Pub Date : 2023-10-11eCollection Date: 2023-01-01DOI: 10.1155/2023/7365503
Le Wang, Xi Chen, Lei Song, Hua Zou
Background: Ovarian cancer (OC) is the leading cause of gynecological cancer death and the fifth most common cause of cancer-related death in women in America. Programmed cell death played a vital role in tumor progression and immunotherapy response in cancer.
Methods: The prognostic cell death signature (CDS) was constructed with an integrative machine learning procedure, including 10 methods, using TCGA, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082 datasets. Several methods and single-cell analysis were used to explore the correlation between CDS and the ecosystem and therapy response of OC patients.
Results: The prognostic CDS constructed by the combination of StepCox (n = both) + Enet (alpha = 0.2) acted as an independent risk factor for the overall survival (OS) of OC patients and showed stable and powerful performance in predicting the OS rate of OC patients. Compared with tumor grade, clinical stage, and many developed signatures, the CDS had a higher C-index. OC patients with low CDS score had a higher level of CD8+ cytotoxic T, B cell, and M1-like macrophage, representing a related immunoactivated ecosystem. A low CDS score indicated a higher PD1 and CTLA4 immunophenoscore, higher tumor mutation burden score, lower tumor immune dysfunction and exclusion score, and lower tumor escape score in OC, demonstrating a better immunotherapy response. OC patients with high CDS score had a higher gene set score of cancer-related hallmarks, including angiogenesis, epithelial-mesenchymal transition, hypoxia, glycolysis, and notch signaling.
Conclusion: The current study constructed a novel CDS for OC, which could serve as an indicator for predicting the prognosis, ecosystem, and immunotherapy benefits of OC patients.
{"title":"Machine Learning Developed a Programmed Cell Death Signature for Predicting Prognosis, Ecosystem, and Drug Sensitivity in Ovarian Cancer.","authors":"Le Wang, Xi Chen, Lei Song, Hua Zou","doi":"10.1155/2023/7365503","DOIUrl":"10.1155/2023/7365503","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) is the leading cause of gynecological cancer death and the fifth most common cause of cancer-related death in women in America. Programmed cell death played a vital role in tumor progression and immunotherapy response in cancer.</p><p><strong>Methods: </strong>The prognostic cell death signature (CDS) was constructed with an integrative machine learning procedure, including 10 methods, using TCGA, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082 datasets. Several methods and single-cell analysis were used to explore the correlation between CDS and the ecosystem and therapy response of OC patients.</p><p><strong>Results: </strong>The prognostic CDS constructed by the combination of StepCox (<i>n</i> = both) + Enet (alpha = 0.2) acted as an independent risk factor for the overall survival (OS) of OC patients and showed stable and powerful performance in predicting the OS rate of OC patients. Compared with tumor grade, clinical stage, and many developed signatures, the CDS had a higher C-index. OC patients with low CDS score had a higher level of CD8+ cytotoxic T, B cell, and M1-like macrophage, representing a related immunoactivated ecosystem. A low CDS score indicated a higher PD1 and CTLA4 immunophenoscore, higher tumor mutation burden score, lower tumor immune dysfunction and exclusion score, and lower tumor escape score in OC, demonstrating a better immunotherapy response. OC patients with high CDS score had a higher gene set score of cancer-related hallmarks, including angiogenesis, epithelial-mesenchymal transition, hypoxia, glycolysis, and notch signaling.</p><p><strong>Conclusion: </strong>The current study constructed a novel CDS for OC, which could serve as an indicator for predicting the prognosis, ecosystem, and immunotherapy benefits of OC patients.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10586435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49693392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Early reperfusion into the myocardium after ischemia causes myocardial ischemia-reperfusion (I/R) injury and ferroptosis was involved. Ischemia activates the expression of a series of oxidative stress genes and their downstream regulatory genes, including ferroptosis-related genes such as nuclear factor E2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and SLC7A11. This study adopted primary cardiomyocytes and I/R in rats to evaluate the ferroptosis and changing of Nrf2-SLC7A11/heme oxygenase-1 (HO-1) in vitro and in vivo. Online analysis tools were used to predict the possible target Kelch-like ECH-associated protein 1 (Keap1) of miR-432-5p. The mimic of miR-432-5p plasmid was constructed to verify the effect of miR-432-5p on ferroptosis. We found that hypoxia/reoxygenation (H/R) in cardiomyocytes and I/R in rats induced lipid peroxidation and ferroptosis in cardiomyocytes. The activation of the Nrf2-SLC7A11/HO-1 pathway protects cardiomyocytes from ferroptosis. Downregulation of miR-432-5p has been confirmed in H/R cardiomyocytes (in vitro) and cardiomyocytes in myocardial infarction rats (in vivo). Upregulation of miR-432-5p inhibited ferroptosis of cardiomyocytes induced by RAS-selective lethal 3 (RSL3), an inhibitor of GPX4 and ferroptosis inducer through decreasing the binding protein of Nrf2, Keap1, which was confirmed by bioinformatics and mutation assay. Knockdown Nrf2 attenuates the protection effect of miR-432-5p on H/R cardiomyocytes. Intravenous delivery of liposome carriers of miR-432-5p remarkably ameliorated cardiomyocyte impairment in the I/R animal model. In conclusion, miR-432-5p inhibits the ferroptosis in cardiomyocytes induced by H/R by activating Nrf2/SLC7A11 axis by degrading Keap1 and is a potential drug target for clinical myocardial infarction treatment.
{"title":"miR-432-5p Inhibits the Ferroptosis in Cardiomyocytes Induced by Hypoxia/Reoxygenation via Activating Nrf2/SLC7A11 Axis by Degrading Keap1.","authors":"Wei Geng, Shaohua Yan, Xinyue Li, Qiumei Liu, Xuefei Zhang, Xinshun Gu, Xiang Tian, Yunfa Jiang","doi":"10.1155/2023/1293200","DOIUrl":"10.1155/2023/1293200","url":null,"abstract":"<p><p>Early reperfusion into the myocardium after ischemia causes myocardial ischemia-reperfusion (I/R) injury and ferroptosis was involved. Ischemia activates the expression of a series of oxidative stress genes and their downstream regulatory genes, including ferroptosis-related genes such as nuclear factor E2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and SLC7A11. This study adopted primary cardiomyocytes and I/R in rats to evaluate the ferroptosis and changing of Nrf2-SLC7A11/heme oxygenase-1 (HO-1) <i>in vitro</i> and <i>in vivo</i>. Online analysis tools were used to predict the possible target Kelch-like ECH-associated protein 1 (Keap1) of miR-432-5p. The mimic of miR-432-5p plasmid was constructed to verify the effect of miR-432-5p on ferroptosis. We found that hypoxia/reoxygenation (H/R) in cardiomyocytes and I/R in rats induced lipid peroxidation and ferroptosis in cardiomyocytes. The activation of the Nrf2-SLC7A11/HO-1 pathway protects cardiomyocytes from ferroptosis. Downregulation of miR-432-5p has been confirmed in H/R cardiomyocytes (<i>in vitro</i>) and cardiomyocytes in myocardial infarction rats (<i>in vivo</i>). Upregulation of miR-432-5p inhibited ferroptosis of cardiomyocytes induced by RAS-selective lethal 3 (RSL3), an inhibitor of GPX4 and ferroptosis inducer through decreasing the binding protein of Nrf2, Keap1, which was confirmed by bioinformatics and mutation assay. Knockdown Nrf2 attenuates the protection effect of miR-432-5p on H/R cardiomyocytes. Intravenous delivery of liposome carriers of miR-432-5p remarkably ameliorated cardiomyocyte impairment in the I/R animal model. In conclusion, miR-432-5p inhibits the ferroptosis in cardiomyocytes induced by H/R by activating Nrf2/SLC7A11 axis by degrading Keap1 and is a potential drug target for clinical myocardial infarction treatment.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10564581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41217664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Interferon regulatory factor 2 (IRF2) participates in the differentiation of immune T cells. Bone marrow mesenchymal stem cell (BM-MSC)-derived exosomes can secret mRNA, miRNAs, and proteins to regulate tumor microenvironment. The present study focused on the miRNA/IRF2 axis in regulating Th1/Th2 ratio and cell apoptosis in acute myeloid leukemia (AML). The flow cytometry analysis was performed to examine the Th1/Th2 ratio and AML apoptosis in vivo and in vitro. The contents of Interferon γ (IFN-γ) and Interleukin-4 (IL-4) were measured using enzyme-linked immunosorbent assay. StarBase was used to predict the potential binding site between miR-222-3p and the 3' untranslated region of IRF2. Luciferase reporter assay was applied for validating the combination of miR-222-3p and IRF2. BM-MSC exosomes were successfully isolated. BM-MSC exosomes increased Th1/Th2 ratio and promoted apoptosis of AML cells. Further analysis showed that IRF2 was targeted by miR-222-3p. Overexpression of miR-222-3p promoted Th1/Th2 ratio and AML cell apoptosis. IRF2 partially reversed the effect that is exerted by miR-222-3p on Th1/Th2 ratio and AML cell apoptosis. Overexpression of miR-222-3p promoted Th1/Th2 ratio and caspase 3 expression in vivo. To sum up, miR-222-3p promotes Th1/Th2 ratio and AML cell apoptosis by regulating IRF2 expression, which provided crucial targets for the treatment of AML.
{"title":"Mesenchymal Stem Cell-Derived Exosomal miRNA-222-3p Increases Th1/Th2 Ratio and Promotes Apoptosis of Acute Myeloid Leukemia Cells.","authors":"Yuan Yuan, Shengfen Tan, Huanhuan Wang, Junfeng Zhu, Jiajia Li, Pingping Zhang, Meng Wang, Feng Zhang","doi":"10.1155/2023/4024887","DOIUrl":"10.1155/2023/4024887","url":null,"abstract":"<p><p>Interferon regulatory factor 2 (IRF2) participates in the differentiation of immune T cells. Bone marrow mesenchymal stem cell (BM-MSC)-derived exosomes can secret mRNA, miRNAs, and proteins to regulate tumor microenvironment. The present study focused on the miRNA/IRF2 axis in regulating Th1/Th2 ratio and cell apoptosis in acute myeloid leukemia (AML). The flow cytometry analysis was performed to examine the Th1/Th2 ratio and AML apoptosis <i>in vivo</i> and <i>in vitro</i>. The contents of Interferon <i>γ</i> (IFN-<i>γ</i>) and Interleukin-4 (IL-4) were measured using enzyme-linked immunosorbent assay. StarBase was used to predict the potential binding site between miR-222-3p and the 3' untranslated region of IRF2. Luciferase reporter assay was applied for validating the combination of miR-222-3p and IRF2. BM-MSC exosomes were successfully isolated. BM-MSC exosomes increased Th1/Th2 ratio and promoted apoptosis of AML cells. Further analysis showed that IRF2 was targeted by miR-222-3p. Overexpression of miR-222-3p promoted Th1/Th2 ratio and AML cell apoptosis. IRF2 partially reversed the effect that is exerted by miR-222-3p on Th1/Th2 ratio and AML cell apoptosis. Overexpression of miR-222-3p promoted Th1/Th2 ratio and caspase 3 expression <i>in vivo</i>. To sum up, miR-222-3p promotes Th1/Th2 ratio and AML cell apoptosis by regulating IRF2 expression, which provided crucial targets for the treatment of AML.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10447000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10081962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: To study the effect of congenital dyskeratosis 1 (DKC1) on neuroblastoma and its regulation mechanism.
Methods: The expression of DKC1 in neuroblastoma was analyzed by TCGA database and molecular assay. NB cells were transfected with siDKC1 to observe the effects of DKC1 on proliferation, cloning, metastasis, and invasion, and apoptosis and apoptosis-related proteins. The tumor-bearing mouse model was constructed, shDKC1 was transfected to observe the tumor growth and tumor tissue changes, and the expression of DKC1 and Ki-67 was detected. Screening and identification of miRNA326-5p targeting DKC1. NB cells were treated with miRNA326-5p mimic or inhibitors to detect the expression of DKC1. NB cells were transfected with miRNA326-5p and DKC1 mimics to detect cell proliferation, apoptosis, and apoptotic protein expression.
Results: DKC1 was highly expressed in NB cells and tissues. The activity, proliferation, invasion, and migration of NB cells were significantly decreased by DKC1 gene knockout, while apoptosis was significantly increased. The expression level of B-cell lymphoma-2 in shDKC1 group was significantly lower than that of the control group, while the expression level of BAK, BAX, and caspase-3 was significantly higher than that of the control group. The results of experiments on tumor-bearing mice were consistent with the above results. The results of miRNA assay showed that miRNA326-5p could bind DKC1 mRNA to inhibit the protein expression, thereby inhibiting the proliferation of NB cells, promoting their apoptosis, and regulating the expression of apoptotic proteins.
Conclusion: miRNA326-5p targeting DKC1 mRNA regulates apoptosis-related proteins to inhibit neuroblastoma proliferation and promote the apoptotic process.
{"title":"miRNA326-5p Targets DKC1 Gene to Regulate Apoptosis-Related Proteins and Intervene in the Development of Neuroblastoma.","authors":"Xiao-Hui Wang, Shu-Feng Zhang, Hai-Ying Wu, Jian Gao, Lin Wang, Xu-Hui Wang, Tian-Hui Gao","doi":"10.1155/2023/6761894","DOIUrl":"10.1155/2023/6761894","url":null,"abstract":"<p><strong>Objective: </strong>To study the effect of congenital dyskeratosis 1 (DKC1) on neuroblastoma and its regulation mechanism.</p><p><strong>Methods: </strong>The expression of DKC1 in neuroblastoma was analyzed by TCGA database and molecular assay. NB cells were transfected with siDKC1 to observe the effects of DKC1 on proliferation, cloning, metastasis, and invasion, and apoptosis and apoptosis-related proteins. The tumor-bearing mouse model was constructed, shDKC1 was transfected to observe the tumor growth and tumor tissue changes, and the expression of DKC1 and Ki-67 was detected. Screening and identification of miRNA326-5p targeting DKC1. NB cells were treated with miRNA326-5p mimic or inhibitors to detect the expression of DKC1. NB cells were transfected with miRNA326-5p and DKC1 mimics to detect cell proliferation, apoptosis, and apoptotic protein expression.</p><p><strong>Results: </strong>DKC1 was highly expressed in NB cells and tissues. The activity, proliferation, invasion, and migration of NB cells were significantly decreased by DKC1 gene knockout, while apoptosis was significantly increased. The expression level of B-cell lymphoma-2 in shDKC1 group was significantly lower than that of the control group, while the expression level of BAK, BAX, and caspase-3 was significantly higher than that of the control group. The results of experiments on tumor-bearing mice were consistent with the above results. The results of miRNA assay showed that miRNA326-5p could bind DKC1 mRNA to inhibit the protein expression, thereby inhibiting the proliferation of NB cells, promoting their apoptosis, and regulating the expression of apoptotic proteins.</p><p><strong>Conclusion: </strong>miRNA326-5p targeting DKC1 mRNA regulates apoptosis-related proteins to inhibit neuroblastoma proliferation and promote the apoptotic process.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10329557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac + 100Ex, Ac + 200Ex, and Ac + 400Ex groups (acetaminophen + thyme extract at doses of 100, 200, 400 mg/kg); and Ac + NA group (acetaminophen + NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac + NA and Ac + 200Ex groups (P = 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac + 400Ex groups showed significant differences from those of the other test groups (P < 0.001). Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in Ac + 200Ex and Ac + NA groups showed a significant decrease compared to those of the other treatment groups (P = 0.043). Total antioxidant capacity (TAC) and glutathione peroxidase (GPx) had the lowest levels in Ac and Ac + 400Ex groups, while malondialdehyde (MDA) had the highest content. In this regard, the liver histopathological indices (necrosis, hyperemia, and hemorrhage) in the Ac + 200Ex and Ac + NA groups reached their lowest grades in the treatment groups. The mean number of erythroid and myeloid cells in the Ac group reached the lowest (17.40 ± 3.48). The microscopic appearance of the bone marrow cells was different from normocytosis in the control group to hypocytosis in the Ac and Ac + 400Ex groups. Thymol, as an effective ingredient in thyme extract at a dose of 200 mg/kg compared to NAC, had a unique effect on reducing bone marrow and liver cell-tissue changes due to the acetaminophen toxicity.
{"title":"Comparative Effect of the Active Substance of Thyme with N-Acetyl Cysteine on Hematological Parameters and Histopathological Changes of Bone Marrow and Liver in Rat Models of Acetaminophen Toxicity.","authors":"Zahra Mokhtari, Mahdieh Raeeszadeh, Loghman Akradi","doi":"10.1155/2023/1714884","DOIUrl":"10.1155/2023/1714884","url":null,"abstract":"<p><p>Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac + 100Ex, Ac + 200Ex, and Ac + 400Ex groups (acetaminophen + thyme extract at doses of 100, 200, 400 mg/kg); and Ac + NA group (acetaminophen + NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac + NA and Ac + 200Ex groups (<i>P</i> = 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac + 400Ex groups showed significant differences from those of the other test groups (<i>P</i> < 0.001). Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in Ac + 200Ex and Ac + NA groups showed a significant decrease compared to those of the other treatment groups (<i>P</i> = 0.043). Total antioxidant capacity (TAC) and glutathione peroxidase (GPx) had the lowest levels in Ac and Ac + 400Ex groups, while malondialdehyde (MDA) had the highest content. In this regard, the liver histopathological indices (necrosis, hyperemia, and hemorrhage) in the Ac + 200Ex and Ac + NA groups reached their lowest grades in the treatment groups. The mean number of erythroid and myeloid cells in the Ac group reached the lowest (17.40 ± 3.48). The microscopic appearance of the bone marrow cells was different from normocytosis in the control group to hypocytosis in the Ac and Ac + 400Ex groups. Thymol, as an effective ingredient in thyme extract at a dose of 200 mg/kg compared to NAC, had a unique effect on reducing bone marrow and liver cell-tissue changes due to the acetaminophen toxicity.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziyuan Que, Kang Yang, Nan Wang, Shuying Li, Tao Li
Malignant bone neoplasms can be represented by osteosarcoma (OS), which accounts for 36% of all sarcomas. To reduce tumor malignancy, extensive efforts have been devoted to find an ideal target from numerous candidates, among which RNA-binding proteins (RBPs) have shown their unparalleled competitiveness. With the special structure of RNA-binding domains, RBPs have the potential to establish relationships with RNAs or small molecules and are considered regulators of different sections of RNA processes, including splicing, transport, translation, and degradation of RNAs. RBPs have considerable significant roles in various cancers, and experiments revealed that there was a strong association of RBPs with tumorigenesis and tumor cell progression. Regarding OS, RBPs are a new orientation, but achievements in hand are noteworthy. Higher or lower expression of RBPs was first found in tumor cells compared to normal tissue. By binding to different molecules, RBPs are capable of influencing tumor cell phenotypes through different signaling pathways or other axes, and researches on medical treatment have been largely inspired. Exploring the prognostic and therapeutic values of RBPs in OS is a hotspot where diverse avenues on regulating RBPs have achieved dramatical effects. In this review, we briefly summarize the contribution of RBPs and their binding molecules to OS oncogenicity and generally introduce distinctive RBPs as samples. Moreover, we focus on the attempts to differentiate RBP's opposite functions in predicting prognosis and collect possible strategies for treatment. Our review provides forwards insight into improving the understanding of OS and suggests RBPs as potential biomarkers for therapies.
{"title":"Functional Role of RBP in Osteosarcoma: Regulatory Mechanism and Clinical Therapy.","authors":"Ziyuan Que, Kang Yang, Nan Wang, Shuying Li, Tao Li","doi":"10.1155/2023/9849719","DOIUrl":"https://doi.org/10.1155/2023/9849719","url":null,"abstract":"<p><p>Malignant bone neoplasms can be represented by osteosarcoma (OS), which accounts for 36% of all sarcomas. To reduce tumor malignancy, extensive efforts have been devoted to find an ideal target from numerous candidates, among which RNA-binding proteins (RBPs) have shown their unparalleled competitiveness. With the special structure of RNA-binding domains, RBPs have the potential to establish relationships with RNAs or small molecules and are considered regulators of different sections of RNA processes, including splicing, transport, translation, and degradation of RNAs. RBPs have considerable significant roles in various cancers, and experiments revealed that there was a strong association of RBPs with tumorigenesis and tumor cell progression. Regarding OS, RBPs are a new orientation, but achievements in hand are noteworthy. Higher or lower expression of RBPs was first found in tumor cells compared to normal tissue. By binding to different molecules, RBPs are capable of influencing tumor cell phenotypes through different signaling pathways or other axes, and researches on medical treatment have been largely inspired. Exploring the prognostic and therapeutic values of RBPs in OS is a hotspot where diverse avenues on regulating RBPs have achieved dramatical effects. In this review, we briefly summarize the contribution of RBPs and their binding molecules to OS oncogenicity and generally introduce distinctive RBPs as samples. Moreover, we focus on the attempts to differentiate RBP's opposite functions in predicting prognosis and collect possible strategies for treatment. Our review provides forwards insight into improving the understanding of OS and suggests RBPs as potential biomarkers for therapies.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial-mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.
广泛的腹膜扩散和远处转移的能力是上皮性卵巢癌(EOC)死亡的主要原因。越来越多的证据表明,白细胞介素-6 (IL-6)促进EOC中肿瘤的侵袭和迁移,尽管其分子机制尚未完全阐明。同时,在几种类型的癌症中,低氧微环境通过触发上皮-间质转化(EMT)而引起转移。在此,我们研究了IL-6和缺氧在两种EOC细胞系A2780细胞和SKOV3细胞中诱导EMT的协同作用。外源重组IL-6和质粒调控IL-6的自分泌均可诱导EOC细胞EMT表型,其特征是E-cadherin下调,vimentin和EMT相关转录因子表达上调。IL-6和缺氧的联合作用比任何一种治疗对EMT的影响更显著。在IL-6处理前抑制缺氧诱导因子-1α (HIF-1α)可抑制EOC细胞的EMT表型和侵袭能力,表明HIF-1α在与IL-6相关的EMT调控通路中占据关键位置。在The Cancer Genome Atlas数据集中的489个卵巢样本中,EMT评分与IL-6、信号换能器和转录激活因子3 (STAT3)和HIF-1α的mRNA水平分别呈正相关。接下来,通过化学抑制剂阻断上述分子,逆转外源性或内源性IL-6诱导的EMT标记蛋白水平的改变。这些发现表明IL-6和HIF-1α之间存在正反馈回路,并通过STAT3信号诱导和维持EMT表型,这可能为EOC的预后预测和治疗靶点提供新的理论基础。
{"title":"Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1<i>α</i> Feedback Loop.","authors":"Tongshuo Zhang, Jing Yang, Yang Sun, Jiangnan Song, Dandan Gao, Suhui Huang, Aibo Pang, Jianhui Zhang, Junhong Wang, Yue Wang, Yanqiu Li","doi":"10.1155/2023/8334881","DOIUrl":"https://doi.org/10.1155/2023/8334881","url":null,"abstract":"<p><p>Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial-mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1<i>α</i> (HIF-1<i>α</i>) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1<i>α</i> occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1<i>α</i>, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1<i>α</i>, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10823547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: Long non-coding RNAs (LncRNAs) OIP5-AS1 and miR-25-3p play important roles in myocardial injury, whereas their roles in lipopolysaccharide (LPS)-induced myocardial injury remain unknown. The purpose of our study was to investigate the functional mechanisms of OIP5-AS1 and miR-25-3p in LPS-induced myocardial injury.
Methods: Rats and H9C2 cells were treated with LPS to establish the model of myocardial injury in vivo and in vitro, respectively. The expression levels of OIP5-AS1 and miR-25-3p were determined by quantitative reverse transcriptase-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to measure the serum levels of IL-6 and TNF-α. The relationship between OIP5-AS1 and miR-25-3p/NOX4 was determined by luciferase reporter assay and/or RNA immunoprecipitation assay. The apoptosis rate was detected by flow cytometry, and cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Western blot was performed to detect the protein levels of Bax, Bcl-2, caspase3, c-caspase3, NOX4, and p-NF-κB p65/NF-κB p65.
Results: OIP5-AS1 was up-regulated, and miR-25-3p was down-regulated in myocardial tissues of LPS-induced rats and LPS-treated H9C2 cells. Knockdown of OIP5-AS1 relieved the myocardial injury in LPS-induced rats. Knockdown of OIP5-AS1 also inhibited the inflammation and apoptosis of myocardial cells in vivo, which was subsequently confirmed by in vitro experiments. In addition, OIP5-AS1 targeted miR-25-3p. MiR-25-3p mimics reversed the effects of OIP5-AS1 overexpression on promoting cell apoptosis and inflammation and on inhibiting cell viability. Besides, miR-25-3p mimics blocked the NOX4/NF-κB signalling pathway in LPS-induced H9C2 cells.
Conclusion: Silencing of lncRNA OIP5-AS1 alleviated LPS-induced myocardial injury by regulating miR-25-3p.
目的:长链非编码rna (LncRNAs) OIP5-AS1和miR-25-3p在心肌损伤中发挥重要作用,而它们在脂多糖(LPS)诱导的心肌损伤中的作用尚不清楚。我们的研究目的是探讨OIP5-AS1和miR-25-3p在lps诱导的心肌损伤中的作用机制。方法:采用LPS处理大鼠和H9C2细胞,分别建立体内和体外心肌损伤模型。定量逆转录-聚合酶链反应检测OIP5-AS1和miR-25-3p的表达水平。采用酶联免疫吸附法测定血清IL-6、TNF-α水平。OIP5-AS1与miR-25-3p/NOX4的关系通过荧光素酶报告基因法和/或RNA免疫沉淀法确定。流式细胞术检测细胞凋亡率,3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2- h -溴化四唑试验检测细胞活力。Western blot检测Bax、Bcl-2、caspase3、c-caspase3、NOX4、p-NF-κB p65/NF-κB p65蛋白表达水平。结果:lps诱导的大鼠心肌组织和lps处理的H9C2细胞中,OIP5-AS1上调,miR-25-3p下调。敲低OIP5-AS1可减轻lps诱导大鼠心肌损伤。在体内,OIP5-AS1的敲低也能抑制心肌细胞的炎症和凋亡,这一点随后在体外实验中得到了证实。此外,OIP5-AS1靶向miR-25-3p。MiR-25-3p模拟物逆转了OIP5-AS1过表达促进细胞凋亡和炎症以及抑制细胞活力的作用。此外,在lps诱导的H9C2细胞中,miR-25-3p模拟物阻断了NOX4/NF-κB信号通路。结论:沉默lncRNA OIP5-AS1可通过调节miR-25-3p减轻lps诱导的心肌损伤。
{"title":"Suppression of lncRNA OIP5-AS1 Attenuates Apoptosis and Inflammation, and Promotes Proliferation by Mediating miR-25-3p Expression in Lipopolysaccharide-Induced Myocardial Injury.","authors":"Jiaju Ma, Hebu Qian, Han Zou","doi":"10.1155/2023/3154223","DOIUrl":"https://doi.org/10.1155/2023/3154223","url":null,"abstract":"<p><strong>Purpose: </strong>Long non-coding RNAs (LncRNAs) OIP5-AS1 and miR-25-3p play important roles in myocardial injury, whereas their roles in lipopolysaccharide (LPS)-induced myocardial injury remain unknown. The purpose of our study was to investigate the functional mechanisms of OIP5-AS1 and miR-25-3p in LPS-induced myocardial injury.</p><p><strong>Methods: </strong>Rats and H9C2 cells were treated with LPS to establish the model of myocardial injury <i>in vivo</i> and <i>in vitro</i>, respectively. The expression levels of OIP5-AS1 and miR-25-3p were determined by quantitative reverse transcriptase-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to measure the serum levels of IL-6 and TNF-<i>α</i>. The relationship between OIP5-AS1 and miR-25-3p/NOX4 was determined by luciferase reporter assay and/or RNA immunoprecipitation assay. The apoptosis rate was detected by flow cytometry, and cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Western blot was performed to detect the protein levels of Bax, Bcl-2, caspase3, c-caspase3, NOX4, and p-NF-<i>κ</i>B p65/NF-<i>κ</i>B p65.</p><p><strong>Results: </strong>OIP5-AS1 was up-regulated, and miR-25-3p was down-regulated in myocardial tissues of LPS-induced rats and LPS-treated H9C2 cells. Knockdown of OIP5-AS1 relieved the myocardial injury in LPS-induced rats. Knockdown of OIP5-AS1 also inhibited the inflammation and apoptosis of myocardial cells <i>in vivo</i>, which was subsequently confirmed by <i>in vitro</i> experiments. In addition, OIP5-AS1 targeted miR-25-3p. MiR-25-3p mimics reversed the effects of OIP5-AS1 overexpression on promoting cell apoptosis and inflammation and on inhibiting cell viability. Besides, miR-25-3p mimics blocked the NOX4/NF-<i>κ</i>B signalling pathway in LPS-induced H9C2 cells.</p><p><strong>Conclusion: </strong>Silencing of lncRNA OIP5-AS1 alleviated LPS-induced myocardial injury by regulating miR-25-3p.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10042636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9959032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Despite the widespread introduction of primary and secondary preventative measures, death rates for cervical cancer are still significantly high among females, especially in developing countries. Pap cytology and human papillomavirus-based screening often lead to unnecessary additional testing. The aim of this study is to analyze diagnostic accuracy of p16INK4a/Ki-67 dual immunostaining (DS) in cervical smear for identifying high-grade cervical intraepithelial neoplasia (CIN2+).
Materials and methods: We studied the diagnostic performance of p16INK4a/Ki-67 DS in cervical smear of those women, who enrolled in cervical cancer screening due to abnormal previous screening results and compared it with Pap test results in identifying CIN2+. The reference standard was histopathology results. p16INK4a/Ki-67 DS and Pap test results for 162 women and histopathology results for 29 women were available, respectively.
Results: In our study, sensitivity, specificity, positive predictive value, and negative predictive value of p16INK4a/Ki-67 DS, irrespective of the morphology of stained cells to detect CIN2+ were 100%, 89%, 85%, and 100% (p < 0.01), respectively. The diagnostic accuracy of p16INK4a/Ki-67 DS is superior to that of existing cervical screening tests in the detection of CIN2+.
Conclusion: The findings of cervical cancer screening based on Pap cytology highlight the importance of assessing the cost-effectiveness of integrating p16INK4a/Ki-67 biomarkers in cervical cancer cytology. Furthermore, these findings emphasize the need to enhance support for preventive programs for cervical cancer in Georgia.
{"title":"Diagnostic Accuracy of p16<sup>INK4a</sup>/Ki-67 Dual Immunostaining for Detection of High-Grade Cervical Intraepithelial Neoplasia in Women Involved in Cervical Cancer Screening in Georgia.","authors":"Sopio Kakaliashvili-Dzagnidze, Omar Khardzeishvili, Sergo Tabagari","doi":"10.1155/2023/7988323","DOIUrl":"https://doi.org/10.1155/2023/7988323","url":null,"abstract":"<p><strong>Background: </strong>Despite the widespread introduction of primary and secondary preventative measures, death rates for cervical cancer are still significantly high among females, especially in developing countries. Pap cytology and human papillomavirus-based screening often lead to unnecessary additional testing. The aim of this study is to analyze diagnostic accuracy of p16<sup>INK4a</sup>/Ki-67 dual immunostaining (DS) in cervical smear for identifying high-grade cervical intraepithelial neoplasia (CIN2+).</p><p><strong>Materials and methods: </strong>We studied the diagnostic performance of p16<sup>INK4a</sup>/Ki-67 DS in cervical smear of those women, who enrolled in cervical cancer screening due to abnormal previous screening results and compared it with Pap test results in identifying CIN2+. The reference standard was histopathology results. p16<sup>INK4a</sup>/Ki-67 DS and Pap test results for 162 women and histopathology results for 29 women were available, respectively.</p><p><strong>Results: </strong>In our study, sensitivity, specificity, positive predictive value, and negative predictive value of p16<sup>INK4a</sup>/Ki-67 DS, irrespective of the morphology of stained cells to detect CIN2+ were 100%, 89%, 85%, and 100% (<i>p</i> < 0.01), respectively. The diagnostic accuracy of p16<sup>INK4a</sup>/Ki-67 DS is superior to that of existing cervical screening tests in the detection of CIN2+.</p><p><strong>Conclusion: </strong>The findings of cervical cancer screening based on Pap cytology highlight the importance of assessing the cost-effectiveness of integrating p16<sup>INK4a</sup>/Ki-67 biomarkers in cervical cancer cytology. Furthermore, these findings emphasize the need to enhance support for preventive programs for cervical cancer in Georgia.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9666251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Methods: The serum selenium level was determined in 45 patients with HBV-positive HCC (HBV+-HCC group), 45 patients with chronic hepatitis B virus infection (CHB group), and 45 healthy cases (HC group). The sodium selenite (Na2SeO3)-treated HepG2.2.15 cells were used to observe the regulatory role of selenium on HBV replication. D-GalN/erastin-added HL7702 was used to determine the regulatory roles of Na2SeO3 on hepatotoxicity or hepatocyte ferroptosis. The wild-type (WT) C57BL/6 mice and HBx-Tg mice were received lipopolysaccharide (LPS)/D-GalN, together with or without Na2SeO3 administration for indicated period. Following euthanasia, the blood and liver tissue samples were collected, and specific markers were evaluated subsequently.
Results: The serum selenium level was downregulated in patients with HBV-positive HCC (HBV+-HCC group) (57.2 ± 22.5 μg/L vs. 91.8 ± 43.9 μg/L, P < 0.001), and its higher level could provide a better prognosis in these patients. The treatment using Na2SeO3, a selenium donor, at high concentration (5 μM), suppressed the HBV replication by about 50% in HepG2.2.15 cells (P < 0.001), through promoting apoptotic cell death and inhibiting cellular inhibitor of apoptosis proteins (cIAPs). In addition, low-dose (500 nM) Na2SeO3 could almost totally reversed the hepatotoxicity induced by hepatitis B virus X protein (HBx) (P < 0.001), which were the main causes of HCC in patients. Studies at the cellular levels showed that low-dose Na2SeO3 inhibited the HBx-related hepatotoxicity by blocking ferroptosis, and glutathione peroxidase 4 (GPX4) mediated this regulatory role. Mice model results confirmed that the treatment with Na2SeO3 could mitigated LPS/D-GalN-induced hepatic injury through ferroptosis pathways.
Conclusion: Selenium regulated the dual cell death in different HCC stages via different signaling pathways, which could partly explain the anti-HBV and anti-HCC properties of selenium.
方法:测定45例HBV阳性HCC患者(HBV+-HCC组)、45例慢性乙型肝炎病毒感染患者(CHB组)和45例健康患者(HC组)血清硒水平。采用亚硒酸钠(Na2SeO3)处理HepG2.2.15细胞,观察硒对HBV复制的调控作用。采用添加D-GalN/erastin的HL7702来测定Na2SeO3对肝毒性或肝细胞铁凋亡的调节作用。野生型(WT) C57BL/6小鼠和HBx-Tg小鼠分别接受脂多糖(LPS)/D-GalN,同时或不同时给予Na2SeO3。安乐死后,采集血液和肝脏组织样本,随后评估特定标志物。结果:HBV阳性HCC患者(HBV+-HCC组)血清硒水平下调(57.2±22.5 μg/L vs. 91.8±43.9 μg/L, P < 0.001),血清硒水平升高可改善预后。高浓度(5 μM)硒供体Na2SeO3通过促进细胞凋亡和抑制细胞凋亡抑制蛋白(cIAPs),抑制HepG2.2.15细胞中HBV复制约50% (P < 0.001)。此外,低剂量(500 nM) Na2SeO3几乎可以完全逆转乙型肝炎病毒X蛋白(HBx)引起的肝毒性(P < 0.001),这是患者HCC的主要原因。细胞水平的研究表明,低剂量Na2SeO3通过阻断铁凋亡抑制hbx相关的肝毒性,而谷胱甘肽过氧化物酶4 (GPX4)介导了这一调节作用。小鼠模型结果证实,Na2SeO3可通过脂多糖/ d - galn诱导的铁下垂途径减轻肝损伤。结论:硒通过不同的信号通路调控肝癌不同分期双细胞死亡,这可以部分解释硒抗hbv和抗HCC的作用。
{"title":"Selenium Donor Inhibited Hepatitis B Virus Associated Hepatotoxicity via the Apoptosis and Ferroptosis Pathways.","authors":"Jingdong Shi, Zhen Liu, Weina Li, Di Wang","doi":"10.1155/2023/6681065","DOIUrl":"https://doi.org/10.1155/2023/6681065","url":null,"abstract":"<p><strong>Methods: </strong>The serum selenium level was determined in 45 patients with HBV-positive HCC (HBV<sup>+</sup>-HCC group), 45 patients with chronic hepatitis B virus infection (CHB group), and 45 healthy cases (HC group). The sodium selenite (Na<sub>2</sub>SeO<sub>3</sub>)-treated HepG2.2.15 cells were used to observe the regulatory role of selenium on HBV replication. D-GalN/erastin-added HL7702 was used to determine the regulatory roles of Na<sub>2</sub>SeO<sub>3</sub> on hepatotoxicity or hepatocyte ferroptosis. The wild-type (WT) C57BL/6 mice and HBx-Tg mice were received lipopolysaccharide (LPS)/D-GalN, together with or without Na<sub>2</sub>SeO<sub>3</sub> administration for indicated period. Following euthanasia, the blood and liver tissue samples were collected, and specific markers were evaluated subsequently.</p><p><strong>Results: </strong>The serum selenium level was downregulated in patients with HBV-positive HCC (HBV<sup>+</sup>-HCC group) (57.2 ± 22.5 <i>μ</i>g/L vs. 91.8 ± 43.9 <i>μ</i>g/L, <i>P</i> < 0.001), and its higher level could provide a better prognosis in these patients. The treatment using Na<sub>2</sub>SeO<sub>3</sub>, a selenium donor, at high concentration (5 <i>μ</i>M), suppressed the HBV replication by about 50% in HepG2.2.15 cells (<i>P</i> < 0.001), through promoting apoptotic cell death and inhibiting cellular inhibitor of apoptosis proteins (cIAPs). In addition, low-dose (500 nM) Na<sub>2</sub>SeO<sub>3</sub> could almost totally reversed the hepatotoxicity induced by hepatitis B virus X protein (HBx) (<i>P</i> < 0.001), which were the main causes of HCC in patients. Studies at the cellular levels showed that low-dose Na<sub>2</sub>SeO<sub>3</sub> inhibited the HBx-related hepatotoxicity by blocking ferroptosis, and glutathione peroxidase 4 (GPX4) mediated this regulatory role. Mice model results confirmed that the treatment with Na<sub>2</sub>SeO<sub>3</sub> could mitigated LPS/D-GalN-induced hepatic injury through ferroptosis pathways.</p><p><strong>Conclusion: </strong>Selenium regulated the dual cell death in different HCC stages via different signaling pathways, which could partly explain the anti-HBV and anti-HCC properties of selenium.</p>","PeriodicalId":49326,"journal":{"name":"Analytical Cellular Pathology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10482541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10567286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}