Biochimica et biophysica acta. Molecular basis of disease最新文献_第7页

Platelets promote metastasis of intrahepatic cholangiocarcinoma through activation of TGF-β/Smad2 pathway

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-18 DOI: 10.1016/j.bbadis.2025.167734

Guijuan Luo , Shuyang Zhu , Liujie He , Qiang Liu , Chao Xu , Qinghua Yao , Heping Hu , Qiang Wang , Shanshan Zou

Intrahepatic cholangiocarcinoma (ICC), an aggressive liver cancer, lacks simple and accurate clinical tests, which poses challenges to postoperative diagnosis and treatment. Recent studies have indicated that platelet levels might be relevant to the postoperative prognosis of ICC. However, their prognostic significance in ICC remains unclarified. This study included 218 ICC patients who underwent hepatic resection. Comprehensive analyses of patients' postoperative prognosis were conducted primarily focusing on their platelet levels associated with prognostic traits. To further investigate the underlying mechanism between platelet levels and patients' postoperative prognosis, we elucidated the association between platelets and tumor metastasis using HCCC-9810 and HUCC-T1 cells as well as mouse models. In the retrospective cohort study, elevated serum platelet levels (≥300 × 10⁹/L) or tumoral platelet levels (≥0.23) individually indicated an unfavorable postoperative prognosis in individuals with ICC. Multivariate analysis showed that tumoral platelet levels can be an independent prognostic factor, while the loss of prognostic superiority of serum platelet levels in the analysis may be attributed to the influence of confounding inclusion variables. Epithelial/mesenchymal transition (EMT) marker expression changes in HCCC-9810 and HUCC-T1 cells with platelet treatment were analyzed to understand how platelets contribute to ICC malignant recurring progression. The significant role of the TGF-β/Smad2 pathway in ICC metastasis was identified. In addition, aspirin was found to have the potential to reduce ICC metastasis by inhibiting platelet function. In conclusion, this study indicated that ICC patients with postoperative serum platelet levels ≥300 × 10⁹/L or tumoral platelet levels ≥0.23 have significantly higher risk of poor postoperative prognosis. This is due to platelet-derived TGFβ1 leading to EMT in ICC cells, thus promoting tumor metastasis.

{"title":"Platelets promote metastasis of intrahepatic cholangiocarcinoma through activation of TGF-β/Smad2 pathway","authors":"Guijuan Luo , Shuyang Zhu , Liujie He , Qiang Liu , Chao Xu , Qinghua Yao , Heping Hu , Qiang Wang , Shanshan Zou","doi":"10.1016/j.bbadis.2025.167734","DOIUrl":"10.1016/j.bbadis.2025.167734","url":null,"abstract":"<div><div>Intrahepatic cholangiocarcinoma (ICC), an aggressive liver cancer, lacks simple and accurate clinical tests, which poses challenges to postoperative diagnosis and treatment. Recent studies have indicated that platelet levels might be relevant to the postoperative prognosis of ICC. However, their prognostic significance in ICC remains unclarified. This study included 218 ICC patients who underwent hepatic resection. Comprehensive analyses of patients' postoperative prognosis were conducted primarily focusing on their platelet levels associated with prognostic traits. To further investigate the underlying mechanism between platelet levels and patients' postoperative prognosis, we elucidated the association between platelets and tumor metastasis using HCCC-9810 and HUCC-T1 cells as well as mouse models. In the retrospective cohort study, elevated serum platelet levels (≥300 × 10<sup>9</sup>/L) or tumoral platelet levels (≥0.23) individually indicated an unfavorable postoperative prognosis in individuals with ICC. Multivariate analysis showed that tumoral platelet levels can be an independent prognostic factor, while the loss of prognostic superiority of serum platelet levels in the analysis may be attributed to the influence of confounding inclusion variables. Epithelial/mesenchymal transition (EMT) marker expression changes in HCCC-9810 and HUCC-T1 cells with platelet treatment were analyzed to understand how platelets contribute to ICC malignant recurring progression. The significant role of the TGF-β/Smad2 pathway in ICC metastasis was identified. In addition, aspirin was found to have the potential to reduce ICC metastasis by inhibiting platelet function. In conclusion, this study indicated that ICC patients with postoperative serum platelet levels ≥300 × 10<sup>9</sup>/L or tumoral platelet levels ≥0.23 have significantly higher risk of poor postoperative prognosis. This is due to platelet-derived TGFβ1 leading to EMT in ICC cells, thus promoting tumor metastasis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167734"},"PeriodicalIF":4.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reduced parenteral glucose supply during neonatal infection attenuates neurological and renal pathology associated with modulation of innate and Th1 immunity

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-18 DOI: 10.1016/j.bbadis.2025.167723

Jingren Zhong , Ole Bæk , Richard Doughty , Benjamin Meyer Jørgensen , Henrik Elvang Jensen , Thomas Thymann , Per Torp Sangild , Anders Brunse , Duc Ninh Nguyen

Background

Premature infants are highly susceptible to infections that can lead to sepsis with life-threatening organ dysfunctions. The clinical practice of high parenteral glucose supply in preterm infants can exacerbate infection outcomes through excessive glycolysis-induced inflammatory response. This in turn can affect the health of vital preterm organs, including the brain and kidneys. We hypothesized that reduced parenteral glucose supply to infected preterm newborns may help protect against pathology in these two key organs.

Methods

Cesarean-delivered preterm pigs were nourished with high or low parenteral glucose levels (21 % vs. 5 %), infused with Staphylococcus epidermidis or saline, and monitored in heated, oxygenated incubators until 22 h. Blood, brain, and kidney samples were collected for histological, immunohistological, q-PCR, ELISA, and biochemical analyses.

Results

Infection led to multiple pathological changes (e.g. edema), increased inflammation and tissue injury (indicated by gene expression data) in both brain and kidneys of preterm piglets. Reduced glucose supply in infected animals alleviated histopathological manifestations in the brain, and reduced neuroinflammation with enhanced M2 microglial phenotype. Reduced glucose supply also decreased plasma creatinine, and the severity of renal edema, tubular vacuolization and dilatation. Multiple genes related to innate and Th1 immunity in both organs were dampened by reduced glucose supply. Correlation analysis showed that renal inflammation was more closely connected to systemic inflammation compared to neuroinflammation.

Conclusion

Reduced glucose supply can reduce renal and neuro-inflammation during neonatal infection, thereby protecting brain and kidney health in infected preterm neonates.

{"title":"Reduced parenteral glucose supply during neonatal infection attenuates neurological and renal pathology associated with modulation of innate and Th1 immunity","authors":"Jingren Zhong , Ole Bæk , Richard Doughty , Benjamin Meyer Jørgensen , Henrik Elvang Jensen , Thomas Thymann , Per Torp Sangild , Anders Brunse , Duc Ninh Nguyen","doi":"10.1016/j.bbadis.2025.167723","DOIUrl":"10.1016/j.bbadis.2025.167723","url":null,"abstract":"<div><h3>Background</h3><div>Premature infants are highly susceptible to infections that can lead to sepsis with life-threatening organ dysfunctions. The clinical practice of high parenteral glucose supply in preterm infants can exacerbate infection outcomes through excessive glycolysis-induced inflammatory response. This in turn can affect the health of vital preterm organs, including the brain and kidneys. We hypothesized that reduced parenteral glucose supply to infected preterm newborns may help protect against pathology in these two key organs.</div></div><div><h3>Methods</h3><div>Cesarean-delivered preterm pigs were nourished with high or low parenteral glucose levels (21 % vs. 5 %), infused with <em>Staphylococcus epidermidis</em> or saline, and monitored in heated, oxygenated incubators until 22 h. Blood, brain, and kidney samples were collected for histological, immunohistological, q-PCR, ELISA, and biochemical analyses.</div></div><div><h3>Results</h3><div>Infection led to multiple pathological changes (e.g. edema), increased inflammation and tissue injury (indicated by gene expression data) in both brain and kidneys of preterm piglets. Reduced glucose supply in infected animals alleviated histopathological manifestations in the brain, and reduced neuroinflammation with enhanced M2 microglial phenotype. Reduced glucose supply also decreased plasma creatinine, and the severity of renal edema, tubular vacuolization and dilatation. Multiple genes related to innate and Th1 immunity in both organs were dampened by reduced glucose supply. Correlation analysis showed that renal inflammation was more closely connected to systemic inflammation compared to neuroinflammation.</div></div><div><h3>Conclusion</h3><div>Reduced glucose supply can reduce renal and neuro-inflammation during neonatal infection, thereby protecting brain and kidney health in infected preterm neonates.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167723"},"PeriodicalIF":4.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VRK2 promotes colorectal cancer growth and impedes immunotherapy and 5-FU treatment efficacy

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-18 DOI: 10.1016/j.bbadis.2025.167729

Yu-Tong Wu , Meng Gao , Kun-Yang Cheng , Le Li , Bai-Qi Wang , Ya-Nan He , Yue Zhang , Xue-Yi Liu , Run-Lei Du , Guo-Qing Li , Yue-Xiu Liang , Jian-Feng Zhang , Xiao-Dong Zhang , Yi Liu

Vaccinia-Related Kinase 2 (VRK2), a member of the vaccinia virus-related protein kinase family, is crucial in regulating apoptosis and tumor cell growth signaling pathways. Despite its established roles in various cancers, investigations into its functions in colorectal cancer have been relatively limited. Utilizing The Cancer Genome Atlas and Genotype-Tissue Expression databases, this study assesses VRK2 expression across 33 cancer types, highlighting significant upregulation and diagnostic relevance, particularly in colorectal cancer, where it marks poor prognosis. VRK2's influence extends across multiple cancer-related signaling pathways, with focused experiments confirming its vital role in the E2F signaling pathway through transcriptomic sequencing and dual-luciferase reporter assays. Deletion of VRK2 markedly inhibits proliferation, cell cycle progression, migration, and tumorigenesis in colorectal cancer cells, whereas overexpression enhances these oncogenic traits. Additionally, VRK2 expression correlates with genomic instability and the tumor microenvironment, influencing antitumor immunity and response to immunotherapy. Importantly, our analysis reveals that VRK2 modulates the chemosensitivity of tumor cells, specifically enhancing resistance to the chemotherapeutic agent 5-FU. These findings underscore VRK2's multifaceted role in promoting colorectal cancer development and suggest its potential as a therapeutic target.

{"title":"VRK2 promotes colorectal cancer growth and impedes immunotherapy and 5-FU treatment efficacy","authors":"Yu-Tong Wu , Meng Gao , Kun-Yang Cheng , Le Li , Bai-Qi Wang , Ya-Nan He , Yue Zhang , Xue-Yi Liu , Run-Lei Du , Guo-Qing Li , Yue-Xiu Liang , Jian-Feng Zhang , Xiao-Dong Zhang , Yi Liu","doi":"10.1016/j.bbadis.2025.167729","DOIUrl":"10.1016/j.bbadis.2025.167729","url":null,"abstract":"<div><div>Vaccinia-Related Kinase 2 (VRK2), a member of the vaccinia virus-related protein kinase family, is crucial in regulating apoptosis and tumor cell growth signaling pathways. Despite its established roles in various cancers, investigations into its functions in colorectal cancer have been relatively limited. Utilizing The Cancer Genome Atlas and Genotype-Tissue Expression databases, this study assesses VRK2 expression across 33 cancer types, highlighting significant upregulation and diagnostic relevance, particularly in colorectal cancer, where it marks poor prognosis. VRK2's influence extends across multiple cancer-related signaling pathways, with focused experiments confirming its vital role in the E2F signaling pathway through transcriptomic sequencing and dual-luciferase reporter assays. Deletion of VRK2 markedly inhibits proliferation, cell cycle progression, migration, and tumorigenesis in colorectal cancer cells, whereas overexpression enhances these oncogenic traits. Additionally, VRK2 expression correlates with genomic instability and the tumor microenvironment, influencing antitumor immunity and response to immunotherapy. Importantly, our analysis reveals that VRK2 modulates the chemosensitivity of tumor cells, specifically enhancing resistance to the chemotherapeutic agent 5-FU. These findings underscore VRK2's multifaceted role in promoting colorectal cancer development and suggest its potential as a therapeutic target.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167729"},"PeriodicalIF":4.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development and validation of a kinase-related gene signature as a novel diagnostic and prognostic model for prostate cancer

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-17 DOI: 10.1016/j.bbadis.2025.167722

Yaqiang Huang , Haiying Zhu , Zhenguo Liang , Weiyang Wei , Hao Yang , Qi Wang , Hongxing Huang , Huichan He , Rujun Mo , Jianheng Ye , Qishan Dai , Weide Zhong , Yingke Liang

Background

Prostate cancer (PCa) is a prevalent malignant tumor in men worldwide. Kinases play a key role in the development of multiple tumors. Nevertheless, the role of kinases in PCa remains largely unclear.

Methods

A kinase-related gene signature was constructed by LASSO Cox regression analysis using the TCGA_PRAD cohort. The diagnostic and prognostic values of the signature were then evaulated. Furthermore, a loss-of-function assay was carried out to explore the function of NEK5 in PCa.

Results

A signature of 13 kinase-related genes (NEK5, FRK, STK39, STYK1, IGF1R, RPS6KC1, TTK, CDK1, NEK2, PTK6, DAPK1, MELK and EPHA10) was constructed. The PCa patients presenting a high-risk score according to the signature demonstrated poorer disease-free survival compared to those with a low score. Additionally, TMB was found to be remarkably increased in patients categorized as high-risk relative to low-risk patients. Moreover, the 13-gene signature may also have good predictive value for PCa diagnosis. Furthermore, NEK5 expression was remarkably elevated in PCa tissues relative to benign tissues. NEK5 deficiency significantly inhibited PCa cell growth and suppressed mitochondrial OXPHOS.

Conclusion

The 13-gene signature constructed in this study may exhibit good performance in PCa diagnosis and prognosis evaluation. We identified the oncogenic role of NEK5 in PCa. NEK5 may serve as a therapeutic target for treatting PCa.

{"title":"Development and validation of a kinase-related gene signature as a novel diagnostic and prognostic model for prostate cancer","authors":"Yaqiang Huang , Haiying Zhu , Zhenguo Liang , Weiyang Wei , Hao Yang , Qi Wang , Hongxing Huang , Huichan He , Rujun Mo , Jianheng Ye , Qishan Dai , Weide Zhong , Yingke Liang","doi":"10.1016/j.bbadis.2025.167722","DOIUrl":"10.1016/j.bbadis.2025.167722","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) is a prevalent malignant tumor in men worldwide. Kinases play a key role in the development of multiple tumors. Nevertheless, the role of kinases in PCa remains largely unclear.</div></div><div><h3>Methods</h3><div>A kinase-related gene signature was constructed by LASSO Cox regression analysis using the TCGA_PRAD cohort. The diagnostic and prognostic values of the signature were then evaulated. Furthermore, a loss-of-function assay was carried out to explore the function of NEK5 in PCa.</div></div><div><h3>Results</h3><div>A signature of 13 kinase-related genes (NEK5, FRK, STK39, STYK1, IGF1R, RPS6KC1, TTK, CDK1, NEK2, PTK6, DAPK1, MELK and EPHA10) was constructed. The PCa patients presenting a high-risk score according to the signature demonstrated poorer disease-free survival compared to those with a low score. Additionally, TMB was found to be remarkably increased in patients categorized as high-risk relative to low-risk patients. Moreover, the 13-gene signature may also have good predictive value for PCa diagnosis. Furthermore, NEK5 expression was remarkably elevated in PCa tissues relative to benign tissues. NEK5 deficiency significantly inhibited PCa cell growth and suppressed mitochondrial OXPHOS.</div></div><div><h3>Conclusion</h3><div>The 13-gene signature constructed in this study may exhibit good performance in PCa diagnosis and prognosis evaluation. We identified the oncogenic role of NEK5 in PCa. NEK5 may serve as a therapeutic target for treatting PCa.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167722"},"PeriodicalIF":4.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microglial pyroptosis drives neuropathic pain and targeting NLRP3 alleviates pain and neuroinflammation

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-17 DOI: 10.1016/j.bbadis.2025.167737

Juhee Shin , Junhua Wu , Hyewon Park , Song I. Kim , Nara Shin , Hyo Jung Shin , Guang Ren , Jeong-a Kim , Patrick T.J. Hwang , Ho-Wook Jun , Sun Yeul Lee , Sangkyu Lee , Hyeong-Geug Kim , Dong Woon Kim

Neuropathic pain is triggered by nerve damage or disease and involves chronic neuroinflammation driven by activated microglia releasing pro-inflammatory cytokines. PANoptosis, a complex cell death program encompassing apoptosis, pyroptosis, and necroptosis, has emerged as a key player in neuroinflammation. While individual PANoptosis pathway have been linked to pain, its systemic role in neuropathic pain remains unclear. This study explored the involvement of PANoptosis in microglia under neuropathic pain and its potential therapeutic targeting. After spinal nerve ligation (SNL), robust microglia activation and pro-inflammatory cytokines were increased in spinal dorsal horn. To figure out the major PANoptosis under neuropathic pain, bioinformatic analysis and protein analysis were explored by using spinal dorsal horn on 14 days of post injury. The results supported that pyroptosis was the dominant pathway after injury, and we further investigated pyroptosis-related markers on microglia specifically. Notably, pyroptosis marker (caspase-1) was elevated in microglia compared to apoptosis (cleaved caspase-3) and necroptosis (p-RIPK3) markers. This finding highlights microglia pyroptosis as a key driver of neuropathic pain development. To harness this knowledge therapeutically, we employed intrathecal injection of NLRP3 siRNA nanoparticles. NLRP3, a crucial component of the inflammasome complex triggering pyroptosis, served as our target. Strikingly, this intervention effectively alleviated mechanical allodynia, a hallmark of neuropathic pain, alongside reducing microgliosis and dampening microglial pyroptosis. Our findings reveal that microglia pyroptosis plays a key role in neuropathic pain and suggest NLRP3 siRNA nanoparticles as a promising therapeutic avenue for pain management.

{"title":"Microglial pyroptosis drives neuropathic pain and targeting NLRP3 alleviates pain and neuroinflammation","authors":"Juhee Shin , Junhua Wu , Hyewon Park , Song I. Kim , Nara Shin , Hyo Jung Shin , Guang Ren , Jeong-a Kim , Patrick T.J. Hwang , Ho-Wook Jun , Sun Yeul Lee , Sangkyu Lee , Hyeong-Geug Kim , Dong Woon Kim","doi":"10.1016/j.bbadis.2025.167737","DOIUrl":"10.1016/j.bbadis.2025.167737","url":null,"abstract":"<div><div>Neuropathic pain is triggered by nerve damage or disease and involves chronic neuroinflammation driven by activated microglia releasing pro-inflammatory cytokines. PANoptosis, a complex cell death program encompassing apoptosis, pyroptosis, and necroptosis, has emerged as a key player in neuroinflammation. While individual PANoptosis pathway have been linked to pain, its systemic role in neuropathic pain remains unclear. This study explored the involvement of PANoptosis in microglia under neuropathic pain and its potential therapeutic targeting. After spinal nerve ligation (SNL), robust microglia activation and pro-inflammatory cytokines were increased in spinal dorsal horn. To figure out the major PANoptosis under neuropathic pain, bioinformatic analysis and protein analysis were explored by using spinal dorsal horn on 14 days of post injury. The results supported that pyroptosis was the dominant pathway after injury, and we further investigated pyroptosis-related markers on microglia specifically. Notably, pyroptosis marker (caspase-1) was elevated in microglia compared to apoptosis (cleaved caspase-3) and necroptosis (p-RIPK3) markers. This finding highlights microglia pyroptosis as a key driver of neuropathic pain development. To harness this knowledge therapeutically, we employed intrathecal injection of NLRP3 siRNA nanoparticles. NLRP3, a crucial component of the inflammasome complex triggering pyroptosis, served as our target. Strikingly, this intervention effectively alleviated mechanical allodynia, a hallmark of neuropathic pain, alongside reducing microgliosis and dampening microglial pyroptosis. Our findings reveal that microglia pyroptosis plays a key role in neuropathic pain and suggest NLRP3 siRNA nanoparticles as a promising therapeutic avenue for pain management.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167737"},"PeriodicalIF":4.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of aryl hydrocarbon receptor attenuates intestinal inflammation by enhancing IRF4-mediated macrophage M2 polarization

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-17 DOI: 10.1016/j.bbadis.2025.167735

Jiajia Li , Lu Wang , Mingyuan Wang, Hongjie Zhang

Background

Crohn's disease (CD) is characterized by immune cell dysregulation, with macrophages playing an indisputable role. Macrophages can exhibit opposing polarization under different conditions, resulting in pro- or anti-inflammatory effects. The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is implicated in intestinal inflammation by regulating both innate and adaptive immune responses. However, the regulatory mechanism between AhR and macrophages in colitis has not been thoroughly investigated.

Methods

Macrophage polarization in the colonic tissue of active CD patients was assessed. Following colitis induction in mice by 2,4,6-trinitro-benzenesulfonic acid (TNBS), an intraperitoneal injection of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) was administered. The severity of colitis was estimated, and macrophage polarization was detected. In an in vitro setting, bone marrow-derived macrophages (BMDMs) were polarized to the M2 phenotype in the presence or absence of FICZ. Interferon regulatory factor 4 (IRF4) siRNA was applied to knockdown IRF4 expression. M2-specific markers were quantified using quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry.

Results

Compared with healthy controls, active CD patients exhibited a lower presence of M2 macrophages in colonic tissue. Experimentally, FICZ was found to protect mice against TNBS-induced colitis, as evidenced by reduced diarrhea, bloody stool, and weight loss. This effect was associated with an increase in M2 macrophages and the release of IL-10 in the intestine. In BMDMs, FICZ promoted the expressions of M2-specific markers, including Ym1, Fizz1, IL-10, and CD206. Furthermore, FICZ upregulated IRF4 expression. After IRF4 silencing with siRNA, the enhancement of macrophage M2 polarization by FICZ was significantly impaired.

Conclusion

Activation of AhR appears to have a beneficial effect on intestinal inflammation by promoting macrophage M2 polarization. This effect is partially mediated by the upregulation of IRF4 expression and may lead to new insight into the pathogenesis of CD.

{"title":"Activation of aryl hydrocarbon receptor attenuates intestinal inflammation by enhancing IRF4-mediated macrophage M2 polarization","authors":"Jiajia Li , Lu Wang , Mingyuan Wang, Hongjie Zhang","doi":"10.1016/j.bbadis.2025.167735","DOIUrl":"10.1016/j.bbadis.2025.167735","url":null,"abstract":"<div><h3>Background</h3><div>Crohn's disease (CD) is characterized by immune cell dysregulation, with macrophages playing an indisputable role. Macrophages can exhibit opposing polarization under different conditions, resulting in pro- or anti-inflammatory effects. The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is implicated in intestinal inflammation by regulating both innate and adaptive immune responses. However, the regulatory mechanism between AhR and macrophages in colitis has not been thoroughly investigated.</div></div><div><h3>Methods</h3><div>Macrophage polarization in the colonic tissue of active CD patients was assessed. Following colitis induction in mice by 2,4,6-trinitro-benzenesulfonic acid (TNBS), an intraperitoneal injection of the natural AhR agonist 6-formylindolo[3,2-<em>b</em>]carbazole (FICZ) was administered. The severity of colitis was estimated, and macrophage polarization was detected. In an <em>in vitro</em> setting, bone marrow-derived macrophages (BMDMs) were polarized to the M2 phenotype in the presence or absence of FICZ. Interferon regulatory factor 4 (IRF4) siRNA was applied to knockdown IRF4 expression. M2-specific markers were quantified using quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry.</div></div><div><h3>Results</h3><div>Compared with healthy controls, active CD patients exhibited a lower presence of M2 macrophages in colonic tissue. Experimentally, FICZ was found to protect mice against TNBS-induced colitis, as evidenced by reduced diarrhea, bloody stool, and weight loss. This effect was associated with an increase in M2 macrophages and the release of IL-10 in the intestine. In BMDMs, FICZ promoted the expressions of M2-specific markers, including Ym1, Fizz1, IL-10, and CD206. Furthermore, FICZ upregulated IRF4 expression. After IRF4 silencing with siRNA, the enhancement of macrophage M2 polarization by FICZ was significantly impaired.</div></div><div><h3>Conclusion</h3><div>Activation of AhR appears to have a beneficial effect on intestinal inflammation by promoting macrophage M2 polarization. This effect is partially mediated by the upregulation of IRF4 expression and may lead to new insight into the pathogenesis of CD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167735"},"PeriodicalIF":4.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pathogenesis and therapeutic effect of sitagliptin in experimental diabetic model of COVID-19

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-17 DOI: 10.1016/j.bbadis.2025.167726

Qinghe Meng , Ikechukwu Jacob , Chunyan Wang , Julia Ma , Liye Suo , Wenlu Zhao , Akinkunmi Lawal , Yuqi Song , Guirong Wang , Robert N. Cooney

This study evaluates the pathogenesis of COVID-19 and the therapeutic efficacy of sitagliptin in diabetic and obese mice. Using a novel double-transgenic mouse model (db/db and K18-hACE2), the findings demonstrates that SARS-CoV-2 infection (Delta variant) causes severe multi-organ damage, glucose metabolism abnormalities, insulin resistance, and pancreatic islet cell damage in diabetic mice. Infected diabetic mice displayed higher mortality, inflammation (elevated TNF-α, IL-6, IL-1β), and fibrinolytic activity (PAI-1), alongside dysregulated diabetes-related hormones (GLP-1, leptin, ghrelin, resistin) compared to non-diabetic controls. Sitagliptin treatment reduced organ injury, hyperglycemia, inflammation, and fibrinolytic activity while improving insulin resistance and glucose metabolism. This was evidenced by decreased fasting blood glucose levels, improved insulin sensitivity, and elevated insulin and GLP-1 levels. These findings suggest sitagliptin is a promising therapeutic strategy to mitigate the severity of COVID-19 in experimental diabetes by modulating inflammation and improving metabolic syndrome. Further mechanistic investigations revealed that the level of hACE2 expression, along with the activation of NF-κB and IRS-1, play critical roles in the development of SARS-CoV-2-induced diabetes, the exacerbation of pre-existing diabetes, and the therapeutic efficacy of sitagliptin.

{"title":"Pathogenesis and therapeutic effect of sitagliptin in experimental diabetic model of COVID-19","authors":"Qinghe Meng , Ikechukwu Jacob , Chunyan Wang , Julia Ma , Liye Suo , Wenlu Zhao , Akinkunmi Lawal , Yuqi Song , Guirong Wang , Robert N. Cooney","doi":"10.1016/j.bbadis.2025.167726","DOIUrl":"10.1016/j.bbadis.2025.167726","url":null,"abstract":"<div><div>This study evaluates the pathogenesis of COVID-19 and the therapeutic efficacy of sitagliptin in diabetic and obese mice. Using a novel double-transgenic mouse model (db/db and K18-hACE2), the findings demonstrates that SARS-CoV-2 infection (Delta variant) causes severe multi-organ damage, glucose metabolism abnormalities, insulin resistance, and pancreatic islet cell damage in diabetic mice. Infected diabetic mice displayed higher mortality, inflammation (elevated TNF-α, IL-6, IL-1β), and fibrinolytic activity (PAI-1), alongside dysregulated diabetes-related hormones (GLP-1, leptin, ghrelin, resistin) compared to non-diabetic controls. Sitagliptin treatment reduced organ injury, hyperglycemia, inflammation, and fibrinolytic activity while improving insulin resistance and glucose metabolism. This was evidenced by decreased fasting blood glucose levels, improved insulin sensitivity, and elevated insulin and GLP-1 levels. These findings suggest sitagliptin is a promising therapeutic strategy to mitigate the severity of COVID-19 in experimental diabetes by modulating inflammation and improving metabolic syndrome. Further mechanistic investigations revealed that the level of hACE2 expression, along with the activation of NF-κB and IRS-1, play critical roles in the development of SARS-CoV-2-induced diabetes, the exacerbation of pre-existing diabetes, and the therapeutic efficacy of sitagliptin.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167726"},"PeriodicalIF":4.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploration of common molecular mechanisms of psoriatic arthritis and aging based on integrated bioinformatics and single-cell RNA-seq analysis

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-17 DOI: 10.1016/j.bbadis.2025.167730

Shuang Liu, Peng Pu, Qing Xiang, Xiangling Pu

Objective

This study investigated the key genes shared between Psoriatic arthritis (PSA) and aging.

Methods

By integrating and analyzing single-cell RNA sequencing data from the synovial fluid of PsA patients, peripheral blood of senescent patients, and the normal population, the subpopulation of cells that were jointly upregulated in both was obtained as the core cellular subpopulation. We analyzed the proposed chronology of this core cellular subpopulations and the function of cellular communication, screened the differentially expressed genes in the core cellular subpopulations compared with other categories, analyzed the causal relationship between the differentially expressed genes and PsA by Mendelian randomization and analyzed the enriched pathways of key genes.

Results

T cell subsets were represented in a significant proportion of both PsA and senescent patients, in which CD8-CM was expressed up-regulated in both PsA and senescent populations, and a total of 98 differentially expressed genes were obtained, and a Mendelian randomization study revealed that TGFBR3, PPP3CC, and APOBEC3G were causally associated with PsA. Colocalization analysis was performed to identify co-localized association signals in the PsA GWAS results and expression quantitative trait Loci (eQTL) dataset of key genes, and metabolic pathways that were predominantly enriched for key genes were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG).

Conclusions

In this study, we found that CD8-CM expression was up-regulated in PsA and senescent populations, and identified key genes for PsA and senescence: TGFBR3, PPP3CC and APOBEC3G. This provides new insights into the pathogenesis and combined treatment of PsA and aging.

{"title":"Exploration of common molecular mechanisms of psoriatic arthritis and aging based on integrated bioinformatics and single-cell RNA-seq analysis","authors":"Shuang Liu, Peng Pu, Qing Xiang, Xiangling Pu","doi":"10.1016/j.bbadis.2025.167730","DOIUrl":"10.1016/j.bbadis.2025.167730","url":null,"abstract":"<div><h3>Objective</h3><div>This study investigated the key genes shared between Psoriatic arthritis (PSA) and aging.</div></div><div><h3>Methods</h3><div>By integrating and analyzing single-cell RNA sequencing data from the synovial fluid of PsA patients, peripheral blood of senescent patients, and the normal population, the subpopulation of cells that were jointly upregulated in both was obtained as the core cellular subpopulation. We analyzed the proposed chronology of this core cellular subpopulations and the function of cellular communication, screened the differentially expressed genes in the core cellular subpopulations compared with other categories, analyzed the causal relationship between the differentially expressed genes and PsA by Mendelian randomization and analyzed the enriched pathways of key genes.</div></div><div><h3>Results</h3><div>T cell subsets were represented in a significant proportion of both PsA and senescent patients, in which CD8-CM was expressed up-regulated in both PsA and senescent populations, and a total of 98 differentially expressed genes were obtained, and a Mendelian randomization study revealed that <em>TGFBR3</em>, <em>PPP3CC</em>, and <em>APOBEC3G</em> were causally associated with PsA. Colocalization analysis was performed to identify co-localized association signals in the PsA GWAS results and expression quantitative trait Loci (eQTL) dataset of key genes, and metabolic pathways that were predominantly enriched for key genes were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG).</div></div><div><h3>Conclusions</h3><div>In this study, we found that CD8-CM expression was up-regulated in PsA and senescent populations, and identified key genes for PsA and senescence: <em>TGFBR3</em>, <em>PPP3CC</em> and <em>APOBEC3G</em>. This provides new insights into the pathogenesis and combined treatment of PsA and aging.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167730"},"PeriodicalIF":4.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dihydroceramide desaturase modulates autolysosome maturation and ameliorates CRB1 retinopathy

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-16 DOI: 10.1016/j.bbadis.2025.167736

Fei-Yang Tzou , Pei-Huan Chuang , Chia-Heng Hsu , Chih-Hsuan Wu , Yi Hsiao , Chung-Chih Liu , Yu-Lian Yu , Yu-Han Yeh , Chih-Wei Lin , Chih-Chaing Chan , Shu-Yi Huang

Variants in the CRB1 gene cause retinal degeneration and subsequent vision impairment in patients of retinitis pigmentosa (RP). No treatments are currently available to cure or impede the progression of CRB1-associated retinopathy. Previous studies have revealed alterations in the endolysosomal systems and autophagy in the absence of CRB1, but their roles in the pathogenesis of CRB1 retinopathy are unclear. Here, we examined the disease mechanism of CRB1 retinopathy using loss-of-function mutants of crumbs (crb), the Drosophila homolog of CRB1. We found that the loss of crb results in overactivation of autophagy in the eye. We also discovered that dihydroceramide desaturase encoded by infertile crescent (ifc), was up-regulated in crb mutants. Overexpression of ifc inhibited autolysosomes and alleviated Atg1-induced autophagic cell death. Mechanistically, ifc enhanced the binding of Rac1 to Atg8 and increased the autophagosomal localization of active Rac1, thus inhibiting autophagy. Importantly, autophagy inhibitions achieved through ifc overexpression, chloroquine treatment, or Beclin-1 RNAi all ameliorated the neurodegeneration of crb mutant eyes. Together, these findings highlight the mechanism of dihydroceramide desaturase in modulating autolysosome functions in crb mutants, providing new insights for developing treatments against CRB1 retinopathy.

CRB1 基因变异会导致视网膜变性，进而损害视网膜色素变性症（RP）患者的视力。目前还没有治疗方法可以治愈或阻止 CRB1 相关视网膜病变的发展。以前的研究发现，在 CRB1 缺失的情况下，内溶酶体系统和自噬发生改变，但它们在 CRB1 视网膜病变发病机制中的作用尚不清楚。在这里，我们利用 CRB1 的果蝇同源物 crumbs（crb）的功能缺失突变体研究了 CRB1 视网膜病变的发病机制。我们发现，crb的缺失会导致眼内自噬过度激活。我们还发现，在crb突变体中，二氢甘油酰胺去饱和酶（由不孕新月体（ifc）编码）上调。过表达 ifc 可抑制自溶酶体，减轻 Atg1 诱导的自噬细胞死亡。从机制上讲，ifc增强了Rac1与Atg8的结合，增加了活性Rac1的自噬体定位，从而抑制了自噬。重要的是，通过ifc过表达、氯喹处理或Beclin-1 RNAi实现的自噬抑制都能改善crb突变体眼球的神经退行性变。这些发现共同强调了二氢甘油酰胺去饱和酶调节crb突变体自溶体功能的机制，为开发CRB1视网膜病变的治疗方法提供了新的见解。

{"title":"Dihydroceramide desaturase modulates autolysosome maturation and ameliorates CRB1 retinopathy","authors":"Fei-Yang Tzou , Pei-Huan Chuang , Chia-Heng Hsu , Chih-Hsuan Wu , Yi Hsiao , Chung-Chih Liu , Yu-Lian Yu , Yu-Han Yeh , Chih-Wei Lin , Chih-Chaing Chan , Shu-Yi Huang","doi":"10.1016/j.bbadis.2025.167736","DOIUrl":"10.1016/j.bbadis.2025.167736","url":null,"abstract":"<div><div>Variants in the <em>CRB1</em> gene cause retinal degeneration and subsequent vision impairment in patients of retinitis pigmentosa (RP). No treatments are currently available to cure or impede the progression of CRB1-associated retinopathy. Previous studies have revealed alterations in the endolysosomal systems and autophagy in the absence of <em>CRB1</em>, but their roles in the pathogenesis of CRB1 retinopathy are unclear. Here, we examined the disease mechanism of CRB1 retinopathy using loss-of-function mutants of <em>crumbs (crb</em>), the <em>Drosophila</em> homolog of <em>CRB1</em>. We found that the loss of <em>crb</em> results in overactivation of autophagy in the eye. We also discovered that dihydroceramide desaturase encoded by <em>infertile crescent</em> (<em>ifc</em>), was up-regulated in <em>crb</em> mutants. Overexpression of <em>ifc</em> inhibited autolysosomes and alleviated Atg1-induced autophagic cell death. Mechanistically, <em>ifc</em> enhanced the binding of Rac1 to Atg8 and increased the autophagosomal localization of active Rac1, thus inhibiting autophagy. Importantly, autophagy inhibitions achieved through <em>ifc</em> overexpression, chloroquine treatment, or <em>Beclin-1 RNAi</em> all ameliorated the neurodegeneration of <em>crb</em> mutant eyes. Together, these findings highlight the mechanism of dihydroceramide desaturase in modulating autolysosome functions in <em>crb</em> mutants, providing new insights for developing treatments against CRB1 retinopathy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167736"},"PeriodicalIF":4.2,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microglia toxicology in α-synuclein pathology

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-16 DOI: 10.1016/j.bbadis.2025.167727

Han Zhang , Jieli Zhang , Xiuna Jing , Kaixun Huang , Ying Chen , Qingyu Shen , Enxiang Tao , Danyu Lin

Oligomeric α-synuclein (α-syn) could activate microglia and induce inflammation to drive the pathogenesis of Parkinson's disease (PD). Our previous study revealed that significant difference of IL6ST in cerebrospinal fluid of PD patients and a decline in IL6ST/JAK2/STAT3 were also observed in α-syn-induced HMC3 cells. JAK2/STAT3 pathway is not only a novel inflammatory pathway but also involved in ferroptosis progress. In this study, our results demonstrated that α-syn could impair cell activity and promote HMC3 cells differentiation into M2 phenotype. Besides, α-syn stimulation led to the inhibit of IL6ST/JAK2/STAT3 pathway and its downstream target, HIF-1α, in HMC3 cells. We further carried out transcriptomic analysis for α-syn-induced HMC3 cells and GSEA showed an association with ferroptosis. Results above implied the role of STAT3 in α-syn induced ferroptosis. Later, we found out α-syn decreased the phosphorylation of STAT3, which contributed to a remarkable morphological change in mitochondria and transcriptional activation of ferroptosis regulation genes (FRGs), such as ASCL4 and SLC7A11. Moreover, α-syn also promoted ferroptosis in microglia by inhibiting P-STAT3 expression and increasing iron metabolism and lipid peroxidation levels, all of which were reversed by the STAT3 activator. In conclusion, the phosphorylation and activation of STAT3 was an important factor that regulated microglia ferroptosis. α-syn stimulation influenced the cell activity, polarization and cellular toxicology in microglia via modulating IL6ST/ JAK2/STAT3/HIF-1α axis.

寡聚α-突触核蛋白（α-syn）可激活小胶质细胞并诱发炎症，从而导致帕金森病（PD）的发病。我们之前的研究发现，在α-syn诱导的HMC3细胞中，帕金森病患者脑脊液中的IL6ST存在显著差异，IL6ST/JAK2/STAT3也出现下降。JAK2/STAT3 通路不仅是一种新的炎症通路，还参与了铁变态反应的进展。本研究结果表明，α-syn 可损害细胞活性，促进 HMC3 细胞分化为 M2 表型。此外，α-syn刺激可抑制HMC3细胞中的IL6ST/JAK2/STAT3通路及其下游靶标HIF-1α。我们进一步对α-syn诱导的HMC3细胞进行了转录组分析，GSEA显示其与铁变态反应有关。上述结果暗示了 STAT3 在 α-syn 诱导的铁变态反应中的作用。随后，我们发现α-syn降低了STAT3的磷酸化，从而导致线粒体形态发生显著变化，并激活了ASCL4和SLC7A11等铁变态反应调控基因（FRGs）的转录。此外，α-syn 还通过抑制 P-STAT3 表达、增加铁代谢和脂质过氧化水平来促进小胶质细胞的铁变态反应，而 STAT3 激活剂可逆转所有这些作用。总之，STAT3的磷酸化和活化是调控小胶质细胞铁跃迁的一个重要因素。α-syn刺激通过调节IL6ST/ JAK2/STAT3/HIF-1α 轴影响小胶质细胞的细胞活性、极化和细胞毒性。

{"title":"Microglia toxicology in α-synuclein pathology","authors":"Han Zhang , Jieli Zhang , Xiuna Jing , Kaixun Huang , Ying Chen , Qingyu Shen , Enxiang Tao , Danyu Lin","doi":"10.1016/j.bbadis.2025.167727","DOIUrl":"10.1016/j.bbadis.2025.167727","url":null,"abstract":"<div><div>Oligomeric α-synuclein (α-syn) could activate microglia and induce inflammation to drive the pathogenesis of Parkinson's disease (PD). Our previous study revealed that significant difference of IL6ST in cerebrospinal fluid of PD patients and a decline in IL6ST/JAK2/STAT3 were also observed in α-syn-induced HMC3 cells. JAK2/STAT3 pathway is not only a novel inflammatory pathway but also involved in ferroptosis progress. In this study, our results demonstrated that α-syn could impair cell activity and promote HMC3 cells differentiation into M2 phenotype. Besides, α-syn stimulation led to the inhibit of IL6ST/JAK2/STAT3 pathway and its downstream target, HIF-1α, in HMC3 cells. We further carried out transcriptomic analysis for α-syn-induced HMC3 cells and GSEA showed an association with ferroptosis. Results above implied the role of STAT3 in α-syn induced ferroptosis. Later, we found out α-syn decreased the phosphorylation of STAT3, which contributed to a remarkable morphological change in mitochondria and transcriptional activation of ferroptosis regulation genes (FRGs), such as ASCL4 and SLC7A11. Moreover, α-syn also promoted ferroptosis in microglia by inhibiting P-STAT3 expression and increasing iron metabolism and lipid peroxidation levels, all of which were reversed by the STAT3 activator. In conclusion, the phosphorylation and activation of STAT3 was an important factor that regulated microglia ferroptosis. α-syn stimulation influenced the cell activity, polarization and cellular toxicology in microglia via modulating IL6ST/ JAK2/STAT3/HIF-1α axis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167727"},"PeriodicalIF":4.2,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0