Pub Date : 2024-10-01DOI: 10.1016/j.yexcr.2024.114271
Shuaijie Sun , Huijin Li , Shanshan Liu , Xiaojuan Xie , Wen Zhai , Jingjing Pan
Metabolic reprogramming is a hallmark of cancer, and abnormal lipid metabolism is associated with drug resistance in bladder cancer cells. The long noncoding RNA (lncRNA) UCA1 is overexpressed in bladder cancer, but its functional contribution to lipid metabolism remains uncharacterized. In this study, we demonstrated that lncRNA UCA1 inhibits epirubicin-induced cell apoptosis by supporting abnormal lipid metabolism in bladder cancer cells. Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPARα mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARα and downstream p-AKT/p-GSK-3β/β-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRα to the lncRNA UCA1 promoter. These findings were verified in a mouse xenograft model and are consistent with the expression patterns in human bladder cancer patients. Overall, these findings establish the role of lncRNA UCA1 in lipid metabolism and bladder cancer cell resistance to epirubicin, suggesting that lncRNA UCA1 may serve as a candidate target for enhancing bladder cancer chemotherapy.
{"title":"Long noncoding RNA UCA1 inhibits epirubicin-induced apoptosis by activating PPARα-mediated lipid metabolism","authors":"Shuaijie Sun , Huijin Li , Shanshan Liu , Xiaojuan Xie , Wen Zhai , Jingjing Pan","doi":"10.1016/j.yexcr.2024.114271","DOIUrl":"10.1016/j.yexcr.2024.114271","url":null,"abstract":"<div><div>Metabolic reprogramming is a hallmark of cancer, and abnormal lipid metabolism is associated with drug resistance in bladder cancer cells. The long noncoding RNA (lncRNA) UCA1 is overexpressed in bladder cancer, but its functional contribution to lipid metabolism remains uncharacterized. In this study, we demonstrated that lncRNA UCA1 inhibits epirubicin-induced cell apoptosis by supporting abnormal lipid metabolism in bladder cancer cells. Mechanistically, lncRNA UCA1 promotes lipid accumulation <em>in vitro</em> and <em>in vivo</em> by upregulating PPARα mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARα and downstream p-AKT/p-GSK-3β/β-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRα to the lncRNA UCA1 promoter. These findings were verified in a mouse xenograft model and are consistent with the expression patterns in human bladder cancer patients. Overall, these findings establish the role of lncRNA UCA1 in lipid metabolism and bladder cancer cell resistance to epirubicin, suggesting that lncRNA UCA1 may serve as a candidate target for enhancing bladder cancer chemotherapy.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114271"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.yexcr.2024.114269
Ke Zhang , Wen Luo , Haijun Liu , Jin Gong
Colorectal cancer (CRC) is the third deadliest cancer in the world, with a high incidence, aggressiveness, poor prognosis, and resistant to drugs. 5-fluorouracil (5-FU) is the most commonly used drug for the chemotherapeutic of CRC, however, CRC is resistant to 5-FU after a period of treatment. Therefore, there is an urgent need to explore the underlying molecular mechanisms of CRC resistance to 5-FU. In the present study, we found that the expression of PANX2 was increased in CRC tissues and metastatic tissues from the TCGA database. The K-M survival curve showed that the high expression of PANX2 was associated with poor cancer prognosis. GDSC database showed that the IC50 of 5-Fu in the PANX2 high expression group was significantly higher, and the results were verified in CRC cells. In vitro cell function and in vivo tumorigenesis experiments showed that PANX2 promoted CRC cell proliferation, clone formation, migration and tumorigenesis in vivo. WB result revealed that PANX2 may lead to resistance to 5-Fu in CRC by affecting the PI3K-AKT signaling pathway. Overall, PANX2 regulates CRC proliferation, clone formation, migration, and 5-Fu resistance by PI3K-AKT signaling pathway.
{"title":"PANX2 promotes malignant transformation of colorectal cancer and 5-Fu resistance through PI3K-AKT signaling pathway","authors":"Ke Zhang , Wen Luo , Haijun Liu , Jin Gong","doi":"10.1016/j.yexcr.2024.114269","DOIUrl":"10.1016/j.yexcr.2024.114269","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the third deadliest cancer in the world, with a high incidence, aggressiveness, poor prognosis, and resistant to drugs. 5-fluorouracil (5-FU) is the most commonly used drug for the chemotherapeutic of CRC, however, CRC is resistant to 5-FU after a period of treatment. Therefore, there is an urgent need to explore the underlying molecular mechanisms of CRC resistance to 5-FU. In the present study, we found that the expression of PANX2 was increased in CRC tissues and metastatic tissues from the TCGA database. The K-M survival curve showed that the high expression of PANX2 was associated with poor cancer prognosis. GDSC database showed that the IC50 of 5-Fu in the PANX2 high expression group was significantly higher, and the results were verified in CRC cells. In vitro cell function and in vivo tumorigenesis experiments showed that PANX2 promoted CRC cell proliferation, clone formation, migration and tumorigenesis in vivo. WB result revealed that PANX2 may lead to resistance to 5-Fu in CRC by affecting the PI3K<strong>-</strong>AKT signaling pathway. Overall, PANX2 regulates CRC proliferation, clone formation, migration, and 5-Fu resistance by PI3K<strong>-</strong>AKT signaling pathway.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114269"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.yexcr.2024.114272
Elsayed G.E. Elsakka , Heba M. Midan , Ahmed I. Abulsoud , Doaa Fathi , Nourhan M. Abdelmaksoud , Sherif S. Abdel Mageed , Mohamed Bakr Zaki , Mai A. Abd-Elmawla , Nehal I. Rizk , Mahmoud A. Elrebehy , Tamer M. Abdelghany , Ahmed E. Elesawy , Reem K. Shahin , Manar Mohammed El Tabaa , Osama A. Mohammed , Mustafa Ahmed Abdel-Reheim , Mohammed S. Elballal , Ahmed S. Doghish
The newly discovered programmed iron-dependent necrosis, ferroptosis, is a novel pathway that is controlled by iron-dependent lipid peroxidation and cellular redox changes. It can be triggered intrinsically by low antioxidant enzyme activity or extrinsically by blocking amino acid transporters or activating iron transporters. The induction of ferroptosis involves the activation of specific proteins, suppression of transporters, and increased endoplasmic reticulum (ER) stress (a condition in which the ER, a crucial organelle involved in protein folding and processing, becomes overwhelmed by an accumulation of misfolded or unfolded proteins. This situation disrupts the normal functioning of the ER, leading to a cellular stress response known as the unfolded protein response), leading to lipid peroxidation byproduct accumulation and toxic reactive oxygen species (ROS), which are highly reactive molecules derived from diatomic oxygen and include various forms such as superoxide (O₂⁻), hydroxyl radicals (•OH), and hydrogen peroxide (H₂O₂). Ferroptosis is closely associated with signaling molecules in lung cancer, including epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1-alpha (HIF-1α), and P53, and is regulated by epigenetic factors such as microRNAs (miRNAs). miRNAs are small non-coding RNA molecules that regulate gene expression by binding to target messenger RNAs (mRNAs), leading to translational repression or degradation. Several miRNAs have been found to modulate ferroptosis by targeting key genes involved in iron metabolism, lipid peroxidation, and antioxidant defense pathways. The research on ferroptosis has expanded to target its role in lung cancer treatment and resistance prevention. This review encapsulates the significance of ferroptosis in lung cancer. Understanding the mechanisms and implications of ferroptosis in lung cancer cells may lead to targeted therapies exploiting cancer cell vulnerabilities to ferroptosis Also, improving treatment outcomes, and overcoming resistance.
{"title":"Emerging insights: miRNA modulation of ferroptosis pathways in lung cancer","authors":"Elsayed G.E. Elsakka , Heba M. Midan , Ahmed I. Abulsoud , Doaa Fathi , Nourhan M. Abdelmaksoud , Sherif S. Abdel Mageed , Mohamed Bakr Zaki , Mai A. Abd-Elmawla , Nehal I. Rizk , Mahmoud A. Elrebehy , Tamer M. Abdelghany , Ahmed E. Elesawy , Reem K. Shahin , Manar Mohammed El Tabaa , Osama A. Mohammed , Mustafa Ahmed Abdel-Reheim , Mohammed S. Elballal , Ahmed S. Doghish","doi":"10.1016/j.yexcr.2024.114272","DOIUrl":"10.1016/j.yexcr.2024.114272","url":null,"abstract":"<div><div>The newly discovered programmed iron-dependent necrosis, ferroptosis, is a novel pathway that is controlled by iron-dependent lipid peroxidation and cellular redox changes. It can be triggered intrinsically by low antioxidant enzyme activity or extrinsically by blocking amino acid transporters or activating iron transporters. The induction of ferroptosis involves the activation of specific proteins, suppression of transporters, and increased endoplasmic reticulum (ER) stress (a condition in which the ER, a crucial organelle involved in protein folding and processing, becomes overwhelmed by an accumulation of misfolded or unfolded proteins. This situation disrupts the normal functioning of the ER, leading to a cellular stress response known as the unfolded protein response), leading to lipid peroxidation byproduct accumulation and toxic reactive oxygen species (ROS), which are highly reactive molecules derived from diatomic oxygen and include various forms such as superoxide (O₂⁻), hydroxyl radicals (•OH), and hydrogen peroxide (H₂O₂). Ferroptosis is closely associated with signaling molecules in lung cancer, including epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1-alpha (HIF-1α), and P53, and is regulated by epigenetic factors such as microRNAs (miRNAs). miRNAs are small non-coding RNA molecules that regulate gene expression by binding to target messenger RNAs (mRNAs), leading to translational repression or degradation. Several miRNAs have been found to modulate ferroptosis by targeting key genes involved in iron metabolism, lipid peroxidation, and antioxidant defense pathways. The research on ferroptosis has expanded to target its role in lung cancer treatment and resistance prevention. This review encapsulates the significance of ferroptosis in lung cancer. Understanding the mechanisms and implications of ferroptosis in lung cancer cells may lead to targeted therapies exploiting cancer cell vulnerabilities to ferroptosis Also, improving treatment outcomes, and overcoming resistance.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114272"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alopecia areata (AA) is a chronic autoimmune disease. Th1/Th2 and Treg/Th17 cells and their cytokines are implicated in AA, and we explored their clinical significance in AA.
Methods
AA patients and healthy people (controls) were enrolled, with their Th1/Th2/Th17/Treg cell proportion changes and serum Th1 (INF-γ)/Th2 (IL-5, IL-6)/Th17 (IL-17, IL-22)/Treg (IL-35) cytokine levels assessed. AA patients were assigned into mild, moderate and severe alopecia according to Severity of Alopecia Tool (SALT). The relationship between alopecia severity and initial onset age, disease course, family/smoking/drinking history and sleep disorders was explored. Th1/Th2 and Treg/Th17 cells and their cytokine levels in AA patients with different severity levels were compared. The correlation between cytokine levels and SALT scores was analyzed using Spearman. Additionally, the changes of serum cytokine levels in inactive/active AA patients were compared.
Results
AA patients differed from controls in family history/smoking history/drinking history/sleep disorders. Peripheral blood Th1/Th2/Th17 cell proportions and INF-γ/IL-5/IL-6/IL-17/IL-22 levels increased, while Treg cell proportions and IL-35 level dropped. With higher alopecia severity, the proportions of Th1, Th2 and Th17 cells increased, and Treg cell proportion decreased. AA patients with mild/moderate alopecia had significant differences in IL-17 level. Serum INF-γ, IL-5, IL-17 and IL-22 levels were elevated, and IL-35 level dropped in severe AA patients versus moderate AA patients.
Conclusion
Th1/Th2/Th17 cell proportions and serum INF-γ/IL-5/IL-6/IL-17/IL-22 levels in AA patients were up-regulated, while Treg cell proportion and IL-35 level were repressed. SALT scores were positively-correlated with serum IL-5/IL-17 levels. SALT scores were negatively-correlated with serum IL-35.
背景资料斑秃（AA）是一种慢性自身免疫性疾病。方法招募AA患者和健康人（对照组），评估他们的Th1/Th2/Th17/Treg细胞比例变化和血清Th1（INF-γ）/Th2（IL-5、IL-6）/Th17（IL-17、IL-22）/Treg（IL-35）细胞因子水平。根据脱发严重程度工具（SALT）将 AA 患者分为轻度、中度和重度脱发。研究还探讨了脱发严重程度与最初发病年龄、病程、家族史/吸烟史/饮酒史和睡眠障碍之间的关系。比较了不同严重程度 AA 患者的 Th1/Th2 和 Treg/Th17 细胞及其细胞因子水平。使用 Spearman 分析了细胞因子水平与 SALT 评分之间的相关性。结果 AAA 患者在家族史/吸烟史/饮酒史/睡眠障碍方面与对照组存在差异。外周血Th1/Th2/Th17细胞比例和INF-γ/IL-5/IL-6/IL-17/IL-22水平升高，而Treg细胞比例和IL-35水平下降。脱发严重程度越高，Th1、Th2 和 Th17 细胞比例越高，Treg 细胞比例越低。轻度/中度脱发的 AA 患者的 IL-17 水平有显著差异。结论AA患者中Th1/Th2/Th17细胞比例和血清INF-γ/IL-5/IL-6/IL-17/IL-22水平上调，而Treg细胞比例和IL-35水平受抑制。SALT 评分与血清 IL-5/IL-17 水平呈正相关。SALT 评分与血清 IL-35 呈负相关。
{"title":"Changes and significance of Th1/Th2 and Treg/Th17 cells and their cytokines in patients with alopecia areata","authors":"Xiaojing Yang , Wei Zhang , Xuming Zhao , Wenli Hou , Yuanhui Wu , Dongmei Feng , Zhaoying Meng , Xiangzhao Zhou","doi":"10.1016/j.yexcr.2024.114259","DOIUrl":"10.1016/j.yexcr.2024.114259","url":null,"abstract":"<div><h3>Background</h3><div>Alopecia areata (AA) is a chronic autoimmune disease. Th1/Th2 and Treg/Th17 cells and their cytokines are implicated in AA, and we explored their clinical significance in AA.</div></div><div><h3>Methods</h3><div>AA patients and healthy people (controls) were enrolled, with their Th1/Th2/Th17/Treg cell proportion changes and serum Th1 (INF-γ)/Th2 (IL-5, IL-6)/Th17 (IL-17, IL-22)/Treg (IL-35) cytokine levels assessed. AA patients were assigned into mild, moderate and severe alopecia according to Severity of Alopecia Tool (SALT). The relationship between alopecia severity and initial onset age, disease course, family/smoking/drinking history and sleep disorders was explored. Th1/Th2 and Treg/Th17 cells and their cytokine levels in AA patients with different severity levels were compared. The correlation between cytokine levels and SALT scores was analyzed using Spearman. Additionally, the changes of serum cytokine levels in inactive/active AA patients were compared.</div></div><div><h3>Results</h3><div>AA patients differed from controls in family history/smoking history/drinking history/sleep disorders. Peripheral blood Th1/Th2/Th17 cell proportions and INF-γ/IL-5/IL-6/IL-17/IL-22 levels increased, while Treg cell proportions and IL-35 level dropped. With higher alopecia severity, the proportions of Th1, Th2 and Th17 cells increased, and Treg cell proportion decreased. AA patients with mild/moderate alopecia had significant differences in IL-17 level. Serum INF-γ, IL-5, IL-17 and IL-22 levels were elevated, and IL-35 level dropped in severe AA patients versus moderate AA patients.</div></div><div><h3>Conclusion</h3><div>Th1/Th2/Th17 cell proportions and serum INF-γ/IL-5/IL-6/IL-17/IL-22 levels in AA patients were up-regulated, while Treg cell proportion and IL-35 level were repressed. SALT scores were positively-correlated with serum IL-5/IL-17 levels. SALT scores were negatively-correlated with serum IL-35.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114259"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-21DOI: 10.1016/j.yexcr.2024.114267
Darmadi Darmadi , Zafar Aminov , Ahmed Hjazi , Roopashree R , Syeda Wajida Kazmi , Yasser Fakri Mustafa , Beneen Hosseen , Abhishek Sharma , Mahmood Hasen Shuhata Alubiady , Salah Hassan Zain Al-Abdeen
The EGF receptors (EGFRs) signaling pathway is essential for tumorigenesis and progression of cancer. Emerging evidence suggests that miRNAs are essential regulators of EGF signaling, influencing various pathway components and tumor behavior. This article discusses the underlying mechanisms and clinical implications of miRNA-mediated regulation of EGF signaling in cancer. miRNAs utilize multiple mechanisms to exert their regulatory effects on EGF signaling. They can target EGF ligands, including EGF and TGF-directly, inhibiting their expression and secretion. In addition, miRNAs can modulate EGF signaling indirectly by targeting EGF receptors, downstream signaling molecules, and transcription factors implicated in regulating the EGF pathway. These miRNAs can disrupt the delicate equilibrium of EGF signaling, resulting in aberrant activation and fostering tumor cell proliferation, survival, angiogenesis, and metastasis. The dysregulation of the expression of specific miRNAs has been linked to clinical outcomes in numerous types of cancer. Specific profiles of miRNA expression have been identified as prognostic markers, reflecting tumor characteristics, invasiveness, metastatic potential, and therapeutic response. These miRNAs can serve as potential therapeutic targets for interventions that modulate EGF signaling and improve patient outcomes. Understanding the intricate relationship between miRNAs and EGF signaling in cancer can transform cancer diagnosis, prognosis, and treatment. The identification of specific miRNAs involved in the regulation of the EGF pathway opens the door to the development of targeted therapies and personalized medicine approaches. In addition, miRNA-based interventions promise to overcome therapeutic resistance and improve the efficacy of existing treatments. miRNAs are crucial regulators of EGF signaling in cancer, affecting tumor behavior and clinical outcomes. Further research is required to decipher the complex network of miRNA-mediated EGF signaling regulation and translate these findings into clinically applicable strategies for enhanced cancer treatment.
{"title":"Investigation of the regulation of EGF signaling by miRNAs, delving into the underlying mechanism and signaling pathways in cancer","authors":"Darmadi Darmadi , Zafar Aminov , Ahmed Hjazi , Roopashree R , Syeda Wajida Kazmi , Yasser Fakri Mustafa , Beneen Hosseen , Abhishek Sharma , Mahmood Hasen Shuhata Alubiady , Salah Hassan Zain Al-Abdeen","doi":"10.1016/j.yexcr.2024.114267","DOIUrl":"10.1016/j.yexcr.2024.114267","url":null,"abstract":"<div><div>The EGF receptors (EGFRs) signaling pathway is essential for tumorigenesis and progression of cancer. Emerging evidence suggests that miRNAs are essential regulators of EGF signaling, influencing various pathway components and tumor behavior. This article discusses the underlying mechanisms and clinical implications of miRNA-mediated regulation of EGF signaling in cancer. miRNAs utilize multiple mechanisms to exert their regulatory effects on EGF signaling. They can target EGF ligands, including EGF and TGF-directly, inhibiting their expression and secretion. In addition, miRNAs can modulate EGF signaling indirectly by targeting EGF receptors, downstream signaling molecules, and transcription factors implicated in regulating the EGF pathway. These miRNAs can disrupt the delicate equilibrium of EGF signaling, resulting in aberrant activation and fostering tumor cell proliferation, survival, angiogenesis, and metastasis. The dysregulation of the expression of specific miRNAs has been linked to clinical outcomes in numerous types of cancer. Specific profiles of miRNA expression have been identified as prognostic markers, reflecting tumor characteristics, invasiveness, metastatic potential, and therapeutic response. These miRNAs can serve as potential therapeutic targets for interventions that modulate EGF signaling and improve patient outcomes. Understanding the intricate relationship between miRNAs and EGF signaling in cancer can transform cancer diagnosis, prognosis, and treatment. The identification of specific miRNAs involved in the regulation of the EGF pathway opens the door to the development of targeted therapies and personalized medicine approaches. In addition, miRNA-based interventions promise to overcome therapeutic resistance and improve the efficacy of existing treatments. miRNAs are crucial regulators of EGF signaling in cancer, affecting tumor behavior and clinical outcomes. Further research is required to decipher the complex network of miRNA-mediated EGF signaling regulation and translate these findings into clinically applicable strategies for enhanced cancer treatment.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114267"},"PeriodicalIF":3.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Type 2 diabetes mellitus (DM) is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). With the increasing prevalence of type 2 DM and MASLD due to lifestyle changes, understanding their impact on liver health is crucial. However, the hepatocellular damage caused by glucose alone is unknown. This study investigates the effect of excess glucose on hepatocytes, focusing on oxidative stress, endoplasmic reticulum stress (ER stress), apoptosis, autophagy, and cell proliferation. We treated an immortalized-human hepatocyte cell line with excess glucose and analyzed. Excess glucose induced oxidative stress and ER stress in a time- and concentration-dependent manner, leading to apoptosis. Oxidative stress and ER stress were independently induced by excess glucose. Proteasome inhibitors and palmitic acid exacerbated glucose-induced stress, leading to the formation of Mallory-Denk body-like inclusion bodies. Despite these stresses, autophagic flux was not altered. Excess glucose also caused DNA damage but did not affect cell proliferation. This suggests that glucose itself can contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH) and carcinogenesis of HCC in patients with type 2 DM. Managing blood glucose levels is crucial to prevent hepatocyte damage and associated complications.
2 型糖尿病（DM）是代谢功能障碍相关性脂肪性肝病（MASLD）和肝细胞癌（HCC）的重要危险因素。随着生活方式的改变，2 型糖尿病和代谢性脂肪肝的发病率不断上升，了解它们对肝脏健康的影响至关重要。然而，仅由葡萄糖引起的肝细胞损伤尚不清楚。本研究调查了过量葡萄糖对肝细胞的影响，重点关注氧化应激、内质网应激（ER应激）、细胞凋亡、自噬和细胞增殖。我们用过量葡萄糖处理了永生化人肝细胞系，并对其进行了分析。过量葡萄糖以时间和浓度依赖的方式诱导氧化应激和ER应激，导致细胞凋亡。过量葡萄糖可独立诱导氧化应激和ER应激。蛋白酶体抑制剂和棕榈酸加剧了葡萄糖诱导的应激，导致马洛里-登克体样包涵体的形成。尽管存在这些应激，自噬通量并没有改变。过量的葡萄糖也会造成 DNA 损伤，但不会影响细胞增殖。这表明，葡萄糖本身可导致 2 型糖尿病患者代谢功能障碍相关性脂肪性肝炎（MASH）和 HCC 癌变的进展。控制血糖水平对于预防肝细胞损伤和相关并发症至关重要。
{"title":"Excess glucose alone induces hepatocyte damage due to oxidative stress and endoplasmic reticulum stress","authors":"Tsuguru Hayashi, Shinji Oe, Koichiro Miyagawa, Masashi Kusanaga, Noriyoshi Ogino, Yuichi Honma, Masaru Harada","doi":"10.1016/j.yexcr.2024.114264","DOIUrl":"10.1016/j.yexcr.2024.114264","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (DM) is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). With the increasing prevalence of type 2 DM and MASLD due to lifestyle changes, understanding their impact on liver health is crucial. However, the hepatocellular damage caused by glucose alone is unknown. This study investigates the effect of excess glucose on hepatocytes, focusing on oxidative stress, endoplasmic reticulum stress (ER stress), apoptosis, autophagy, and cell proliferation. We treated an immortalized-human hepatocyte cell line with excess glucose and analyzed. Excess glucose induced oxidative stress and ER stress in a time- and concentration-dependent manner, leading to apoptosis. Oxidative stress and ER stress were independently induced by excess glucose. Proteasome inhibitors and palmitic acid exacerbated glucose-induced stress, leading to the formation of Mallory-Denk body-like inclusion bodies. Despite these stresses, autophagic flux was not altered. Excess glucose also caused DNA damage but did not affect cell proliferation. This suggests that glucose itself can contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH) and carcinogenesis of HCC in patients with type 2 DM. Managing blood glucose levels is crucial to prevent hepatocyte damage and associated complications.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114264"},"PeriodicalIF":3.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To the best of our knowledge, there are no reports of proteomic analysis for the identification of unknown proteins involved in resistance to anaplastic lymphoma kinase (ALK) inhibitors. In this study, we investigated the proteins involved in resistance to alectinib, a representative ALK inhibitor, through proteomic analysis and the possibility of overcoming resistance.
Methods
An ALK-positive lung adenocarcinoma cell line (ABC-11) and the corresponding alectinib-resistant cell line (ABC-11/CHR2) were used. Two-dimensional difference gel electrophoresis (2D DIGE) was performed; the stained gel was scanned and the spots were analyzed using DeCyder TM2D 7.0. Mass spectrometry (MS) with the UltrafleXtreme matrix-assisted laser desorption ionization-tandem time-of-flight (MALDI-TOF/TOF) MS system was performed. For the MS/MS analysis, the samples were spotted on an AnchorChipTM 600 TF plate. The peptide masses obtained in the reflector positive mode were acquired at m/z of 400−6000. MS/MS data were searched against the NCBI protein databases. Growth inhibition was measured using an MTT assay. The isobologram and combination index were calculated based on the median-effect analysis. Western blotting was performed using antibodies, including superoxide dismutase (SOD) 1, MET, ERK, PARP, AKT, and BRCA1.
Results
The 2D DIGE for ABC-11 and ABC-11/CHR2 showed different expression levels in about 2000 spots. SOD was identified from spots highly expressed in resistant strains. Western blotting also confirmed SOD1 overexpression in ABC-11/CHR2. siSOD1 enhanced the growth inhibitory effects of alectinib, increased cleaved PARP levels, and decreased pERK, pAKT, and BRCA1 levels with a combination of alectinib. In addition, the combination of LCS-1, an SOD1 inhibitor, and alectinib synergistically suppressed the growth in ABC-11/CHR2, but not in ABC-11.
Conclusions
SOD1 overexpression is thought to be a mechanism for alectinib resistance, suggesting the possibility of overcoming resistance using SOD1 inhibitors.
{"title":"A novel molecular target, superoxide dismutase 1, in ALK inhibitor-resistant lung cancer cells, detected through proteomic analysis","authors":"Noriko Miyake , Nobuaki Ochi , Masami Takeyama , Hideko Isozaki , Eiki Ichihara , Hiromichi Yamane , Takuya Fukazawa , Yasunari Nagasaki , Tatsuyuki Kawahara , Hidekazu Nakanishi , Akio Hiraki , Katsuyuki Kiura , Nagio Takigawa","doi":"10.1016/j.yexcr.2024.114266","DOIUrl":"10.1016/j.yexcr.2024.114266","url":null,"abstract":"<div><h3>Backgrounds</h3><div>To the best of our knowledge, there are no reports of proteomic analysis for the identification of unknown proteins involved in resistance to anaplastic lymphoma kinase (ALK) inhibitors. In this study, we investigated the proteins involved in resistance to alectinib, a representative ALK inhibitor, through proteomic analysis and the possibility of overcoming resistance.</div></div><div><h3>Methods</h3><div>An ALK-positive lung adenocarcinoma cell line (ABC-11) and the corresponding alectinib-resistant cell line (ABC-11/CHR2) were used. Two-dimensional difference gel electrophoresis (2D DIGE) was performed; the stained gel was scanned and the spots were analyzed using DeCyder TM2D 7.0. Mass spectrometry (MS) with the UltrafleXtreme matrix-assisted laser desorption ionization-tandem time-of-flight (MALDI-TOF/TOF) MS system was performed. For the MS/MS analysis, the samples were spotted on an AnchorChipTM 600 TF plate. The peptide masses obtained in the reflector positive mode were acquired at <em>m</em>/<em>z</em> of 400−6000. MS/MS data were searched against the NCBI protein databases. Growth inhibition was measured using an MTT assay. The isobologram and combination index were calculated based on the median-effect analysis. Western blotting was performed using antibodies, including superoxide dismutase (SOD) 1, MET, ERK, PARP, AKT, and BRCA1.</div></div><div><h3>Results</h3><div>The 2D DIGE for ABC-11 and ABC-11/CHR2 showed different expression levels in about 2000 spots. SOD was identified from spots highly expressed in resistant strains. Western blotting also confirmed SOD1 overexpression in ABC-11/CHR2. siSOD1 enhanced the growth inhibitory effects of alectinib, increased cleaved PARP levels, and decreased pERK, pAKT, and BRCA1 levels with a combination of alectinib. In addition, the combination of LCS-1, an SOD1 inhibitor, and alectinib synergistically suppressed the growth in ABC-11/CHR2, but not in ABC-11.</div></div><div><h3>Conclusions</h3><div>SOD1 overexpression is thought to be a mechanism for alectinib resistance, suggesting the possibility of overcoming resistance using SOD1 inhibitors.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114266"},"PeriodicalIF":3.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1016/j.yexcr.2024.114263
Yuan Yuan, Tong Liu
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disorder characterized by alterations in the balance between inflammatory and regulatory cytokines. Mesenchymal stem cells (MSCs), which are non-hematopoietic stem cells with multipotent differentiation potential, due to their immunomodulatory, tissue repair, low immunogenicity, and chemotactic properties, have garnered increasing interest in SLE treatment. Studies increasingly reveal the heterogeneous nature of MSC populations. With sources including dental pulp, adipose tissue, bone marrow, and umbilical cord, the therapeutic effects of MSCs on SLE vary depending on their origin. This review consolidates clinical research on MSCs from different sources in treating SLE and analyzes the possible causes underlying these variable outcomes. Additionally, it elucidates five potential factors impacting the outcomes of MSC therapy in SLE: the influence of the microenvironment on MSCs, the complexity and paradoxical aspects of MSC mechanisms in SLE treatment, the heterogeneity of MSCs, the in vivo differentiation potential and post-transplant survival rates of MSCs, and disparities in MSC preparation conditions.
{"title":"Influence of mesenchymal stem cells from different origins on the therapeutic effectiveness of systemic lupus erythematosus","authors":"Yuan Yuan, Tong Liu","doi":"10.1016/j.yexcr.2024.114263","DOIUrl":"10.1016/j.yexcr.2024.114263","url":null,"abstract":"<div><div>Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disorder characterized by alterations in the balance between inflammatory and regulatory cytokines. Mesenchymal stem cells (MSCs), which are non-hematopoietic stem cells with multipotent differentiation potential, due to their immunomodulatory, tissue repair, low immunogenicity, and chemotactic properties, have garnered increasing interest in SLE treatment. Studies increasingly reveal the heterogeneous nature of MSC populations. With sources including dental pulp, adipose tissue, bone marrow, and umbilical cord, the therapeutic effects of MSCs on SLE vary depending on their origin. This review consolidates clinical research on MSCs from different sources in treating SLE and analyzes the possible causes underlying these variable outcomes. Additionally, it elucidates five potential factors impacting the outcomes of MSC therapy in SLE: the influence of the microenvironment on MSCs, the complexity and paradoxical aspects of MSC mechanisms in SLE treatment, the heterogeneity of MSCs, the <em>in vivo</em> differentiation potential and post-transplant survival rates of MSCs, and disparities in MSC preparation conditions.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114263"},"PeriodicalIF":3.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1016/j.yexcr.2024.114255
Jing Guan , Lengyun Yin , Qi Huang , Jiamei Chen , Hui Liu , Jianmin Li
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease. N6-methyladenosine (m6A) is a reversible RNA modification that was shown to be associated with IPF development. The present study aimed to explore the function and potential mechanism of the m6A methylation enzyme zinc finger CCCH-type containing 13 (ZC3H13) in IPF. In the study, bioinformatic screening yielded a differentially expressed m6A gene, ZC3H13, which was down-regulated in GEO microarrays, BLM-induced mouse models, and cellular models. Overexpression of ZC3H13 reduced histopathological damage of lung tissues in mice, mitigated fibrosis (including reduced α-SMA, collagen Ⅰ, and Vimentin levels, and elevated E-cadherin levels), decreased lung/body weight ratio and lung hydroxyproline levels, reduced oxidative stress (increased SOD activity and GSH-Px activity and decreased MDA levels), suppressed apoptosis within lung tissues and MLE-12 cells, promoted Bcl-2 expression, and inhibited Bax expression. Bax expression was found to be negatively correlated with ZC3H13 expression by correlation analysis. ZC3H13 could bind Bax mRNA and promote its m6A methylation through reading protein YTHDC1, thereby inhibiting its stability. Bax inhibition ameliorated BLM-induced MLE-12 cell dysfunction and partially abrogated the inhibition of MLE-12 cell function by ZC3H13 downregulation. In conclusion, m6A methyltransferase ZC3H13 impedes lung epithelial cell apoptosis and thus improves pulmonary fibrosis by promoting Bax mRNA m6A methylation and down-regulating Bax expression through reading protein YTHDC1.
{"title":"m6A methyltransferase ZC3H13 improves pulmonary fibrosis in mice through regulating Bax expression","authors":"Jing Guan , Lengyun Yin , Qi Huang , Jiamei Chen , Hui Liu , Jianmin Li","doi":"10.1016/j.yexcr.2024.114255","DOIUrl":"10.1016/j.yexcr.2024.114255","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease. N6-methyladenosine (m<sup>6</sup>A) is a reversible RNA modification that was shown to be associated with IPF development. The present study aimed to explore the function and potential mechanism of the m<sup>6</sup>A methylation enzyme zinc finger CCCH-type containing 13 (ZC3H13) in IPF. In the study, bioinformatic screening yielded a differentially expressed m<sup>6</sup>A gene, ZC3H13, which was down-regulated in GEO microarrays, BLM-induced mouse models, and cellular models. Overexpression of ZC3H13 reduced histopathological damage of lung tissues in mice, mitigated fibrosis (including reduced α-SMA, collagen Ⅰ, and Vimentin levels, and elevated E-cadherin levels), decreased lung/body weight ratio and lung hydroxyproline levels, reduced oxidative stress (increased SOD activity and GSH-Px activity and decreased MDA levels), suppressed apoptosis within lung tissues and MLE-12 cells, promoted Bcl-2 expression, and inhibited Bax expression. Bax expression was found to be negatively correlated with ZC3H13 expression by correlation analysis. ZC3H13 could bind Bax mRNA and promote its m<sup>6</sup>A methylation through reading protein YTHDC1, thereby inhibiting its stability. Bax inhibition ameliorated BLM-induced MLE-12 cell dysfunction and partially abrogated the inhibition of MLE-12 cell function by ZC3H13 downregulation. In conclusion, m<sup>6</sup>A methyltransferase ZC3H13 impedes lung epithelial cell apoptosis and thus improves pulmonary fibrosis by promoting Bax mRNA m<sup>6</sup>A methylation and down-regulating Bax expression through reading protein YTHDC1.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114255"},"PeriodicalIF":3.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.yexcr.2024.114262
You Fu , Chen-Jun Guo , Zhi-Jie Liu , Ji-Long Liu
The cytoophidium is a novel type of membraneless organelle, first observed in the ovaries of Drosophila using fluorescence microscopy. In vitro, purified Drosophila melanogaster CTPS (dmCTPS) can form metabolic filaments under the presence of either substrates or products, and their structures that have been analyzed using cryo-electron microscopy (cryo-EM). These dmCTPS filaments are considered the fundamental units of cytoophidia. However, due to the resolution gap between light and electron microscopy, the precise assembly pattern of cytoophidia remains unclear. In this study, we find that dmCTPS filaments can spontaneously assemble in vitro, forming network structures that reach micron-scale dimensions. Using cryo-electron tomography (cryo-ET), we reconstruct the network structures formed by dmCTPS filaments under substrate or product binding conditions and elucidate their assembly process. The dmCTPS filaments initially form structural bundles, which then further assemble into larger networks. By identifying, tracking, and statistically analyzing the filaments, we observed distinct characteristics of the structural bundles formed under different conditions. This study provides the first systematic analysis of dmCTPS filament networks, offering new insights into the relationship between cytoophidia and metabolic filaments.
{"title":"Architecture of CTPS filament networks revealed by cryo-electron tomography","authors":"You Fu , Chen-Jun Guo , Zhi-Jie Liu , Ji-Long Liu","doi":"10.1016/j.yexcr.2024.114262","DOIUrl":"10.1016/j.yexcr.2024.114262","url":null,"abstract":"<div><div>The cytoophidium is a novel type of membraneless organelle, first observed in the ovaries of <em>Drosophila</em> using fluorescence microscopy. <em>In vitro</em>, purified <em>Drosophila melanogaster</em> CTPS (dmCTPS) can form metabolic filaments under the presence of either substrates or products, and their structures that have been analyzed using cryo-electron microscopy (cryo-EM). These dmCTPS filaments are considered the fundamental units of cytoophidia. However, due to the resolution gap between light and electron microscopy, the precise assembly pattern of cytoophidia remains unclear. In this study, we find that dmCTPS filaments can spontaneously assemble <em>in vitro</em>, forming network structures that reach micron-scale dimensions. Using cryo-electron tomography (cryo-ET), we reconstruct the network structures formed by dmCTPS filaments under substrate or product binding conditions and elucidate their assembly process. The dmCTPS filaments initially form structural bundles, which then further assemble into larger networks. By identifying, tracking, and statistically analyzing the filaments, we observed distinct characteristics of the structural bundles formed under different conditions. This study provides the first systematic analysis of dmCTPS filament networks, offering new insights into the relationship between cytoophidia and metabolic filaments.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114262"},"PeriodicalIF":3.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014482724003537/pdfft?md5=24f45cf814818b4c23776844d32d213c&pid=1-s2.0-S0014482724003537-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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