International Journal of Biological Sciences最新文献_第3页

The Antitumor and Sorafenib-resistant Reversal Effects of Ursolic Acid on Hepatocellular Carcinoma via Targeting ING5. 熊果酸通过靶向 ING5 对肝细胞癌的抗肿瘤和索拉非尼耐药逆转作用

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-05 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97720

Yin-Jie Fan, Fu-Zhi Pan, Zheng-Guo Cui, Hua-Chuan Zheng

{"title":"The Antitumor and Sorafenib-resistant Reversal Effects of Ursolic Acid on Hepatocellular Carcinoma via Targeting ING5.","authors":"Yin-Jie Fan, Fu-Zhi Pan, Zheng-Guo Cui, Hua-Chuan Zheng","doi":"10.7150/ijbs.97720","DOIUrl":"https://doi.org/10.7150/ijbs.97720","url":null,"abstract":"Inhibitor of growth 5 (ING5) has been reported to be involved in the malignant progression of cancers. Ursolic acid (UA) has shown remarkable antitumor effects. However, its antitumor mechanisms regarding of ING5 in hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UA significantly suppressed the proliferation, anti-apoptosis, migration and invasion of HCC cells. In addition, ING5 expression in HCC cells treated with UA was obviously downregulated in a concentration- and time-dependent manner. Additionally, the pro-oncogenic role of ING5 was confirmed in HCC cells. Further investigation revealed that UA exerted antitumor effects on HCC by inhibiting ING5-mediated activation of PI3K/Akt pathway. Notably, UA could also reverse sorafenib resistance of HCC cells by suppressing the ING5-ACC1/ACLY-lipid droplets (LDs) axis. UA abrogated ING5 transcription and downregulated its expression by reducing SRF and YY1 expression and the SRF-YY1 complex formation. Alb/JCPyV T antigen mice were used for in vivo experiments since T antigen upregulated ING5 expression by inhibiting the ubiquitin-mediated degradation and promoting the T antigen-SRF-YY1-ING5 complex-associated transcription. UA suppressed JCPyV T antigen-induced spontaneous HCC through inhibiting ING5-mediated PI3K/Akt signaling pathway. These findings suggest that UA has the dual antitumoral functions of inhibiting hepatocellular carcinogenesis and reversing sorafenib resistance of HCC cells through targeting ING5, which could serve as a potential therapeutic strategy for HCC.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153953","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

Innovative Insights into Ferroptosis in Oligodendrocytes Following Intracerebral Hemorrhage: Implications for Neuroprotection and Therapeutic Strategies. 对脑内出血后少突胶质细胞铁突变的创新见解：对神经保护和治疗策略的启示

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.100754

Fangming Liu, Guohua Wang

引用次数: 0

mTOR Signaling: Roles in Hepatitis B Virus Infection and Hepatocellular Carcinoma. mTOR 信号：在乙型肝炎病毒感染和肝细胞癌中的作用

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.95894

Ling Mei, Huizhen Sun, Ying Yan, Huimin Ji, Qian Su, Le Chang, Lunan Wang

{"title":"mTOR Signaling: Roles in Hepatitis B Virus Infection and Hepatocellular Carcinoma.","authors":"Ling Mei, Huizhen Sun, Ying Yan, Huimin Ji, Qian Su, Le Chang, Lunan Wang","doi":"10.7150/ijbs.95894","DOIUrl":"https://doi.org/10.7150/ijbs.95894","url":null,"abstract":"Currently, chronic hepatitis B virus infection is still one of the most serious public health problems in the world. Though current strategies are effective in controlling infection and slowing down the disease process, it remains a big challenge to achieve a functional cure for chronic hepatitis B in a majority of patients due to the inability to clear the cccDNA pool. The mammalian target of rapamycin (mTOR) integrates nutrition, energy, growth factors, and other extracellular signals, participating in gene transcription, protein translation, ribosome synthesis, and other biological processes. Additionally, mTOR plays an extremely important role in cell growth, apoptosis, autophagy, and metabolism. More and more evidence show that HBV infection can activate the mTOR pathway, suggesting that HBV uses or hijacks the mTOR pathway to facilitate its own replication. Therefore, mTOR signaling pathway may be a key target for controlling HBV infection. However, the role of the central cytokine mTOR in the pathogenesis of HBV infection has not yet been systematically addressed. Notably, mTOR is commonly activated in hepatocellular carcinoma, which can progress from chronic hepatitis B. This review systematically summarizes the role of mTOR in the life cycle of HBV and its impact on the clinical progression of HBV infection.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153945","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

Nerve growth factor promote VCAM-1-dependent monocyte adhesion and M2 polarization in osteosarcoma microenvironment: Implications for larotrectinib therapy. 神经生长因子促进骨肉瘤微环境中依赖 VCAM-1 的单核细胞粘附和 M2 极化：拉罗替尼疗法的意义。

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.95463

Syuan-Ling Lin, Shang-Yu Yang, Chun-Hao Tsai, Yi-Chin Fong, Wei-Li Chen, Ju-Fang Liu, Chih-Yang Lin, Chih-Hsin Tang

{"title":"Nerve growth factor promote VCAM-1-dependent monocyte adhesion and M2 polarization in osteosarcoma microenvironment: Implications for larotrectinib therapy.","authors":"Syuan-Ling Lin, Shang-Yu Yang, Chun-Hao Tsai, Yi-Chin Fong, Wei-Li Chen, Ju-Fang Liu, Chih-Yang Lin, Chih-Hsin Tang","doi":"10.7150/ijbs.95463","DOIUrl":"https://doi.org/10.7150/ijbs.95463","url":null,"abstract":"Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In osteosarcoma samples from the Genomic Data Commons data portal, we detected higher levels of NGF and M2 macrophage markers, but not M1 macrophage markers. In cellular experiments, NGF-stimulated osteosarcoma conditional medium was shown to facilitate macrophage polarization from the M0 to the M2 phenotype. NGF also enhanced VCAM-1-dependent monocyte adhesion within the osteosarcoma microenvironment by down-regulating miR-513c-5p levels through the FAK and c-Src cascades. In in vivo xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153948","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

METTL16 Promotes Stability of SYNPO2L mRNA and leading to Cancer Cell Lung Metastasis by Secretion of COL10A1 and attract the Cancer-Associated Fibroblasts. METTL16 通过分泌 COL10A1 和吸引癌症相关成纤维细胞促进 SYNPO2L mRNA 的稳定并导致癌细胞肺转移。

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.95375

Jianlong Wu, Peng Ouyang, Rui Huang, Yao Cui, Zhihao Yang, Wei Xu, Rui Ma, Guoan Xiang, Wei Zeng, Wang Wu, Jian Li

{"title":"METTL16 Promotes Stability of SYNPO2L mRNA and leading to Cancer Cell Lung Metastasis by Secretion of COL10A1 and attract the Cancer-Associated Fibroblasts.","authors":"Jianlong Wu, Peng Ouyang, Rui Huang, Yao Cui, Zhihao Yang, Wei Xu, Rui Ma, Guoan Xiang, Wei Zeng, Wang Wu, Jian Li","doi":"10.7150/ijbs.95375","DOIUrl":"https://doi.org/10.7150/ijbs.95375","url":null,"abstract":"The occurrence of metastasis is a major factor contributing to poor prognosis in colorectal cancer. Different stages of the disease play a crucial role in distant metastasis. Furthermore, m6A has been demonstrated to play a significant role in regulating tumor metastasis. Therefore, we conducted an analysis of transcriptome data from high-stage and low-stage colorectal cancer patients in The Cancer Genome Atlas (TCGA) to identify genes associated with m6A-related regulation. We identified SYNPO2L as a core gene regulated by m6A, and it is correlated with adverse prognosis and metastasis in patients. Additionally, we demonstrated that the m6A writer gene Mettl16 can regulate the stability of SYNPO2L through interaction with YTHDC1. Subsequently, using Weighted Gene Co-expression Network Analysis (WGCNA), we discovered that SYNPO2L can regulate COL10A1, mediating the actions of Cancer-Associated Fibroblasts. SYNPO2L promotes the secretion of COL10A1 and the infiltration of tumor-associated fibroblasts, thereby facilitating Epithelial-Mesenchymal Transition (EMT) in tumor cells and making them more prone to distant metastasis.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153943","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

N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. LATS2的N6-甲基腺苷修饰通过YAP1/ATF4/PSAT1轴抑制铁突变，从而促进肝母细胞瘤的进展。

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.92413

Guoqing Zhu, Yi Xie, Zhixuan Bian, Ji Ma, Ni Zhen, Tianshu Chen, Jiabei Zhu, Siwei Mao, Xiaochen Tang, Li Liu, Song Gu, Miao Ding, Qiuhui Pan

{"title":"N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis.","authors":"Guoqing Zhu, Yi Xie, Zhixuan Bian, Ji Ma, Ni Zhen, Tianshu Chen, Jiabei Zhu, Siwei Mao, Xiaochen Tang, Li Liu, Song Gu, Miao Ding, Qiuhui Pan","doi":"10.7150/ijbs.92413","DOIUrl":"https://doi.org/10.7150/ijbs.92413","url":null,"abstract":"Ferroptosis has attracted extensive interest from cancer researchers due to its substantial potential as a therapeutic target. The role of LATS2, a core component of the Hippo pathway cascade, in ferroptosis initiation in hepatoblastoma (HB) has not yet been investigated. Furthermore, the underlying mechanism of decreased LATS2 expression remains largely unknown. In the present study, we demonstrated decreased LATS2 expression in HB and that LATS2 overexpression inhibits HB cell proliferation by inducing ferroptosis. Increased LATS2 expression reduced glycine and cysteine concentrations via the ATF4/PSAT1 axis. Physical binding between YAP1/ATF4 and the PSAT1 promoter was confirmed through ChIP‒qPCR. Moreover, METTL3 was identified as the writer of the LATS2 mRNA m6A modification at a specific site in the 5' UTR. Subsequently, YTHDF2 recognizes the m6A modification site and recruits the CCR4-NOT complex, leading to its degradation by mRNA deadenylation. In summary, N6-methyladenosine modification of LATS2 facilitates its degradation. Reduced LATS2 expression promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. Targeting LATS2 is a potential strategy for HB therapy.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153947","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

Catalpol attenuates hepatic glucose metabolism disorder and oxidative stress in triptolide-induced liver injury by regulating the SIRT1/HIF-1α pathway. 梓醇通过调节SIRT1/HIF-1α途径减轻三苯氧胺诱导的肝损伤中的肝糖代谢紊乱和氧化应激。

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97362

Weijue Nie, Hong Zhu, Xin Sun, Jie Zhou, Heng Xu, Zhichao Yu, Minghao Lu, Baoping Jiang, Lingling Zhou, Xueping Zhou

{"title":"Catalpol attenuates hepatic glucose metabolism disorder and oxidative stress in triptolide-induced liver injury by regulating the SIRT1/HIF-1α pathway.","authors":"Weijue Nie, Hong Zhu, Xin Sun, Jie Zhou, Heng Xu, Zhichao Yu, Minghao Lu, Baoping Jiang, Lingling Zhou, Xueping Zhou","doi":"10.7150/ijbs.97362","DOIUrl":"10.7150/ijbs.97362","url":null,"abstract":"Triptolide (TP), known for its effectiveness in treating various rheumatoid diseases, is also associated with significant hepatotoxicity risks. This study explored Catalpol (CAT), an iridoid glycoside with antioxidative and anti-inflammatory effects, as a potential defense against TP-induced liver damage. In vivo and in vitro models of liver injury were established using TP in combination with different concentrations of CAT. Metabolomics analyses were conducted to assess energy metabolism in mouse livers. Additionally, a Seahorse XF Analyzer was employed to measure glycolysis rate, mitochondrial respiratory functionality, and real-time ATP generation rate in AML12 cells. The study also examined the expression of proteins related to glycogenolysis and gluconeogenesis. Using both in vitro SIRT1 knockout/overexpression and in vivo liver-specific SIRT1 knockout models, we confirmed SIRT1 as a mechanism of action for CAT. Our findings revealed that CAT could alleviate TP-induced liver injury by activating SIRT1, which inhibited lysine acetylation of hypoxia-inducible factor-1α (HIF-1α), thereby restoring the balance between glycolysis and oxidative phosphorylation. This action improved mitochondrial dysfunction and reduced glucose metabolism disorder and oxidative stress caused by TP. Taken together, these insights unveil a hitherto undocumented mechanism by which CAT ameliorates TP-induced liver injury, positioning it as a potential therapeutic agent for managing TP-induced hepatotoxicity.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901656","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

Exosomes: Emerging Insights into the Progression of Pancreatic Cancer. 外泌体：胰腺癌进展的新见解。

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97076

Xulin Zhou, Yongmin Yan, Ye Shen, Min Xu, Wenrong Xu

引用次数: 0

FGF7 and FGF10 Promote Fate Transition of Human Epidermal Cell-derived Organoids to an Eccrine Gland Phenotype. FGF7和FGF10促进人表皮细胞衍生的器官组织向生殖腺表型的命运转变

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97422

Junhong Zhao, Lei Zhang, Yonghong Zhang, Manxiu Cao, Cangyu Wang, Anqi Hu, Leilei Cao, Qizhi Luo, Zhen You, Xueping Ma, Liang Gong, Cuiping Zhang, Haihong Li

{"title":"FGF7 and FGF10 Promote Fate Transition of Human Epidermal Cell-derived Organoids to an Eccrine Gland Phenotype.","authors":"Junhong Zhao, Lei Zhang, Yonghong Zhang, Manxiu Cao, Cangyu Wang, Anqi Hu, Leilei Cao, Qizhi Luo, Zhen You, Xueping Ma, Liang Gong, Cuiping Zhang, Haihong Li","doi":"10.7150/ijbs.97422","DOIUrl":"https://doi.org/10.7150/ijbs.97422","url":null,"abstract":"Rationale: Reconstruction of hair follicles (HFs) and eccrine sweat glands (ESGs) is essential for functional skin regeneration. In skin reconstruction research, we found that foreskin-derived epidermal cells reconstructed HF organoids unidirectionally, but not ESG organoids. Methods: To investigate key genes and pathways influencing the fate of ESG and HF, a transcriptome profiling of ESG placode-containing skin and HF placode-containing skin was employed, and key DEGs were identified and validated by RT-qPCR and immunofluorescence staining in mice and rats. Subsequently, adult human epidermal cell-derived organoids were reconstructed to probe functional roles and mechanisms of FGF7 and FGF10 by series of approaches integrating RT-qPCR, immunofluorescence-staining, WB, apoptosis assay, and pathway interference assay. Results: All members of FGF7 subfamily were among the key DEGs screened, the differential expression of FGF7 and FGF10 and their receptors FGFR1/FGFR2 was verified between ESG placode-containing skin and HF placode-containing skin. In vivo and in vitro Matrigel plug models showed that both FGF7 and FGF10 promoted fate transition of human epidermal cell-derived organoids to ESG phenotype organoids, FGF7 and FGF10 had a synergistic effect, and mainly function through the FGFR1/2-MEK1/2-ERK1/2 pathway. Conclusions: Adult epidermal cells can be manipulated to reconstruct personalized HF and ESG to meet different needs.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153937","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

NRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes. NRF2-HIF2α信号传导可减轻糖尿病内皮细胞衰老并维持细胞间连接

IF 8.2 2区生物学

International Journal of Biological Sciences Pub Date : 2024-07-22 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.96719

Jian Shen, Yifan Lai, Yaner Lu, Yabin Liu, Jinlong Zhang, Yan Wu, Yunan Pan, Haibo Chen, Qiyue Gao, Qucheng Wei, Yuwen Chen, Jian Ye, Yinuo Lin, Bingchen Liu, Jun Jiang, Jinliang Nan

{"title":"NRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes.","authors":"Jian Shen, Yifan Lai, Yaner Lu, Yabin Liu, Jinlong Zhang, Yan Wu, Yunan Pan, Haibo Chen, Qiyue Gao, Qucheng Wei, Yuwen Chen, Jian Ye, Yinuo Lin, Bingchen Liu, Jun Jiang, Jinliang Nan","doi":"10.7150/ijbs.96719","DOIUrl":"10.7150/ijbs.96719","url":null,"abstract":"In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901665","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