Jitendra Shrestha, Khem Raj Limbu, Rashmi Bhandari Chhetri, Keshav Raj Paudel, Philip M. Hansbro, Yoon Sin Oh, Dong Jae Baek, Sung-Hwan Ki, Eun-Young Park
Reactive oxygen species are involved in the pathogenesis of cancers and metabolic diseases, including diabetes, obesity, and fatty liver disease. Thus, inhibiting the generation of free radicals is a promising strategy to control the onset of metabolic diseases and cancer progression. Various synthetic drugs and natural product-derived compounds that exhibit antioxidant activity have been reported to have a protective effect against a range of metabolic diseases and cancer. This review highlights the development and aggravation of cancer and metabolic diseases due to the imbalance between pro-oxidants and endogenous antioxidant molecules. In addition, we discuss the function of proteins that regulate the production of reactive oxygen species as a strategy to treat metabolic diseases. In particular, we summarize the role of proteins such as nuclear factor-like 2, Sestrin, and heme oxygenase-1, which regulate the expression of various antioxidant genes in metabolic diseases and cancer. We have included recent literature to discuss the latest research on identifying novel signals of antioxidant genes that can control metabolic diseases and cancer.
{"title":"Antioxidant genes in cancer and metabolic diseases: Focusing on Nrf2, Sestrin, and heme oxygenase 1","authors":"Jitendra Shrestha, Khem Raj Limbu, Rashmi Bhandari Chhetri, Keshav Raj Paudel, Philip M. Hansbro, Yoon Sin Oh, Dong Jae Baek, Sung-Hwan Ki, Eun-Young Park","doi":"10.7150/ijbs.98846","DOIUrl":"https://doi.org/10.7150/ijbs.98846","url":null,"abstract":"Reactive oxygen species are involved in the pathogenesis of cancers and metabolic diseases, including diabetes, obesity, and fatty liver disease. Thus, inhibiting the generation of free radicals is a promising strategy to control the onset of metabolic diseases and cancer progression. Various synthetic drugs and natural product-derived compounds that exhibit antioxidant activity have been reported to have a protective effect against a range of metabolic diseases and cancer. This review highlights the development and aggravation of cancer and metabolic diseases due to the imbalance between pro-oxidants and endogenous antioxidant molecules. In addition, we discuss the function of proteins that regulate the production of reactive oxygen species as a strategy to treat metabolic diseases. In particular, we summarize the role of proteins such as nuclear factor-like 2, Sestrin, and heme oxygenase-1, which regulate the expression of various antioxidant genes in metabolic diseases and cancer. We have included recent literature to discuss the latest research on identifying novel signals of antioxidant genes that can control metabolic diseases and cancer.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"26 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258177","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}
Background: By regulating the functions of multiple RNAs, 5-methylcytosine (m5C) RNA methylation, particularly mediated by NOP2, is involved in tumorigenesis and developments. However, the specific functions and potential mechanisms of m5C, especially involving NOP2, in clear-cell renal cell carcinoma (ccRCC), remain unclear./nMethods: NOP2 expression in cell lines and patient tissues was detected using western blotting, quantitative real-time polymerase chain reaction (RT-qPCR), and immunohistochemistry. The biological effects of NOP2 on ccRCC cells were investigated through a series of in vitro and in vivo experiments. To explore the potential regulatory mechanisms by which NOP2 affects ccRCC progression, m5C bisulfite sequencing, RNA-sequencing, RNA immunoprecipitation and methylated RNA immunoprecipitation (RIP/MeRIP) RT-qPCR assay, luciferase reporter assay, RNA stability assay, and bioinformatic analysis were performed./nResults: NOP2 expression was significantly upregulated in ccRCC tissues and was associated with poor prognosis. Moreover, loss-of-function and gain-of-function assays demonstrated that NOP2 altered ccRCC cell proliferation, migration, and invasion. Mechanistically, NOP2 stimulated m5C modification of apolipoprotein L1 (APOL1) mRNA, and m5C reader YBX1 stabilized APOL1 mRNA through recognizing and binding to m5C site in the 3′-untranslated regions. Silencing APOL1 expression inhibited ccRCC cell proliferation in vitro and tumor formation in vivo. Furthermore, NOP2/APOL1 affected ccRCC progression via the PI3K-Akt signaling pathway./nConclusion: NOP2 functions as an oncogene in ccRCC by promoting tumor progression through the m5C-dependent stabilization of APOL1, which in turn regulates the PI3K-Akt signaling pathway, suggesting a potential therapeutic target for ccRCC.
{"title":"NOP2-mediated 5-methylcytosine modification of APOL1 messenger RNA activates PI3K-Akt and facilitates clear cell renal cell carcinoma progression","authors":"Junjie Tian, Jianguo Gao, Cheng Cheng, Zhijie Xu, Xiaoyi Chen, Yunfei Wu, Guanghou Fu, Baiye Jin","doi":"10.7150/ijbs.97503","DOIUrl":"https://doi.org/10.7150/ijbs.97503","url":null,"abstract":"<b>Background:</b> By regulating the functions of multiple RNAs, 5-methylcytosine (m<sup>5</sup>C) RNA methylation, particularly mediated by NOP2, is involved in tumorigenesis and developments. However, the specific functions and potential mechanisms of m<sup>5</sup>C, especially involving NOP2, in clear-cell renal cell carcinoma (ccRCC), remain unclear./n<b>Methods:</b> NOP2 expression in cell lines and patient tissues was detected using western blotting, quantitative real-time polymerase chain reaction (RT-qPCR), and immunohistochemistry. The biological effects of NOP2 on ccRCC cells were investigated through a series of <i>in vitro</i> and <i>in vivo</i> experiments. To explore the potential regulatory mechanisms by which NOP2 affects ccRCC progression, m<sup>5</sup>C bisulfite sequencing, RNA-sequencing, RNA immunoprecipitation and methylated RNA immunoprecipitation (RIP/MeRIP) RT-qPCR assay, luciferase reporter assay, RNA stability assay, and bioinformatic analysis were performed./n<b>Results:</b> NOP2 expression was significantly upregulated in ccRCC tissues and was associated with poor prognosis. Moreover, loss-of-function and gain-of-function assays demonstrated that NOP2 altered ccRCC cell proliferation, migration, and invasion. Mechanistically, NOP2 stimulated m<sup>5</sup>C modification of apolipoprotein L1 (APOL1) mRNA, and m<sup>5</sup>C reader YBX1 stabilized APOL1 mRNA through recognizing and binding to m<sup>5</sup>C site in the 3′-untranslated regions. Silencing APOL1 expression inhibited ccRCC cell proliferation <i>in vitro</i> and tumor formation <i>in vivo</i>. Furthermore, NOP2/APOL1 affected ccRCC progression via the PI3K-Akt signaling pathway./n<b>Conclusion:</b> NOP2 functions as an oncogene in ccRCC by promoting tumor progression through the m<sup>5</sup>C-dependent stabilization of APOL1, which in turn regulates the PI3K-Akt signaling pathway, suggesting a potential therapeutic target for ccRCC.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"13 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258121","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}
Ferroptosis is a recently discovered iron-dependent mode of oxidatively regulated cell death. It is not only associated with a wide range of diseases, but it is also a key component of many signaling pathways. In general, ferroptosis is a double-edged sword. On one hand, it induces nonapoptotic destruction of cancer cells, but on the other, it may lead to organ damage. Therefore, ferroptosis can be drug-targeted as a novel means of therapy. The properties of curcumin have been known for many years. It has a positive impact on the treatment of diseases such as cancer and inflammation. In this review, we focus on the regulation of ferroptosis by curcumin and its derivatives and review the main mechanisms by which curcumin affects ferroptosis. In conclusion, curcumin is a ferroptosis inducer with excellent anticancer efficacy, although it also exhibits organ protective and reparative effects by acting as a ferroptosis inhibitor. The differential regulation of ferroptosis by curcumin may be related to dose and cell type.
{"title":"Potential Roles and Mechanisms of Curcumin and its Derivatives in the Regulation of Ferroptosis","authors":"Yuan Zhang, Chenghao Yu, Cheng Peng, Fu Peng","doi":"10.7150/ijbs.90798","DOIUrl":"https://doi.org/10.7150/ijbs.90798","url":null,"abstract":"Ferroptosis is a recently discovered iron-dependent mode of oxidatively regulated cell death. It is not only associated with a wide range of diseases, but it is also a key component of many signaling pathways. In general, ferroptosis is a double-edged sword. On one hand, it induces nonapoptotic destruction of cancer cells, but on the other, it may lead to organ damage. Therefore, ferroptosis can be drug-targeted as a novel means of therapy. The properties of curcumin have been known for many years. It has a positive impact on the treatment of diseases such as cancer and inflammation. In this review, we focus on the regulation of ferroptosis by curcumin and its derivatives and review the main mechanisms by which curcumin affects ferroptosis. In conclusion, curcumin is a ferroptosis inducer with excellent anticancer efficacy, although it also exhibits organ protective and reparative effects by acting as a ferroptosis inhibitor. The differential regulation of ferroptosis by curcumin may be related to dose and cell type.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"40 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258175","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}
Zhanyong Zhu, Keyu Zhu, Jun Zhang, Yunhua Zhou, Qi Zhang
Breast cancer (BC) persists as a highly prevalent malignancy in females, characterized by diverse molecular signatures and necessitating personalized therapeutic approaches. The equilibrium of copper within the organism is meticulously maintained through regulated absorption, distribution, and elimination, underpinning not only cellular equilibrium but also various essential biological functions. The process of cuproptosis is initiated by copper's interaction with lipoylases within the tricarboxylic acid (TCA) cycle, which triggers the conglomeration of lipoylated proteins and diminishes the integrity of Fe-S clusters, culminating in cell demise through proteotoxic stress. In BC, aberrations in cuproptosis are prominent and represent a crucial molecular incident that contributes to the disease progression. It influences BC cell metabolism and affects critical traits such as proliferation, invasiveness, and resistance to chemotherapy. Therapeutic strategies that target cuproptosis have shown promising antitumor efficacy. Moreover, a plethora of cuproptosis-centric genes, including cuproptosis-related genes (CRGs), CRG-associated non-coding RNAs (ncRNAs), and cuproptosis-associated regulators, have been identified, offering potential for the development of risk assessment models or diagnostic signatures. In this review, we provide a comprehensive exposition of the fundamental principles of cuproptosis, its influence on the malignant phenotypes of BC, the prognostic implications of cuproptosis-based markers, and the substantial prospects of exploiting cuproptosis for BC therapy, thereby laying a theoretical foundation for targeted interventions in this domain.
乳腺癌（BC）是女性高发的恶性肿瘤，具有多种分子特征，需要个性化的治疗方法。铜在生物体内的平衡是通过调节吸收、分布和排出精心维持的，这不仅是细胞平衡的基础，也是各种基本生物功能的基础。铜氧化过程是由铜与三羧酸（TCA）循环中的脂酰酶相互作用而启动的，它会引发脂酰化蛋白质的聚集，并降低Fe-S簇的完整性，最终导致细胞因蛋白质毒性应激而死亡。在 BC 中，杯突畸变非常突出，是导致疾病进展的关键分子事件。它影响 BC 细胞的新陈代谢，并影响增殖、侵袭性和对化疗的耐受性等关键特征。针对杯突的治疗策略已显示出良好的抗肿瘤疗效。此外，还发现了大量以杯突症为中心的基因，包括杯突相关基因（CRGs）、CRG相关非编码RNAs（ncRNAs）和杯突相关调控因子，为开发风险评估模型或诊断特征提供了可能。在这篇综述中，我们全面阐述了杯突症的基本原理、杯突症对BC恶性表型的影响、基于杯突症标志物的预后意义以及利用杯突症治疗BC的巨大前景，从而为该领域的靶向干预奠定了理论基础。
{"title":"Elucidating the evolving role of cuproptosis in breast cancer progression","authors":"Zhanyong Zhu, Keyu Zhu, Jun Zhang, Yunhua Zhou, Qi Zhang","doi":"10.7150/ijbs.98806","DOIUrl":"https://doi.org/10.7150/ijbs.98806","url":null,"abstract":"Breast cancer (BC) persists as a highly prevalent malignancy in females, characterized by diverse molecular signatures and necessitating personalized therapeutic approaches. The equilibrium of copper within the organism is meticulously maintained through regulated absorption, distribution, and elimination, underpinning not only cellular equilibrium but also various essential biological functions. The process of cuproptosis is initiated by copper's interaction with lipoylases within the tricarboxylic acid (TCA) cycle, which triggers the conglomeration of lipoylated proteins and diminishes the integrity of Fe-S clusters, culminating in cell demise through proteotoxic stress. In BC, aberrations in cuproptosis are prominent and represent a crucial molecular incident that contributes to the disease progression. It influences BC cell metabolism and affects critical traits such as proliferation, invasiveness, and resistance to chemotherapy. Therapeutic strategies that target cuproptosis have shown promising antitumor efficacy. Moreover, a plethora of cuproptosis-centric genes, including cuproptosis-related genes (CRGs), CRG-associated non-coding RNAs (ncRNAs), and cuproptosis-associated regulators, have been identified, offering potential for the development of risk assessment models or diagnostic signatures. In this review, we provide a comprehensive exposition of the fundamental principles of cuproptosis, its influence on the malignant phenotypes of BC, the prognostic implications of cuproptosis-based markers, and the substantial prospects of exploiting cuproptosis for BC therapy, thereby laying a theoretical foundation for targeted interventions in this domain.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"29 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258176","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}
Pub Date : 2024-09-05eCollection Date: 2024-01-01DOI: 10.7150/ijbs.101944
Fei Han, Mei Xue, Yunpeng Chang, Xiaoyu Li, Yang Yang, Bei Sun, Liming Chen
[This corrects the article DOI: 10.7150/ijbs.20485.].
[此处更正了文章 DOI：10.7150/ijbs.20485.]。
{"title":"Erratum: Triptolide Suppresses Glomerular Mesangial Cell Proliferation in Diabetic Nephropathy Is Associated with Inhibition of PDK1/Akt/mTOR Pathway: Erratum.","authors":"Fei Han, Mei Xue, Yunpeng Chang, Xiaoyu Li, Yang Yang, Bei Sun, Liming Chen","doi":"10.7150/ijbs.101944","DOIUrl":"https://doi.org/10.7150/ijbs.101944","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.7150/ijbs.20485.].</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 12","pages":"4781-4782"},"PeriodicalIF":8.2,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11414400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142286340","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}
Han Gyung Kim, Ji Hye Kim, Kyung-Hee Kim, Byong Chul Yoo, Sung-Ung Kang, Young Bong Kim, Sangmin Kim, Hyun-June Paik, Jeong Eon Lee, Seok Jin Nam, Narayanan Parameswaran, Jeung-Whan Han, Balachandran Manavalan, Jae Youl Cho
Methyltransferase-like (METTL)18 has histidine methyltransferase activity on the RPL3 protein and is involved in ribosome biosynthesis and translation elongations. Several studies have reported that actin polymerization serves as a Src regulator, and HSP90 is involved in forming polymerized actin bundles. To understand the role of METTL18 in breast cancer and to demonstrate the importance of METTL18 in HER-2 negative breast cancer metastasis, we used biochemical, molecular biological, and immunological approaches in vitro (breast tumor cell lines), in vivo (tumor xenograft model), and in samples of human breast tumors. A gene expression comparison of 31 METTL series genes and 22 methyltransferases in breast cancer patients revealed that METTL18 is highly amplified in human HER2-negative breast cancer. In addition, elevated levels of METTL18 expression in patients with HER2-negative breast cancer are associated with poor prognosis. Loss of METTL18 significantly reduced the metastatic responses of breast tumor cells in vitro and in vivo. Mechanistically, METTL18 indirectly regulates the phosphorylation of the proto-oncogene tyrosine-protein kinase Src and its downstream molecules in MDA-MB-231 cells via METTL18-mediated RPL3 methylation, which is also involved in determining HSP90 integrity and protein levels. In confocal microscopy and F/G-actin assays, METTL18 was found to induce actin polymerization via HSP90. Molecular events involving METTL18, RPL3, HSP90, and actin polymerization yielded Src phosphorylated at both tyrosine 419 and tyrosine 530 with kinase activity and oncogenic functions. Therefore, it is suggested that the METTL18-HSP90-Actin-Src regulatory axis plays critical oncogenic roles in the metastatic responses of HER2-negative breast cancer and could be a promising therapeutic target.
{"title":"METTL18 functions as a Phenotypic Regulator in Src-Dependent Oncogenic Responses of HER2-Negative Breast Cancer","authors":"Han Gyung Kim, Ji Hye Kim, Kyung-Hee Kim, Byong Chul Yoo, Sung-Ung Kang, Young Bong Kim, Sangmin Kim, Hyun-June Paik, Jeong Eon Lee, Seok Jin Nam, Narayanan Parameswaran, Jeung-Whan Han, Balachandran Manavalan, Jae Youl Cho","doi":"10.7150/ijbs.96487","DOIUrl":"https://doi.org/10.7150/ijbs.96487","url":null,"abstract":"Methyltransferase-like (METTL)18 has histidine methyltransferase activity on the RPL3 protein and is involved in ribosome biosynthesis and translation elongations. Several studies have reported that actin polymerization serves as a Src regulator, and HSP90 is involved in forming polymerized actin bundles. To understand the role of METTL18 in breast cancer and to demonstrate the importance of METTL18 in HER-2 negative breast cancer metastasis, we used biochemical, molecular biological, and immunological approaches <i>in vitro</i> (breast tumor cell lines), <i>in vivo</i> (tumor xenograft model), and in samples of human breast tumors. A gene expression comparison of 31 METTL series genes and 22 methyltransferases in breast cancer patients revealed that METTL18 is highly amplified in human HER2-negative breast cancer. In addition, elevated levels of METTL18 expression in patients with HER2-negative breast cancer are associated with poor prognosis. Loss of METTL18 significantly reduced the metastatic responses of breast tumor cells <i>in vitro</i> and <i>in vivo</i>. Mechanistically, METTL18 indirectly regulates the phosphorylation of the proto-oncogene tyrosine-protein kinase Src and its downstream molecules in MDA-MB-231 cells via METTL18-mediated RPL3 methylation, which is also involved in determining HSP90 integrity and protein levels. In confocal microscopy and F/G-actin assays, METTL18 was found to induce actin polymerization via HSP90. Molecular events involving METTL18, RPL3, HSP90, and actin polymerization yielded Src phosphorylated at both tyrosine 419 and tyrosine 530 with kinase activity and oncogenic functions. Therefore, it is suggested that the METTL18-HSP90-Actin-Src regulatory axis plays critical oncogenic roles in the metastatic responses of HER2-negative breast cancer and could be a promising therapeutic target.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258182","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}
Diabetic kidney disease (DKD) is becoming the most leading cause of end-stage renal disease (ESRD). Podocyte injury plays a critical role in DKD progression. Notably, mitochondrial dysfunction is crucial for podocyte injury. MicroRNAs (miRNAs) involves in various kidney diseases. Herein, we discovered miR-29b was induced in the urine of 126 patients with DKD (stage I and II), and negatively correlated with kidney function and podocyte homeostasis. Mechanically, miR-29b targeted peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a co-activator of transcription factors regulating mitochondrial biogenesis and energy metabolism. In vitro, ectopic miR-29b downregulated PGC-1α and promoted podocyte injury, while inhibition of miR-29b alleviated podocyte injury. Consistently, inhibition of miR-29b mitigated podocyte injury and preserved kidney function in ADR nephropathy and db/db mice, and overexpression of miR-29b accelerated disease. Knockout miR-29b specifically in podocyte inhibited mitochondrial dysfunction and podocyte injury. These results revealed miR-29b plays a crucial role in mitochondrial dysfunction through targeted inhibition on PGC-1α, leading to podocyte injury and DKD progression. Importantly, miR-29b could serve as a novel biomarker of podocyte injury and assists to early diagnose DKD.
{"title":"MicroRNA-29b Plays a Vital Role in Podocyte Injury and Glomerular Diseases through Inducing Mitochondrial Dysfunction","authors":"Jiafeng Liu, Yabing Xiong, Hongyan Mo, Hongxin Niu, Jinhua Miao, Weiwei Shen, Shan Zhou, Xiaoxu Wang, Xiaolong Li, Yunfang Zhang, Kunling Ma, Lili Zhou","doi":"10.7150/ijbs.93506","DOIUrl":"https://doi.org/10.7150/ijbs.93506","url":null,"abstract":"Diabetic kidney disease (DKD) is becoming the most leading cause of end-stage renal disease (ESRD). Podocyte injury plays a critical role in DKD progression. Notably, mitochondrial dysfunction is crucial for podocyte injury. MicroRNAs (miRNAs) involves in various kidney diseases. Herein, we discovered miR-29b was induced in the urine of 126 patients with DKD (stage I and II), and negatively correlated with kidney function and podocyte homeostasis. Mechanically, miR-29b targeted peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a co-activator of transcription factors regulating mitochondrial biogenesis and energy metabolism. In vitro, ectopic miR-29b downregulated PGC-1α and promoted podocyte injury, while inhibition of miR-29b alleviated podocyte injury. Consistently, inhibition of miR-29b mitigated podocyte injury and preserved kidney function in ADR nephropathy and db/db mice, and overexpression of miR-29b accelerated disease. Knockout miR-29b specifically in podocyte inhibited mitochondrial dysfunction and podocyte injury. These results revealed miR-29b plays a crucial role in mitochondrial dysfunction through targeted inhibition on PGC-1α, leading to podocyte injury and DKD progression. Importantly, miR-29b could serve as a novel biomarker of podocyte injury and assists to early diagnose DKD.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"32 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258179","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}
Yuan Wang, Bin Sun, Wei Wei, Tao Han, Jing Ma, Xiaodong Li, Chuanchun Han, Zhikun Lin
Background: The important role of nucleobindin 2 (NUCB2) in various cancers has been recently recognized. However, its biological functions and regulatory mechanisms in hepatocellular carcinoma (HCC) remain unclear./nMethods: The expression level of NUCB2 in HCC was assessed using public databases, immunohistochemistry, and Western blotting. The effects of NUCB2 on cell proliferation and metastasis were investigated using colony formation, EdU, Transwell assays, and an in vivo mouse xenograft model. Regulation of E2F4 by NUCB2 was identified by protein half-life and in vivo ubiquitylation assays. The relationship between E2F4 and prostaglandin reductase 1 (PTGR1) was investigated by qRT-PCR, RT-PCR, and chromatin immunoprecipitation assays./nResults: This study found that NUCB2 expression was significantly higher in HCC tissues than in normal liver tissues, and patients with high expression displayed shorter survival rates. Inhibition of NUCB2 reduced the proliferation and metastatic potential of HCC cells in vitro and in vivo. NUCB2 depletion reduced PTGR1 expression, which reduced cell proliferation and migration. Our findings suggested that NUCB2 suppressed E2F4 degradation by interacting with E2F4. Additionally, increased E2F4 levels facilitated PTGR1 transcription by directly binding to the PTGR1 promoter./nConclusion: This study demonstrated the oncogenic properties of NUCB2 in HCC and suggested that NUCB2 facilitates hepatocellular carcinoma progression by activating the E2F4/PTGR1 axis./n/n
{"title":"NUCB2 promotes hepatocellular carcinoma cell growth and metastasis by activating the E2F4/PTGR1 axis","authors":"Yuan Wang, Bin Sun, Wei Wei, Tao Han, Jing Ma, Xiaodong Li, Chuanchun Han, Zhikun Lin","doi":"10.7150/ijbs.97861","DOIUrl":"https://doi.org/10.7150/ijbs.97861","url":null,"abstract":"<b>Background:</b> The important role of nucleobindin 2 (NUCB2) in various cancers has been recently recognized. However, its biological functions and regulatory mechanisms in hepatocellular carcinoma (HCC) remain unclear./n<b>Methods:</b> The expression level of NUCB2 in HCC was assessed using public databases, immunohistochemistry, and Western blotting. The effects of NUCB2 on cell proliferation and metastasis were investigated using colony formation, EdU, Transwell assays, and an <i>in vivo</i> mouse xenograft model. Regulation of E2F4 by NUCB2 was identified by protein half-life and <i>in vivo</i> ubiquitylation assays. The relationship between E2F4 and prostaglandin reductase 1 (PTGR1) was investigated by qRT-PCR, RT-PCR, and chromatin immunoprecipitation assays./n<b>Results:</b> This study found that NUCB2 expression was significantly higher in HCC tissues than in normal liver tissues, and patients with high expression displayed shorter survival rates. Inhibition of NUCB2 reduced the proliferation and metastatic potential of HCC cells <i>in vitro</i> and <i>in vivo</i>. NUCB2 depletion reduced PTGR1 expression, which reduced cell proliferation and migration. Our findings suggested that NUCB2 suppressed E2F4 degradation by interacting with E2F4. Additionally, increased E2F4 levels facilitated PTGR1 transcription by directly binding to the PTGR1 promoter./n<b>Conclusion:</b> This study demonstrated the oncogenic properties of NUCB2 in HCC and suggested that NUCB2 facilitates hepatocellular carcinoma progression by activating the E2F4/PTGR1 axis./n/n\u0000","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"29 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258183","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}
Bingheng Li, Bisheng Cheng, Hao Huang, Shanhe Huang, Shunli Yu, Zean Li, Shirong Peng, Tao Du, Ruihui Xie, Hai Huang
Darolutamide, an androgen receptor inhibitor, has been approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer (PCa), especially for patients with androgen receptor mutations. Owing to the unique lipidomic profile of PCa and the effect of darolutamide, the relationship between darolutamide and ferroptosis remains unclear. The present study showed that darolutamide significantly induces ferroptosis in AR+ PCa cells. Mechanistically, darolutamide promotes ferroptosis by downregulating SREBP1, which then inhibits the transcription of FASN. FASN knockdown modulates phospholipid remodeling by disrupting the balance between polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs), which induces ferroptosis. Clinically, SREBP1 and FASN are significantly overexpressed in PCa tissues and are related to poor prognosis. Moreover, the synergistic antitumor effect of combination therapy with darolutamide and ferroptosis inducers (FINs) was confirmed in PCa organoids and a mouse xenografts model. Overall, these findings revealed a novel mechanism of darolutamide mediated ferroptosis in PCa, laying the foundation for the combination of darolutamide and FINs as a new therapeutic strategy for PCa patients.
{"title":"Darolutamide-mediated phospholipid remodeling induces ferroptosis through the SREBP1-FASN axis in prostate cancer","authors":"Bingheng Li, Bisheng Cheng, Hao Huang, Shanhe Huang, Shunli Yu, Zean Li, Shirong Peng, Tao Du, Ruihui Xie, Hai Huang","doi":"10.7150/ijbs.101039","DOIUrl":"https://doi.org/10.7150/ijbs.101039","url":null,"abstract":"Darolutamide, an androgen receptor inhibitor, has been approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer (PCa), especially for patients with androgen receptor mutations. Owing to the unique lipidomic profile of PCa and the effect of darolutamide, the relationship between darolutamide and ferroptosis remains unclear. The present study showed that darolutamide significantly induces ferroptosis in AR<sup>+</sup> PCa cells. Mechanistically, darolutamide promotes ferroptosis by downregulating SREBP1, which then inhibits the transcription of FASN. FASN knockdown modulates phospholipid remodeling by disrupting the balance between polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs), which induces ferroptosis. Clinically, SREBP1 and FASN are significantly overexpressed in PCa tissues and are related to poor prognosis. Moreover, the synergistic antitumor effect of combination therapy with darolutamide and ferroptosis inducers (FINs) was confirmed in PCa organoids and a mouse xenografts model. Overall, these findings revealed a novel mechanism of darolutamide mediated ferroptosis in PCa, laying the foundation for the combination of darolutamide and FINs as a new therapeutic strategy for PCa patients.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"206 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258178","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}
Extensive loss of alveolar epithelial cells (AECs) undergoing necroptosis is a crucial mechanism of acute lung injury (ALI), but its triggering mechanism needs to be thoroughly investigated. Neutrophil extracellular traps (NETs) play a significant role in ALI. However, the effect of NETs on AECs' death has not been clarified. Our study found that intratracheal instillation of NETs disrupted lung tissue structure, suggesting that NETs could induce ALI in mice. Moreover, we observed that NETs could trigger necroptosis of AECs in vivo and in vitro. The phosphorylation levels of RIPK3 and MLKL were increased in MLE12 cells after NETs treatment (P < 0.05). Mechanistically, NETs taken up by AECs through endocytosis activated the cGAS-STING pathway and triggered AECs necroptosis. The expression of cGAS, STING, TBK1 and IRF3 were increased in MLE12 cells treated with NETs (P < 0.05). Furthermore, the cGAS inhibitor RU.521 inhibited NETs-triggered AECs necroptosis and alleviated the pulmonary damage induced by NETs in mice. In conclusion, our study demonstrates that NETs taken up by AECs via endocytosis can activate the cGAS-STING pathway and trigger AECs necroptosis to promote ALI in mice. Our findings indicate that targeting the NETs/cGAS-STING/necroptosis pathway in AECs is an effective strategy for treating ALI.
{"title":"Neutrophil extracellular traps trigger alveolar epithelial cell necroptosis through the cGAS-STING pathway during acute lung injury in mice","authors":"Han-Xi Sha, Yu-Biao Liu, Yan-Ling Qiu, Wen-Jing Zhong, Nan-Shi-Yu Yang, Chen-Yu Zhang, Jia-Xi Duan, Jian-Bing Xiong, Cha-Xiang Guan, Yong Zhou","doi":"10.7150/ijbs.99456","DOIUrl":"https://doi.org/10.7150/ijbs.99456","url":null,"abstract":"Extensive loss of alveolar epithelial cells (AECs) undergoing necroptosis is a crucial mechanism of acute lung injury (ALI), but its triggering mechanism needs to be thoroughly investigated. Neutrophil extracellular traps (NETs) play a significant role in ALI. However, the effect of NETs on AECs' death has not been clarified. Our study found that intratracheal instillation of NETs disrupted lung tissue structure, suggesting that NETs could induce ALI in mice. Moreover, we observed that NETs could trigger necroptosis of AECs <i>in vivo</i> and <i>in vitro</i>. The phosphorylation levels of RIPK3 and MLKL were increased in MLE12 cells after NETs treatment (<i>P</i> < 0.05). Mechanistically, NETs taken up by AECs through endocytosis activated the cGAS-STING pathway and triggered AECs necroptosis. The expression of cGAS, STING, TBK1 and IRF3 were increased in MLE12 cells treated with NETs (<i>P</i> < 0.05). Furthermore, the cGAS inhibitor RU.521 inhibited NETs-triggered AECs necroptosis and alleviated the pulmonary damage induced by NETs in mice. In conclusion, our study demonstrates that NETs taken up by AECs <i>via</i> endocytosis can activate the cGAS-STING pathway and trigger AECs necroptosis to promote ALI in mice. Our findings indicate that targeting the NETs/cGAS-STING/necroptosis pathway in AECs is an effective strategy for treating ALI.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"43 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258181","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}
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