demonstrated that prolonged CPs exposure aggravated AD-associated pathology, as evidenced by increased amyloid-beta deposition and glial cell activation, ultimately accelerating cognitive decline.
Conclusion
These findings provide compelling evidence of the potential health risks associated with long-term dietary exposure to CPs and provide insight into the relationship between foodborne risk factors and neurodegenerative diseases.
{"title":"Toxicological mechanisms of carbon polymers in accelerating cognitive decline in Alzheimer’s disease","authors":"Zihe Qi, Juanjuan Cao, Jianghua Liu, Jian Chen, Shasha Chen, Luyao Zhang, Jingwen Xu, Di Wu, Yongning Wu, Guoliang Li","doi":"10.1016/j.jare.2025.02.017","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.017","url":null,"abstract":"<h3>Introduction</h3>Alzheimer’s disease (AD) is the primary cause of dementia and is emerging as a global threat to human health. Increased availability of processed food is identified as a crucial environmental risk factor underlying the prevalence of Alzheimer’s disease. Carbon polymers (CPs), as neo-formed substances and ubiquitous in thermally processed foods, the relationship between them and AD onset is remains unclear.<h3>Objectives</h3>The effect of CPs on AD onset was examined and the toxicological mechanisms of prolonged exposure to CPs derived from thermal processed foods on AD progression were comprehensively investigated using a scopolamine-induced neuroinflammatory cell models and the transgenic APPswe/PSEN1dE9 (APP/PS1) AD mouse.<h3>Methods</h3>The CPs were extracted from thermally processed foods and the effects of CPs exposure on oxidative stress in neuroinflammatory cells were evaluated using scopolamine-induced PC12 cells as a neuroinflammation model. Furthermore, APP/PS1 AD mice were used to validate the potential adverse impacts of prolonged exposure to CPs on AD progression through the Morris water maze and open field test. In addition, histopathological examination, including immunofluorescence, immunohistochemistry, Nissl staining, and H&E, of the brain tissue in AD mice after chronic CPs treatment was performed to elucidate the underlying risk of dietary exposure to CPs on AD progression.<h3>Results</h3>Exposure to CPs enhanced oxidative damage in neuroinflammatory cells, as demonstrated by impaired mitochondrial function and activated NF-κB/MAPK signaling pathways. Further results from electron spin resonance substantiated the catalytic properties of CPs, which accelerated oxidative damage through promoting free radical generation. Using transgenic AD mice model, our findings also demonstrated that prolonged CPs exposure aggravated AD-associated pathology, as evidenced by increased amyloid-beta deposition and glial cell activation, ultimately accelerating cognitive decline.<h3>Conclusion</h3>These findings provide compelling evidence of the potential health risks associated with long-term dietary exposure to CPs and provide insight into the relationship between foodborne risk factors and neurodegenerative diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"89 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451710","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}
<h3>Introduction</h3>Hepatocellular carcinoma (HCC) is an extremely heterogeneous malignancy with a poor prognosis, highlighting the need to target specific vulnerabilities within the tumor during treatment.<h3>Objectives</h3>This study employs multi-omics analysis techniques to provide novel insights into personalized therapeutic strategies for HCC patients.<h3>Methods</h3>We performed proteomic and transcriptomic sequencing on 178 and 94 clinical samples of primary HCC without prior treatment, respectively. We employed an unbiased Kinome CRISPR-Cas9 library screening approach to systematically evaluate and identify novel therapeutic strategies that specifically target replication stress (RS). The synergy between oxaliplatin and adavosertib was verified using in vitro and in vivo models, including hydrodynamic injection, patient-derived organoids, and patient-derived xenografts.<h3>Results</h3>In both proteomic- and transcriptomic-based subtyping analyses, subtypes characterized by hyperproliferative features demonstrated the poorest prognosis and the highest levels of RS. Among all first-line chemotherapeutic agents in these analyses, oxaliplatin accumulated the highest RS levels in HCC, while resistance remained a major challenge. With unbiased Kinome CRISPR loss-of-function gene screening, WEE1 was identified as a synthetic lethal target of oxaliplatin. The synergy between the WEE1 inhibitor adavosertib and oxaliplatin has been demonstrated in multiple in vitro and in vivo models. Mechanistically, adavosertib inhibits oxaliplatin-induced homologous recombination repair and G2/M checkpoint activation, leading to the accumulation of lethal DNA damage. Furthermore, patients with HCC showing high RS levels had poor prognoses and responded well to adavosertib and oxaliplatin combination treatments. This was validated by preclinical models and unsupervised clustering analysis.<h3>Conclusions</h3>Our findings provide promising insights into the precise therapeutic targeting of RS in HCC at both the proteomic and transcriptomic levels. Furthermore, our study highlights the potential of combining oxaliplatin with adavosertib as a treatment approach for HCC.In this study, we analyzed 178 and 94 pairs of clinical HCC samples using proteomic and transcriptomic sequencing, respectively. We discovered that the subtype characterized by high proliferation had the worst prognosis and highest RS level. Drug screening revealed that oxaliplatin promotes RS accumulation in HCC, but its resistance remains a challenge. Through unbiased CRISPR deletion-gene screening, WEE1 was identified as a lethal target of oxaliplatin. The WEE1 inhibitor adavosertib inhibits oxaliplatin-induced DNA repair, leading to lethal DNA damage accumulation. Furthermore, our clustering analysis based on RS levels demonstrated that HCC patients with high RS levels have poorer prognoses and be more beneficial from adavosertib and oxaliplatin combination therapy. These findings support an ind
{"title":"Comprehensive multi-omics analyses exposes a precision therapy strategy that targets replication stress in hepatocellular carcinoma using WEE1 inhibition","authors":"Xing Jia, Xingxin Zhu, Shinuo Chen, Qiongzi Qiu, Wenfeng Song, Shiyu Zhang, Haijiang Dong, Zequn Li, Suchen Bian, Hao Wu, Haojiang Dai, Cheng Jin, Mengqiao Zhou, Chen Jun, Zefeng Xuan, Pengfei Liu, Qiufang Zeng, Haiyang Xie, Shusen Zheng, Penghong Song","doi":"10.1016/j.jare.2025.02.016","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.016","url":null,"abstract":"<h3>Introduction</h3>Hepatocellular carcinoma (HCC) is an extremely heterogeneous malignancy with a poor prognosis, highlighting the need to target specific vulnerabilities within the tumor during treatment.<h3>Objectives</h3>This study employs multi-omics analysis techniques to provide novel insights into personalized therapeutic strategies for HCC patients.<h3>Methods</h3>We performed proteomic and transcriptomic sequencing on 178 and 94 clinical samples of primary HCC without prior treatment, respectively. We employed an unbiased Kinome CRISPR-Cas9 library screening approach to systematically evaluate and identify novel therapeutic strategies that specifically target replication stress (RS). The synergy between oxaliplatin and adavosertib was verified using in vitro and in vivo models, including hydrodynamic injection, patient-derived organoids, and patient-derived xenografts.<h3>Results</h3>In both proteomic- and transcriptomic-based subtyping analyses, subtypes characterized by hyperproliferative features demonstrated the poorest prognosis and the highest levels of RS. Among all first-line chemotherapeutic agents in these analyses, oxaliplatin accumulated the highest RS levels in HCC, while resistance remained a major challenge. With unbiased Kinome CRISPR loss-of-function gene screening, WEE1 was identified as a synthetic lethal target of oxaliplatin. The synergy between the WEE1 inhibitor adavosertib and oxaliplatin has been demonstrated in multiple in vitro and in vivo models. Mechanistically, adavosertib inhibits oxaliplatin-induced homologous recombination repair and G2/M checkpoint activation, leading to the accumulation of lethal DNA damage. Furthermore, patients with HCC showing high RS levels had poor prognoses and responded well to adavosertib and oxaliplatin combination treatments. This was validated by preclinical models and unsupervised clustering analysis.<h3>Conclusions</h3>Our findings provide promising insights into the precise therapeutic targeting of RS in HCC at both the proteomic and transcriptomic levels. Furthermore, our study highlights the potential of combining oxaliplatin with adavosertib as a treatment approach for HCC.In this study, we analyzed 178 and 94 pairs of clinical HCC samples using proteomic and transcriptomic sequencing, respectively. We discovered that the subtype characterized by high proliferation had the worst prognosis and highest RS level. Drug screening revealed that oxaliplatin promotes RS accumulation in HCC, but its resistance remains a challenge. Through unbiased CRISPR deletion-gene screening, WEE1 was identified as a lethal target of oxaliplatin. The WEE1 inhibitor adavosertib inhibits oxaliplatin-induced DNA repair, leading to lethal DNA damage accumulation. Furthermore, our clustering analysis based on RS levels demonstrated that HCC patients with high RS levels have poorer prognoses and be more beneficial from adavosertib and oxaliplatin combination therapy. These findings support an ind","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"17 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451829","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 : 2025-02-17DOI: 10.1016/j.jare.2025.02.022
Mi Wu, Zhiyong Xu, Chao Fu, Nian Wang, Ruiting Zhang, Yu Le, Meilin Chen, Ningyu Yang, Yuanxue Li, Xianlong Zhang, Ximei Li, Zhongxu Lin
Introduction
Fiber strength is a critical determinant of fiber quality, with stronger fibers being highly preferred in the cotton textile industry. However, the genetic basis and the specific regulatory mechanism underlying the formation of cotton fiber strength remain largely unknown.
Objectives
To explore fiber strength-related genes, QTL mapping, map-based cloning, and gene function verification were conducted in a backcross inbred line BS41 derived from interspecific hybridization between upland cotton and sea-island cotton.
Methods
Upland cotton Emian22 (E22) and an interspecific backcross inbred line (BIL) BS41 were used as parents to construct secondary segregation populations for BSA and QTL mapping of fiber strength. The candidate gene GbNTL9 was identified through map-based cloning and expression analysis. The function of NTL9 was determined through transgenic experiments and cytological observations. The regulatory mechanisms of NTL9 were explored using RNA-seq, RT-qPCR, yeast two-hybrid, bimolecular fluorescence complementation, and yeast one-hybrid.
Results
A major QTL for fiber strength, qFS-A11-1, was mapped to a 14.6-kb genomic region using segregating populations from E22 × BS41. GbNTL9, which encodes a NAC transcription factor, was identified as the candidate gene. Overexpression of both upland cotton genotype NTL9E22 and sea-island genotype NTL9BS41 in upland cotton enhanced fiber strength by facilitating the dense accumulation and orderly organization of cellulose microfibrils within the cell wall. Transcriptomic analysis revealed that NTL9 inhibited the expression of genes involved in secondary wall synthesis, such as CESA4, CESA7, and CESA8, thereby delaying cell wall cellulose deposition and altering the microfibril deposition pattern. NTL9 interacted with MYB6 and functioned as a downstream gene in the ethylene signaling pathway. Additionally, an effective gene marker NTL9-24 was developed to distinguish haplotypes from G. barbadense and G. hirsutum for fiber quality breeding program.
Conclusion
Our findings demonstrate that GbNTL9 positively regulates fiber strength through altering the microfibril deposition pattern, and provide a new insight into the molecular mechanism underlying fiber strength.
{"title":"NAC transcription factor GbNTL9 modifies the accumulation and organization of cellulose microfibrils to enhance cotton fiber strength","authors":"Mi Wu, Zhiyong Xu, Chao Fu, Nian Wang, Ruiting Zhang, Yu Le, Meilin Chen, Ningyu Yang, Yuanxue Li, Xianlong Zhang, Ximei Li, Zhongxu Lin","doi":"10.1016/j.jare.2025.02.022","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.022","url":null,"abstract":"<h3>Introduction</h3>Fiber strength is a critical determinant of fiber quality, with stronger fibers being highly preferred in the cotton textile industry. However, the genetic basis and the specific regulatory mechanism underlying the formation of cotton fiber strength remain largely unknown.<h3>Objectives</h3>To explore fiber strength-related genes, QTL mapping, map-based cloning, and gene function verification were conducted in a backcross inbred line BS41 derived from interspecific hybridization between upland cotton and sea-island cotton.<h3>Methods</h3>Upland cotton Emian22 (E22) and an interspecific backcross inbred line (BIL) BS41 were used as parents to construct secondary segregation populations for BSA and QTL mapping of fiber strength. The candidate gene <em>GbNTL9</em> was identified through map-based cloning and expression analysis. The function of <em>NTL9</em> was determined through transgenic experiments and cytological observations. The regulatory mechanisms of <em>NTL9</em> were explored using RNA-seq, RT-qPCR, yeast two-hybrid, bimolecular fluorescence complementation, and yeast one-hybrid.<h3>Results</h3>A major QTL for fiber strength, <em>qFS-A11-1</em>, was mapped to a 14.6-kb genomic region using segregating populations from E22 × BS41. <em>GbNTL9</em>, which encodes a NAC transcription factor, was identified as the candidate gene. Overexpression of both upland cotton genotype <em>NTL9</em><sup>E22</sup> and sea-island genotype <em>NTL9</em><sup>BS41</sup> in upland cotton enhanced fiber strength by facilitating the dense accumulation and orderly organization of cellulose microfibrils within the cell wall. Transcriptomic analysis revealed that <em>NTL9</em> inhibited the expression of genes involved in secondary wall synthesis, such as <em>CESA4</em>, <em>CESA7</em>, and <em>CESA8</em>, thereby delaying cell wall cellulose deposition and altering the microfibril deposition pattern. NTL9 interacted with MYB6 and functioned as a downstream gene in the ethylene signaling pathway. Additionally, an effective gene marker NTL9-24 was developed to distinguish haplotypes from <em>G. barbadense</em> and <em>G. hirsutum</em> for fiber quality breeding program.<h3>Conclusion</h3>Our findings demonstrate that <em>GbNTL9</em> positively regulates fiber strength through altering the microfibril deposition pattern, and provide a new insight into the molecular mechanism underlying fiber strength.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435792","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 : 2025-02-16DOI: 10.1016/j.jare.2025.02.021
Aristo Vojdani, Abbas F. Almulla, Elroy Vojdani, Jing Li, Yingqian Zhang, Michael Maes
Background
The pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is linked to autoimmune attacks against myelin proteins, and reactivation of Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). However, the connection between viral reactivation and autoimmune biomarkers has remained unclear.
Objectives
To investigate immunoglobulin (Ig)G/IgA/IgM responses targeting myelin-related proteins in association with EBV and HHV-6 replication markers in RRMS.
Methods
We recruited 55 patients with RRMS and 63 healthy controls and assessed IgG/IgA/IgM responses against seven myelin-related components, as well as EBV nuclear antigen 1 (EBNA-1) and deoxyuridine-triphosphate nucleotidohydrolase (dUTPases). Disability was evaluated using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS).
Results
IgG/IgA/IgM levels targeting seven myelin-related proteins were significantly higher in RRMS than in controls. IgG against myelin basic protein (MBP) (IgG-MBP), IgM-myelin-associated glycoprotein (IgM-MAG)-37–60, IgA-MBP, and IgA-myelin-oligodendrocyte-glycoprotein (IgA-MOG-31–55) distinguished RRMS from controls with a predictive accuracy of 96.6 % (sensitivity = 95.7 %, specificity = 95.2 %) and an area under the ROC curve of 0.991. A large part of the variance in the EDSS (around 75 %) and MSSS score (62.8 %) was explained by IgG-MBP, IgM-MBP, IgA-MOG-31–55, and IgM-MAG. Part of the variance (47.4 %) in the IgG/IgA/IgM responses to myelin-related proteins was explained by immune responses to EBNA and dUTPases of EBV and HHV-6.
Conclusions
Autoimmune reactivities targeting myelin-related proteins are valuable biomarkers of RRMS and the severity and progression of RRMS. Reactivation of EBV and HHV-6 may trigger or maintain these autoimmune responses thereby impacting disease progression.
{"title":"Autoimmune responses to myelin-associated proteins as diagnostic and prognostic biomarkers of relapsing-remitting multiple sclerosis: Associations with human herpesvirus-6 and Epstein-Barr virus reactivation","authors":"Aristo Vojdani, Abbas F. Almulla, Elroy Vojdani, Jing Li, Yingqian Zhang, Michael Maes","doi":"10.1016/j.jare.2025.02.021","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.021","url":null,"abstract":"<h3>Background</h3>The pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is linked to autoimmune attacks against myelin proteins, and reactivation of Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). However, the connection between viral reactivation and autoimmune biomarkers has remained unclear.<h3>Objectives</h3>To investigate immunoglobulin (Ig)G/IgA/IgM responses targeting myelin-related proteins in association with EBV and HHV-6 replication markers in RRMS.<h3>Methods</h3>We recruited 55 patients with RRMS and 63 healthy controls and assessed IgG/IgA/IgM responses against seven myelin-related components, as well as EBV nuclear antigen 1 (EBNA-1) and deoxyuridine-triphosphate nucleotidohydrolase (dUTPases). Disability was evaluated using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS).<h3>Results</h3>IgG/IgA/IgM levels targeting seven myelin-related proteins were significantly higher in RRMS than in controls. IgG against myelin basic protein (MBP) (IgG-MBP), IgM-myelin-associated glycoprotein (IgM-MAG)-37–60, IgA-MBP, and IgA-myelin-oligodendrocyte-glycoprotein (IgA-MOG-31–55) distinguished RRMS from controls with a predictive accuracy of 96.6 % (sensitivity = 95.7 %, specificity = 95.2 %) and an area under the ROC curve of 0.991. A large part of the variance in the EDSS (around 75 %) and MSSS score (62.8 %) was explained by IgG-MBP, IgM-MBP, IgA-MOG-31–55, and IgM-MAG. Part of the variance (47.4 %) in the IgG/IgA/IgM responses to myelin-related proteins was explained by immune responses to EBNA and dUTPases of EBV and HHV-6.<h3>Conclusions</h3>Autoimmune reactivities targeting myelin-related proteins are valuable biomarkers of RRMS and the severity and progression of RRMS. Reactivation of EBV and HHV-6 may trigger or maintain these autoimmune responses thereby impacting disease progression.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"21 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427342","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 : 2025-02-16DOI: 10.1016/j.jare.2025.02.020
Ying Yang, Lulu Song, Liping Yu, Jinping Zhang, Bo Zhang
Aims
To investigate the role and potential mechanisms of H4K12 lactylation modifications in diabetes-related cognitive impairment (DACD).
Methods
Behavioral tests, HE staining, and immunohistochemistry were employed to assess cognitive function and the extent of brain tissue injury. Metabolomics and proteomics were applied to profile the metabolic regulatory network. We measured lactic acid and Pan-Kla levels in the brains of T2DM mice and high glucose-treated microglia. CUT&Tag technology was utilized to identify genes regulated by H4K12la. Small interfering RNA (siRNA) sequences and adeno-associated viruses (AAVs) were used to knock down key components in signaling pathways, evaluating the impact of histone lactylation on microglial polarization.
Results
Lactic acid levels were significantly higher in the brains of T2DM mice and high glucose-treated microglia compared to controls, leading to an increase in pan histone lysine lactylation (Kla). We found that lactate directly induced an increase in H4K12la. CUT&Tag analysis revealed that elevated H4K12la activates the FOXO1/PGC-1α signaling pathway by enhancing binding to the FOXO1 promoter, promoting mitochondrial oxidative stress.
Conclusion
This study demonstrated that elevated H4K12la directly activates the FOXO1 signaling pathway, promoting oxidative stress and contributing to DACD phenotypes.
{"title":"H4K12 lactylation potentiates mitochondrial oxidative stress via the Foxo1 pathway in diabetes-induced cognitive impairment","authors":"Ying Yang, Lulu Song, Liping Yu, Jinping Zhang, Bo Zhang","doi":"10.1016/j.jare.2025.02.020","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.020","url":null,"abstract":"<h3>Aims</h3>To investigate the role and potential mechanisms of H4K12 lactylation modifications in diabetes-related cognitive impairment (DACD).<h3>Methods</h3>Behavioral tests, HE staining, and immunohistochemistry were employed to assess cognitive function and the extent of brain tissue injury. Metabolomics and proteomics were applied to profile the metabolic regulatory network. We measured lactic acid and Pan-Kla levels in the brains of T2DM mice and high glucose-treated microglia. CUT&Tag technology was utilized to identify genes regulated by H4K12la. Small interfering RNA (siRNA) sequences and adeno-associated viruses (AAVs) were used to knock down key components in signaling pathways, evaluating the impact of histone lactylation on microglial polarization.<h3>Results</h3>Lactic acid levels were significantly higher in the brains of T2DM mice and high glucose-treated microglia compared to controls, leading to an increase in pan histone lysine lactylation (Kla). We found that lactate directly induced an increase in H4K12la. CUT&Tag analysis revealed that elevated H4K12la activates the FOXO1/PGC-1α signaling pathway by enhancing binding to the FOXO1 promoter, promoting mitochondrial oxidative stress.<h3>Conclusion</h3>This study demonstrated that elevated H4K12la directly activates the FOXO1 signaling pathway, promoting oxidative stress and contributing to DACD phenotypes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"136 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427341","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 : 2025-02-15DOI: 10.1016/j.jare.2025.02.018
Juan Li, Mengjuan Xuan, Li Yang, Yingru Liu, Na Lou, Leiya Fu, Qingmiao Shi, Chen Xue
Introduction
Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.
Objectives
This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.
Methods
Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.
Results
Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206+CD73+ M2-like macrophages and PDL1-CD39-CCR2+ neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP+NGP+CD177+ phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP+NGP+CD177+ neutrophils, altering intercellular communication within the septic liver immune microenvironment.
Conclusion
This study demonstrated TPPU’s protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.
{"title":"Comprehensive single-cell analysis deciphered the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury","authors":"Juan Li, Mengjuan Xuan, Li Yang, Yingru Liu, Na Lou, Leiya Fu, Qingmiao Shi, Chen Xue","doi":"10.1016/j.jare.2025.02.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.018","url":null,"abstract":"<h3>Introduction</h3>Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.<h3>Objectives</h3>This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.<h3>Methods</h3>Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.<h3>Results</h3>Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206<sup>+</sup>CD73<sup>+</sup> M2-like macrophages and PDL1<sup>-</sup>CD39<sup>-</sup>CCR2<sup>+</sup> neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP<sup>+</sup>NGP<sup>+</sup>CD177<sup>+</sup> phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP<sup>+</sup>NGP<sup>+</sup>CD177<sup>+</sup> neutrophils, altering intercellular communication within the septic liver immune microenvironment.<h3>Conclusion</h3>This study demonstrated TPPU’s protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"24 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418165","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}
Accumulating evidence suggest that imbalanced macronutrient composition would increase the risk of chronic diseases. However, previous studies that predominantly focused on individual macronutrients often failed to thoroughly elucidate this complex association.
Objectives
This study aimed to comprehensively analyze the relationship between macronutrient clusters and all-cause mortality.
Methods
The study included 26,615 adults aged 20–75 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. A three-dimensional cube method was employed to categorize clusters of macronutrients intake. The association between dietary macronutrient clusters and all-cause mortality was investigated using Cox proportional hazards modeling and restricted cubic spline (RCS) analysis.
Results
Over a weighted median follow-up duration of 7.58 years, 3,998 deaths were recorded. After adjusting for potential confounders, compared with the reference Cluster Pm:Fm:Cmh, 4 specific Clusters were associated with reduced all-cause mortality: Cluster Pm:Fm:Cm (HR: 0.79, 95 % CI: 0.67–0.92), Cluster Pm:Fmh:Cml (HR: 0.76, 95 % CI: 0.61–0.95), Cluster Pm:Fmh:Cm (HR: 0.86, 95 % CI: 0.75–0.97), and Cluster Pl:Fm:Cmh (HR: 0.73, 95 % CI: 0.60–0.89). Three-node RCS analysis revealed non-linear relationships between carbohydrate within Cluster Pm:Fm:Cm and protein within Cluster Pl:Fm:Cmh and overall mortality. Subgroup and sensitivity analyses corroborated the robustness of these associations across different age, gender, and energy intake levels.
Conclusions
This study employed a three-dimensional cube approach to categorize the human macronutrients intake into 24 clusters. Cluster Pm:Fm:Cm, Clusters Pm:Fmh:Cml, Cluster Pm:Fmh:Cm, and Cluster Pl:Fm:Cmh exhibited a lower mortality risk. Different clusters of macronutrients could be a precondition in nutrition intervene strategy.
{"title":"Specific Macronutrient clusters associated with lower mortality Risk: Evidence from NHANES 1999–2018","authors":"Jiaying Yu, Yang Chen, Defang Li, Lan Zhang, Yuting Zhang, Jiaqi Zhang, Jiayu Zhu, Zican Li, Hongxin Fu, Dongwei Guan, Runan Zhang, Liyan Liu, Cheng Wang, Changhao Sun, Rennan Feng","doi":"10.1016/j.jare.2025.02.019","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.019","url":null,"abstract":"<h3>Introduction</h3>Accumulating evidence suggest that imbalanced macronutrient composition would increase the risk of chronic diseases. However, previous studies that predominantly focused on individual macronutrients often failed to thoroughly elucidate this complex association.<h3>Objectives</h3>This study aimed to comprehensively analyze the relationship between macronutrient clusters and all-cause mortality.<h3>Methods</h3>The study included 26,615 adults aged 20–75 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. A three-dimensional cube method was employed to categorize clusters of macronutrients intake. The association between dietary macronutrient clusters and all-cause mortality was investigated using Cox proportional hazards modeling and restricted cubic spline (RCS) analysis.<h3>Results</h3>Over a weighted median follow-up duration of 7.58 years, 3,998 deaths were recorded. After adjusting for potential confounders, compared with the reference Cluster <sub>Pm:Fm:Cmh</sub>, 4 specific Clusters were associated with reduced all-cause mortality: Cluster <sub>Pm:Fm:Cm</sub> (HR: 0.79, 95 % CI: 0.67–0.92), Cluster <sub>Pm:Fmh:Cml</sub> (HR: 0.76, 95 % CI: 0.61–0.95), Cluster <sub>Pm:Fmh:Cm</sub> (HR: 0.86, 95 % CI: 0.75–0.97), and Cluster <sub>Pl:Fm:Cmh</sub> (HR: 0.73, 95 % CI: 0.60–0.89). Three-node RCS analysis revealed non-linear relationships between carbohydrate within Cluster <sub>Pm:Fm:Cm</sub> and protein within Cluster <sub>Pl:Fm:Cmh</sub> and overall mortality. Subgroup and sensitivity analyses corroborated the robustness of these associations across different age, gender, and energy intake levels.<h3>Conclusions</h3>This study employed a three-dimensional cube approach to categorize the human macronutrients intake into 24 clusters. Cluster <sub>Pm:Fm:Cm</sub>, Clusters <sub>Pm:Fmh:Cml</sub>, Cluster <sub>Pm:Fmh:Cm</sub>, and Cluster <sub>Pl:Fm:Cmh</sub> exhibited a lower mortality risk. Different clusters of macronutrients could be a precondition in nutrition intervene strategy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"24 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418203","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 : 2025-02-13DOI: 10.1016/j.jare.2025.02.005
Ximing Yang, Siyi Wang, Hanxiong Liu, Tuo Zhang, Shuzhen Cheng, Ming Du
Zinc deficiency is a global health issue that impairs immune function, growth, and energy metabolism. Although conventional zinc supplements have been developed, their effectiveness is limited by poor bioavailability and susceptibility to dietary inhibitors. In this study, a peptide-zinc complex (IE-Zn) derived from oysters was developed to enhance zinc uptake and address metabolic disruptions caused by deficiency. It was determined that Zn2+ binds with high affinity to the IE peptide, promoting structural flexibility that facilitates zinc transport through both zinc ion transporters and oligopeptide transporters. In Caco-2 and IEC-6 cell models, IE-Zn was shown to significantly improve zinc absorption and retention compared to ZnSO4, driven by the upregulation of ZIP4 and PEPT1 transporters. In vivo studies in a zinc-deficient mouse model confirmed enhanced zinc absorption and distribution across serum, intestine, and liver. Moreover, IE-Zn restored energy homeostasis by activating the AMPK/PGC1-α/NRF-1/TFAM signaling pathway, promoting mitochondrial biogenesis and reducing oxidative stress. These findings suggest that IE-Zn is a superior zinc supplement with higher bioavailability and serves as a potent regulator of cellular energy metabolism, offering therapeutic potential for managing conditions related to zinc deficiency and mitochondrial dysfunction. This study lays the foundation for further exploration of peptide-mineral complexes as advanced nutritional supplements with broad applications. Subsequent studies will further investigate the absorption pathway and targeting of peptide-zinc complex. The hope is to provide potential preventive applications for people in need, including zinc deficiency and a range of diseases caused by zinc deficiency.
{"title":"A dual absorption pathway of novel oyster-derived peptide-zinc complex enhances zinc bioavailability and restores mitochondrial function","authors":"Ximing Yang, Siyi Wang, Hanxiong Liu, Tuo Zhang, Shuzhen Cheng, Ming Du","doi":"10.1016/j.jare.2025.02.005","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.005","url":null,"abstract":"Zinc deficiency is a global health issue that impairs immune function, growth, and energy metabolism. Although conventional zinc supplements have been developed, their effectiveness is limited by poor bioavailability and susceptibility to dietary inhibitors. In this study, a peptide-zinc complex (IE-Zn) derived from oysters was developed to enhance zinc uptake and address metabolic disruptions caused by deficiency. It was determined that Zn<sup>2+</sup> binds with high affinity to the IE peptide, promoting structural flexibility that facilitates zinc transport through both zinc ion transporters and oligopeptide transporters. In Caco-2 and IEC-6 cell models, IE-Zn was shown to significantly improve zinc absorption and retention compared to ZnSO<sub>4</sub>, driven by the upregulation of ZIP4 and PEPT1 transporters. <em>In vivo</em> studies in a zinc-deficient mouse model confirmed enhanced zinc absorption and distribution across serum, intestine, and liver. Moreover, IE-Zn restored energy homeostasis by activating the AMPK/PGC1-α/NRF-1/TFAM signaling pathway, promoting mitochondrial biogenesis and reducing oxidative stress. These findings suggest that IE-Zn is a superior zinc supplement with higher bioavailability and serves as a potent regulator of cellular energy metabolism, offering therapeutic potential for managing conditions related to zinc deficiency and mitochondrial dysfunction. This study lays the foundation for further exploration of peptide-mineral complexes as advanced nutritional supplements with broad applications. Subsequent studies will further investigate the absorption pathway and targeting of peptide-zinc complex. The hope is to provide potential preventive applications for people in need, including zinc deficiency and a range of diseases caused by zinc deficiency.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"21 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401281","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 : 2025-02-12DOI: 10.1016/j.jare.2025.02.013
Wei Yang, Ying Xu, Shuai Liu, Lin Gao, Shi Li, Xina Xie, Qiaoxia Zhang, Obaid Habib, Ronglin Chen, Xiongfei Sun, Zesong Li
Background
Despite notable advancements in AML therapy in recent years, a substantial proportion of patients remain refractory or at high risk of recurrence with limited efficacy. Therefore, it’s urgent to develop novel drugs for treating AML.
Methods
The small molecule drug library was utilized to screen for drugs that elicit the inflammatory death of AML cells. Cell viability, cell morphological analysis, western blotting, and RNA-seq were used to determine the pathway of Mebendazole (MBD)-induced AML cell death. Cell cycle analysis, protein expression profiling, molecular docking, western blotting and lentivirus overexpression were used to analyze the target protein of MBD in AML cells. The anti-AML activity of MBD in vivo was evaluated using tumor xenograft models constructed by AML cell lines and patient-derived primary AML cells.
Results
In this study, we have identified Mebendazole (MBD), a conventional anthelmintic drug known for its low toxicity and cost, as a potent agent that exerts significant anti-AML effects in vitro. Furthermore, we have observed its inhibitory effects on the invasion of AML cell lines and primary AML cells in xenograft mouse models, while noting its negligible toxic side effects in normal mice in vivo. Mechanically, MBD inhibits the cell cycle in G2/M phase by inhibiting tubulin α1A (TUBA1A) and promotes ZBP-1 mediated PANoptosis in AML cells. Our results confirm that MBD exerts anti-AML activity in preclinical models.
Conclusion
These results highlight the remarkable clinical translational potential of MBD, providing new potential medicine for AML patients. In addition, TUBA1A can be used potential novel therapeutic target in tumors with abnormal TUBA1A expression.
{"title":"Mebendazole induces ZBP-1 mediated PANoptosis of acute myeloid leukemia cells by targeting TUBA1A and exerts antileukemia effect","authors":"Wei Yang, Ying Xu, Shuai Liu, Lin Gao, Shi Li, Xina Xie, Qiaoxia Zhang, Obaid Habib, Ronglin Chen, Xiongfei Sun, Zesong Li","doi":"10.1016/j.jare.2025.02.013","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.013","url":null,"abstract":"<h3>Background</h3>Despite notable advancements in AML therapy in recent years, a substantial proportion of patients remain refractory or at high risk of recurrence with limited efficacy. Therefore, it’s urgent to develop novel drugs for treating AML.<h3>Methods</h3>The small molecule drug library was utilized to screen for drugs that elicit the inflammatory death of AML cells. Cell viability, cell morphological analysis, western blotting, and RNA-seq were used to determine the pathway of Mebendazole (MBD)-induced AML cell death. Cell cycle analysis, protein expression profiling, molecular docking, western blotting and lentivirus overexpression were used to analyze the target protein of MBD in AML cells. The anti-AML activity of MBD <em>in vivo</em> was evaluated using tumor xenograft models constructed by AML cell lines and patient-derived primary AML cells.<h3>Results</h3>In this study, we have identified Mebendazole (MBD), a conventional anthelmintic drug known for its low toxicity and cost, as a potent agent that exerts significant anti-AML effects <em>in vitro</em>. Furthermore, we have observed its inhibitory effects on the invasion of AML cell lines and primary AML cells in xenograft mouse models, while noting its negligible toxic side effects in normal mice <em>in vivo</em>. Mechanically, MBD inhibits the cell cycle in G2/M phase by inhibiting tubulin α1A (TUBA1A) and promotes ZBP-1 mediated PANoptosis in AML cells. Our results confirm that MBD exerts anti-AML activity in preclinical models.<h3>Conclusion</h3>These results highlight the remarkable clinical translational potential of MBD, providing new potential medicine for AML patients. In addition, TUBA1A can be used potential novel therapeutic target in tumors with abnormal TUBA1A expression.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"17 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401279","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 : 2025-02-12DOI: 10.1016/j.jare.2025.02.012
Nikita Basnet, Hyunkyung Cho, Arjun Sapkota, Seungbae Park, Chaemin Lim, Bhakta Prasad Gaire, Donghee Kim, Joo-Youn Lee, Jae Hui Been, Seunghee Lee, Bong Yong Lee, Ji Woong Choi, Sanghee Kim
Introduction
The functions of S1P receptors have been revealed using genetic and pharmacological tools, including the potent non-selective modulator FTY720. However, studies on subtype-specific agonists and antagonists are limited; hence, the role of S1P4 remains unclear.
Objectives
To identify a novel function of S1P4 as a pathogenic factor in stroke using a newly developed S1P4-selective modulator and S1P4 knockdown.
Methods
Heteroaromatic analogs of FTY720 were synthesized, a β-arrestin assay was conducted against S1P receptors, and the developed compound (NXC736) was characterized as a functional S1P4 antagonist. To clarify the function of S1P4, the therapeutic potential of NXC736 in ischemic stroke was determined using a transient middle cerebral artery occlusion (tMCAO) mouse model, which was validated using S1P4 knockdown. The S1P4-dependent pathogenic mechanisms were determined using immunohistochemical and biochemical analyses.
Results
Molecular modeling studies provide valuable clues for understanding S1P4 selectivity of NXC736. NXC736 contains a triazole ring instead of a phenyl ring and exhibits S1P4-selective activity as a functional antagonist. Its action on S1P4 does not require phosphorylation by sphingosine kinase 2. Notably, NXC736 exhibited substantial therapeutic activity against ischemic stroke by attenuating tMCAO-induced acute brain injuries, including brain infarction, neurological deficits, and neuronal apoptosis. This suggested that S1P4 is a pathogenic factor in ischemic stroke. This function was confirmed using AAV-based S1P4 knockdown. NXC736 or S1P4 knockdown attenuated blood–brain barrier disruption, neutrophil infiltration, microglial activation and proliferation, and the upregulation of pro-inflammatory cytokines, thereby demonstrating that S1P4 influences neuroinflammatory responses in ischemic stroke. The underlying mechanisms were activation of NLRP3 inflammasome, NF-κB, and MAPKs. S1P4 also contributed to chronic brain injuries caused by ischemic stroke because NXC736 exerted long-term neuroprotective effects against tMCAO challenge.
Conclusion
Using a functional S1P4 antagonist (NXC736) and a genetic tool for S1P4 knockdown, we identified S1P4 as a novel pathogenic factor in ischemic stroke.
{"title":"Blocking S1P4 signaling attenuates brain injury in mice with ischemic stroke","authors":"Nikita Basnet, Hyunkyung Cho, Arjun Sapkota, Seungbae Park, Chaemin Lim, Bhakta Prasad Gaire, Donghee Kim, Joo-Youn Lee, Jae Hui Been, Seunghee Lee, Bong Yong Lee, Ji Woong Choi, Sanghee Kim","doi":"10.1016/j.jare.2025.02.012","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.012","url":null,"abstract":"<h3>Introduction</h3>The functions of S1P receptors have been revealed using genetic and pharmacological tools, including the potent non-selective modulator FTY720. However, studies on subtype-specific agonists and antagonists are limited; hence, the role of S1P<sub>4</sub> remains unclear.<h3>Objectives</h3>To identify a novel function of S1P<sub>4</sub> as a pathogenic factor in stroke using a newly developed S1P<sub>4</sub>-selective modulator and S1P<sub>4</sub> knockdown.<h3>Methods</h3>Heteroaromatic analogs of FTY720 were synthesized, a β-arrestin assay was conducted against S1P receptors, and the developed compound (NXC736) was characterized as a functional S1P<sub>4</sub> antagonist. To clarify the function of S1P<sub>4</sub>, the therapeutic potential of NXC736 in ischemic stroke was determined using a transient middle cerebral artery occlusion (tMCAO) mouse model, which was validated using S1P<sub>4</sub> knockdown. The S1P<sub>4</sub>-dependent pathogenic mechanisms were determined using immunohistochemical and biochemical analyses.<h3>Results</h3>Molecular modeling studies provide valuable clues for understanding S1P<sub>4</sub> selectivity of NXC736. NXC736 contains a triazole ring instead of a phenyl ring and exhibits S1P<sub>4</sub>-selective activity as a functional antagonist. Its action on S1P<sub>4</sub> does not require phosphorylation by sphingosine kinase 2. Notably, NXC736 exhibited substantial therapeutic activity against ischemic stroke by attenuating tMCAO-induced acute brain injuries, including brain infarction, neurological deficits, and neuronal apoptosis. This suggested that S1P<sub>4</sub> is a pathogenic factor in ischemic stroke. This function was confirmed using AAV-based S1P<sub>4</sub> knockdown. NXC736 or S1P<sub>4</sub> knockdown attenuated blood–brain barrier disruption, neutrophil infiltration, microglial activation and proliferation, and the upregulation of pro-inflammatory cytokines, thereby demonstrating that S1P<sub>4</sub> influences neuroinflammatory responses in ischemic stroke. The underlying mechanisms were activation of NLRP3 inflammasome, NF-κB, and MAPKs. S1P<sub>4</sub> also contributed to chronic brain injuries caused by ischemic stroke because NXC736 exerted long-term neuroprotective effects against tMCAO challenge.<h3>Conclusion</h3>Using a functional S1P<sub>4</sub> antagonist (NXC736) and a genetic tool for S1P<sub>4</sub> knockdown, we identified S1P<sub>4</sub> as a novel pathogenic factor in ischemic stroke.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"132 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393647","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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