The burgeoning field of immunomedicine is primed to expand beyond oncology (Aghajanian et al., 2022). Over the past several decades, many cell-based therapies have been proposed, developed, and deployed in the clinic. The recent explosion of targeted cell therapies has primarily been aimed at oncological malignancies. In parallel, cardiology researchers have been investigating the various cell types that contribute to heart diseases, especially those responsible for tissue fibrosis and myocardial dysfunction. Our laboratory proposed in 2019 to unite these two disciplines: could a targeted cell therapy be used to ameliorate cardiac fibrosis (Aghajanian et al., 2019). Although preliminary results were encouraging, the genetic engineering approach used to manufacture immune cells would result in persistent cytolytic T cell if directly translated to humans. This would pose a safety concern since activated fibroblasts are essential cells in the setting of acute injury. Therefore, we developed a novel technology to deliver modified RNA to T cells in vivo, resulting in a transient antiactivated fibroblast therapeutic (Rurik et al., 2022). Although active for only a few days, these cells were sufficient to significantly improve cardiac function in a murine model of cardiac fibrosis. These results pave the way for low-cost and scalable, and dose-able and immune therapy for fibrotic disorders.
新兴的免疫医学领域已准备好扩展到肿瘤学以外的领域(Aghajanian et al.， 2022)。在过去的几十年里，许多基于细胞的治疗方法被提出、发展并应用于临床。最近爆发的靶向细胞疗法主要针对肿瘤恶性肿瘤。与此同时，心脏病学研究人员一直在研究导致心脏病的各种细胞类型，特别是那些导致组织纤维化和心肌功能障碍的细胞类型。我们的实验室在2019年提出将这两个学科结合起来:靶向细胞疗法是否可以用于改善心脏纤维化(Aghajanian et al.， 2019)。虽然初步结果令人鼓舞，但用于制造免疫细胞的基因工程方法如果直接转化为人类，将导致持久的细胞溶解性T细胞。这将引起安全问题，因为活化的成纤维细胞是急性损伤的必要细胞。因此，我们开发了一种新的技术，将修饰的RNA传递到体内的T细胞，从而产生一种短暂的抗活化成纤维细胞治疗(Rurik et al.， 2022)。虽然这些细胞只有几天的活性，但足以显著改善小鼠心脏纤维化模型的心功能。这些结果为纤维化疾病的低成本、可扩展、可剂量和免疫治疗铺平了道路。
{"title":"Uniting Disciplines to Develop Therapeutics: Targeted mRNA Lipid Nanoparticles Reprogram the Immune System <i>In Vivo</i> to Treat Heart Disease.","authors":"Joel G Rurik, Jonathan A Epstein","doi":"10.1089/dna.2022.0171","DOIUrl":"https://doi.org/10.1089/dna.2022.0171","url":null,"abstract":"<p><p>The burgeoning field of immunomedicine is primed to expand beyond oncology (Aghajanian <i>et al.</i>, 2022). Over the past several decades, many cell-based therapies have been proposed, developed, and deployed in the clinic. The recent explosion of targeted cell therapies has primarily been aimed at oncological malignancies. In parallel, cardiology researchers have been investigating the various cell types that contribute to heart diseases, especially those responsible for tissue fibrosis and myocardial dysfunction. Our laboratory proposed in 2019 to unite these two disciplines: could a targeted cell therapy be used to ameliorate cardiac fibrosis (Aghajanian <i>et al.</i>, 2019). Although preliminary results were encouraging, the genetic engineering approach used to manufacture immune cells would result in persistent cytolytic T cell if directly translated to humans. This would pose a safety concern since activated fibroblasts are essential cells in the setting of acute injury. Therefore, we developed a novel technology to deliver modified RNA to T cells <i>in vivo</i>, resulting in a transient antiactivated fibroblast therapeutic (Rurik <i>et al.</i>, 2022). Although active for only a few days, these cells were sufficient to significantly improve cardiac function in a murine model of cardiac fibrosis. These results pave the way for low-cost and scalable, and dose-able and immune therapy for fibrotic disorders.</p>","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":"41 6","pages":"539-543"},"PeriodicalIF":3.1,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245726/pdf/dna.2022.0171.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9556415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-01DOI: 10.1089/dna.2018.4441.retract
{"title":"Retraction of: miR-142 Suppresses Endometrial Cancer Proliferation In Vitro and In Vivo by Targeting Cyclin D1 (10.1089/dna.2018.4441).","authors":"","doi":"10.1089/dna.2018.4441.retract","DOIUrl":"https://doi.org/10.1089/dna.2018.4441.retract","url":null,"abstract":"","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":"41 6 1","pages":"641"},"PeriodicalIF":3.1,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43042108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Feng Jiang, Q. Shen, Fan Zhang, Jiali Fu, Li-Zhen Hu, Junjun Wang, Huixin Zhou, Jian Chen, Yumin Wang
Lung adenocarcinoma (LUAD) is a common form of lung cancer. Although cisplatin chemotherapy is an effective treatment option, some patients with LUAD can develop drug resistance. Modulated ADH1C expression has been reported in various cancer types. However, the mechanism by which ADH1C potentially influences progression and cisplatin resistance of LUAD remains poorly understood. In this study, we aimed to explore the role of ADH1C with respect to cisplatin resistance and to uncover the clinical significance of methionine adenosyltransferase (MAT1A). Compared with cisplatin-sensitive A549 cells, ADH1C was highly enriched in cisplatin-resistant A549/cis-dichlorodiammineplatinum II (DDP) cells. Inhibition of ADH1C expression in the latter suppressed cell proliferation and decreased their resistance to cisplatin. Furthermore, the proliferative capacity under cisplatin stimulation was reduced. Downregulation of ADH1C expression inhibited the expression of proliferating cell nuclear antigen and excision repair cross-complementing 1 (ERCC1). Knockdown of ADH1C resulted in arrested cell cycle (in G2/M phase). The proliferative capacity and cisplatin sensitivity induced by ADH1C upregulation in A549 cells were reversed upon knockdown of ADH1C. Bioinformatic analyses revealed ADH1C to be mainly enriched in cell cycle, RNA transport, biosynthesis of amino acids, and platinum drug resistance pathways. Meanwhile, the gene MAT1A with considerable positive association with ADH1C was identified. Furthermore, expression of MAT1A was upregulated in LUAD tissues relative to the paired adjacent normal specimens. Human Protein Atlas, The university of alabama at birmingham cancer data analysis portal (UALCAN), and Kaplan-Meier Plotter analysis indicated that upregulated MAT1A expression is correlated with poor prognosis of LUAD. Our results indicate that the ADH1C/MAT1A axis possibly increases cisplatin resistance in LUAD cells. The experiment was repeated three times and approved by the Medical Ethical Committee of the First Affiliated Hospital of Wenzhou Medical University (approval No.YS2018001).
{"title":"ADH1C Facilitates Cisplatin Resistance of Lung Adenocarcinoma Cells.","authors":"Feng Jiang, Q. Shen, Fan Zhang, Jiali Fu, Li-Zhen Hu, Junjun Wang, Huixin Zhou, Jian Chen, Yumin Wang","doi":"10.1089/dna.2021.0877","DOIUrl":"https://doi.org/10.1089/dna.2021.0877","url":null,"abstract":"Lung adenocarcinoma (LUAD) is a common form of lung cancer. Although cisplatin chemotherapy is an effective treatment option, some patients with LUAD can develop drug resistance. Modulated ADH1C expression has been reported in various cancer types. However, the mechanism by which ADH1C potentially influences progression and cisplatin resistance of LUAD remains poorly understood. In this study, we aimed to explore the role of ADH1C with respect to cisplatin resistance and to uncover the clinical significance of methionine adenosyltransferase (MAT1A). Compared with cisplatin-sensitive A549 cells, ADH1C was highly enriched in cisplatin-resistant A549/cis-dichlorodiammineplatinum II (DDP) cells. Inhibition of ADH1C expression in the latter suppressed cell proliferation and decreased their resistance to cisplatin. Furthermore, the proliferative capacity under cisplatin stimulation was reduced. Downregulation of ADH1C expression inhibited the expression of proliferating cell nuclear antigen and excision repair cross-complementing 1 (ERCC1). Knockdown of ADH1C resulted in arrested cell cycle (in G2/M phase). The proliferative capacity and cisplatin sensitivity induced by ADH1C upregulation in A549 cells were reversed upon knockdown of ADH1C. Bioinformatic analyses revealed ADH1C to be mainly enriched in cell cycle, RNA transport, biosynthesis of amino acids, and platinum drug resistance pathways. Meanwhile, the gene MAT1A with considerable positive association with ADH1C was identified. Furthermore, expression of MAT1A was upregulated in LUAD tissues relative to the paired adjacent normal specimens. Human Protein Atlas, The university of alabama at birmingham cancer data analysis portal (UALCAN), and Kaplan-Meier Plotter analysis indicated that upregulated MAT1A expression is correlated with poor prognosis of LUAD. Our results indicate that the ADH1C/MAT1A axis possibly increases cisplatin resistance in LUAD cells. The experiment was repeated three times and approved by the Medical Ethical Committee of the First Affiliated Hospital of Wenzhou Medical University (approval No.YS2018001).","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2022-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42550548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Sui, Yichao Wu, Ran Zhang, Tiantian Zhang, Yang Zhang, Jiaojiao Xi, Yanyu Ding, Jiyue Wen, Yong Hu
Osteoarthritis (OA) is a chronic joint disease characterized by the deterioration of cartilage and subchondral bone in the joints. Currently, there is no complete cure for OA, only treatments designed to temporarily relieve pain and improve function. Compared with the high cost of surgical treatment, medical treatment of OA is more acceptable and cost-effective. Rutin, as a flavonoid, has been shown to have anti-OA properties. We evaluated the effects of rutin on chondrocytes in lipopolysaccharide (LPS)-induced OA and on OA in rats induced by anterior cruciate ligament transection. We found that rutin effectively reduced the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase 13 (MMP-13) and increased the expression of Col II and aggrecan (p < 0.001). In addition, we also found that rutin increased the expression of cystathionine-β-synthase (CBS) and inhibited the expression of Rho-related coiled-coil protein kinase (ROCK) in chondrocytes (p < 0.05), thereby effectively inhibiting the inflammatory progression of OA. We concluded that rutin inhibits the inflammatory progression of OA through the CBS-mediated RhoA/ROCK signaling pathway.
{"title":"Rutin Inhibits the Progression of Osteoarthritis Through CBS-Mediated RhoA/ROCK Signaling.","authors":"C. Sui, Yichao Wu, Ran Zhang, Tiantian Zhang, Yang Zhang, Jiaojiao Xi, Yanyu Ding, Jiyue Wen, Yong Hu","doi":"10.1089/dna.2021.1182","DOIUrl":"https://doi.org/10.1089/dna.2021.1182","url":null,"abstract":"Osteoarthritis (OA) is a chronic joint disease characterized by the deterioration of cartilage and subchondral bone in the joints. Currently, there is no complete cure for OA, only treatments designed to temporarily relieve pain and improve function. Compared with the high cost of surgical treatment, medical treatment of OA is more acceptable and cost-effective. Rutin, as a flavonoid, has been shown to have anti-OA properties. We evaluated the effects of rutin on chondrocytes in lipopolysaccharide (LPS)-induced OA and on OA in rats induced by anterior cruciate ligament transection. We found that rutin effectively reduced the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase 13 (MMP-13) and increased the expression of Col II and aggrecan (p < 0.001). In addition, we also found that rutin increased the expression of cystathionine-β-synthase (CBS) and inhibited the expression of Rho-related coiled-coil protein kinase (ROCK) in chondrocytes (p < 0.05), thereby effectively inhibiting the inflammatory progression of OA. We concluded that rutin inhibits the inflammatory progression of OA through the CBS-mediated RhoA/ROCK signaling pathway.","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2022-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47079565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genetic variants in several long noncoding RNA genes have been implicated in the occurrence and development of colorectal cancer (CRC). In this study, we explored the association between HAND2-AS1 gene rs2276941 polymorphism and the risk and clinical stage of CRC. A direct sequencing method was used to detect the rs2276941 polymorphism in 576 CRC patients and 864 healthy individuals. Real-time quantitative PCR technology was used to explore the expression of HAND2-AS1 and hsa-miR-1275 in colorectal tissues with different rs2276941 genotypes. Dual-luciferase reporter assay was used to assess the function of the rs2276941 polymorphism. We found that the rs2276941 polymorphism was associated with a decreased risk of CRC (TT vs. CC, OR = 0.38, 95% CI = 0.16-0.89, p = 0.03; TT vs. [CC+CT], OR = 0.40, 95% CI = 0.17-0.94, p = 0.03). Furthermore, a significant negative correlation was observed between the expression of HAND2-AS1 and hsa-miR-1275 in colorectal tissues with rs2276941 TT genotype. Functional experimental results showed that the rs2276941 T allele might promote the binding of HAND2-AS1 to hsa-miR-1275. The current study results suggested that HAND2-AS1 gene rs2276941 polymorphism affecting the binding of hsa-miR-1275 was associated with CRC risk and might serve as a CRC susceptibility biomarker.
一些长链非编码RNA基因的遗传变异与结直肠癌(CRC)的发生和发展有关。在本研究中，我们探讨了HAND2-AS1基因rs2276941多态性与结直肠癌风险和临床分期的关系。采用直接测序方法检测576例结直肠癌患者和864例健康人rs2276941基因多态性。采用实时定量PCR技术检测不同rs2276941基因型结直肠组织中HAND2-AS1和hsa-miR-1275的表达情况。采用双荧光素酶报告基因法评估rs2276941多态性的功能。我们发现rs2276941多态性与CRC风险降低相关(TT vs. CC, OR = 0.38, 95% CI = 0.16-0.89, p = 0.03;TT与(CC + CT),或= 0.40,95% CI -0.94 = 0.17, p = 0.03)。此外，在rs2276941 TT基因型的结直肠组织中，HAND2-AS1和hsa-miR-1275的表达呈显著负相关。功能实验结果显示，rs2276941 T等位基因可能促进HAND2-AS1与hsa-miR-1275的结合。目前的研究结果提示，影响hsa-miR-1275结合的HAND2-AS1基因rs2276941多态性与结直肠癌风险相关，可能作为结直肠癌易感性生物标志物。
{"title":"HAND2-AS1 rs2276941 Polymorphism Affecting the Binding of hsa-miR-1275 Is Associated with the Risk of Colorectal Cancer.","authors":"Xueren Gao, Shulong Zhang, Xiaoting Wang","doi":"10.1089/dna.2021.0910","DOIUrl":"https://doi.org/10.1089/dna.2021.0910","url":null,"abstract":"Genetic variants in several long noncoding RNA genes have been implicated in the occurrence and development of colorectal cancer (CRC). In this study, we explored the association between HAND2-AS1 gene rs2276941 polymorphism and the risk and clinical stage of CRC. A direct sequencing method was used to detect the rs2276941 polymorphism in 576 CRC patients and 864 healthy individuals. Real-time quantitative PCR technology was used to explore the expression of HAND2-AS1 and hsa-miR-1275 in colorectal tissues with different rs2276941 genotypes. Dual-luciferase reporter assay was used to assess the function of the rs2276941 polymorphism. We found that the rs2276941 polymorphism was associated with a decreased risk of CRC (TT vs. CC, OR = 0.38, 95% CI = 0.16-0.89, p = 0.03; TT vs. [CC+CT], OR = 0.40, 95% CI = 0.17-0.94, p = 0.03). Furthermore, a significant negative correlation was observed between the expression of HAND2-AS1 and hsa-miR-1275 in colorectal tissues with rs2276941 TT genotype. Functional experimental results showed that the rs2276941 T allele might promote the binding of HAND2-AS1 to hsa-miR-1275. The current study results suggested that HAND2-AS1 gene rs2276941 polymorphism affecting the binding of hsa-miR-1275 was associated with CRC risk and might serve as a CRC susceptibility biomarker.","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42182947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The liver of poultry is the primary site of lipid synthesis. The excessive production of lipids accumulates in liver tissues causing lipid metabolism disorders, which result in fatty liver disease and have a transgenerational effect of acquired phenotypes. However, its specific mechanisms have not yet been fully understood. In this study, the differentially expressed miR-375 as well as its target gene MAP3K1 (mitogen-activated protein kinase kinase kinase 1) were screened out by interaction network analysis of microRNA sequencing results and transcriptome profiling in the fatty liver group of the F0-F3 generation (p < 0.05 or p < 0.01). Furthermore, the results showed that the number of lipid droplets and triglyceride content were significantly decreased after upregulation of miR-375 in primary hepatocyte culture in vitro (p < 0.05 or p < 0.01). The MAP3K1 knockdown group exhibited the opposite trends (p < 0.05 or p < 0.01). P53, Bcl-x, PMP22, and CDKN2C related to cell proliferation were significantly upregulated or downregulated after knocking down MAP3K1 (p < 0.05). This research uniquely revealed that silencing miR-375 inhibits lipid biosynthesis and promotes cell proliferation, which may be due to the partial regulation of the expression level of MAP3K1, thereby further participating in the transgenerational inheritance process of regulating liver lipid metabolism. These results reveal the pathogenesis of fatty liver in noncoding RNA and provide good candidate genes for breeding progress of disease resistance in chickens.
{"title":"miR-375 Induced the Formation and Transgenerational Inheritance of Fatty Liver in Poultry by Targeting MAP3K1.","authors":"Heng-li Xie, Yonghong Zhang, Xiaoyang Tan, Yi Zheng, Hongyu Ni, Lijie Dong, Jinlei Zheng, Jinfu Diao, Yijing Yin, Jiabao Zhang, Xuefeng Sun, Yuwei Yang","doi":"10.1089/dna.2022.0078","DOIUrl":"https://doi.org/10.1089/dna.2022.0078","url":null,"abstract":"The liver of poultry is the primary site of lipid synthesis. The excessive production of lipids accumulates in liver tissues causing lipid metabolism disorders, which result in fatty liver disease and have a transgenerational effect of acquired phenotypes. However, its specific mechanisms have not yet been fully understood. In this study, the differentially expressed miR-375 as well as its target gene MAP3K1 (mitogen-activated protein kinase kinase kinase 1) were screened out by interaction network analysis of microRNA sequencing results and transcriptome profiling in the fatty liver group of the F0-F3 generation (p < 0.05 or p < 0.01). Furthermore, the results showed that the number of lipid droplets and triglyceride content were significantly decreased after upregulation of miR-375 in primary hepatocyte culture in vitro (p < 0.05 or p < 0.01). The MAP3K1 knockdown group exhibited the opposite trends (p < 0.05 or p < 0.01). P53, Bcl-x, PMP22, and CDKN2C related to cell proliferation were significantly upregulated or downregulated after knocking down MAP3K1 (p < 0.05). This research uniquely revealed that silencing miR-375 inhibits lipid biosynthesis and promotes cell proliferation, which may be due to the partial regulation of the expression level of MAP3K1, thereby further participating in the transgenerational inheritance process of regulating liver lipid metabolism. These results reveal the pathogenesis of fatty liver in noncoding RNA and provide good candidate genes for breeding progress of disease resistance in chickens.","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2022-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43195809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jurong Ding, Hong-bin Jiang, B. Su, Shanmei Wang, Xiaolan Chen, Yanlin Tan, L. Shen, Jingjing Wang, M. Shi, Haixu Lin, Zhemin Zhang
Sepsis is a global health care issue that affects millions of people. DNA methyltransferase I (DNMT1)-mediated DNA methylation is involved in a number of human diseases by affecting many types of cellular progression events. However, the role and underlying molecular mechanism of DNMT1 in development of sepsis remain largely unknown. Lipopolysaccharide (LPS) induced lung fibrosis in the sepsis mouse model, and DNMT1 was upregulated in lung tissues of a sepsis mouse model compared with lung tissues from control mice. Then, this study demonstrated that LPS induced the production of interleukin (IL)-7 and tumor necrosis factor (TNF)-α and promoted DNMT1 expression in primary type II alveolar epithelial cells (AECII cells). Knockdown of DNMT1 inhibited IL-7 and TNF-α secretion in AECII cells exposed to LPS. Further study demonstrated that DNMT1 repressed the expression of miR-130a in AECII cells with or without LPS exposure. Next, this study demonstrated that miR-130a inhibited ZEB1 expression in AECII cells exposed to LPS. Ultimately, this study revealed the role of the DNMT1/miR-130a/ZEB1 regulatory pathway in AECII cells exposed to LPS. Overall, our data revealed that LPS induced the secretion of inflammatory factors by modulating the DNMT1/miR-130a/ZEB1 regulatory pathway in AECII cells, thus providing a novel theoretical basis that might be beneficial for establishment of diagnostic and therapeutic strategies for sepsis.
{"title":"DNMT1/miR-130a/ZEB1 Regulatory Pathway Affects the Inflammatory Response in Lipopolysaccharide-Induced Sepsis.","authors":"Jurong Ding, Hong-bin Jiang, B. Su, Shanmei Wang, Xiaolan Chen, Yanlin Tan, L. Shen, Jingjing Wang, M. Shi, Haixu Lin, Zhemin Zhang","doi":"10.1089/dna.2021.1060","DOIUrl":"https://doi.org/10.1089/dna.2021.1060","url":null,"abstract":"Sepsis is a global health care issue that affects millions of people. DNA methyltransferase I (DNMT1)-mediated DNA methylation is involved in a number of human diseases by affecting many types of cellular progression events. However, the role and underlying molecular mechanism of DNMT1 in development of sepsis remain largely unknown. Lipopolysaccharide (LPS) induced lung fibrosis in the sepsis mouse model, and DNMT1 was upregulated in lung tissues of a sepsis mouse model compared with lung tissues from control mice. Then, this study demonstrated that LPS induced the production of interleukin (IL)-7 and tumor necrosis factor (TNF)-α and promoted DNMT1 expression in primary type II alveolar epithelial cells (AECII cells). Knockdown of DNMT1 inhibited IL-7 and TNF-α secretion in AECII cells exposed to LPS. Further study demonstrated that DNMT1 repressed the expression of miR-130a in AECII cells with or without LPS exposure. Next, this study demonstrated that miR-130a inhibited ZEB1 expression in AECII cells exposed to LPS. Ultimately, this study revealed the role of the DNMT1/miR-130a/ZEB1 regulatory pathway in AECII cells exposed to LPS. Overall, our data revealed that LPS induced the secretion of inflammatory factors by modulating the DNMT1/miR-130a/ZEB1 regulatory pathway in AECII cells, thus providing a novel theoretical basis that might be beneficial for establishment of diagnostic and therapeutic strategies for sepsis.","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":"1 1","pages":"1-8"},"PeriodicalIF":3.1,"publicationDate":"2022-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42805174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lin Li, Lei Lin, S. Lei, Si Shi, Chun Chen, Z. Xia
Apoptosis, necroptosis, and autophagy are the major programmed cell death in myocardial ischemia-reperfusion injury (MIRI). Maslinic acid (MA) has been found to regulate pathophysiological processes that mediate programmed cell death in MIRI, such as inflammation and oxidative stress. However, its effects on MIRI remain unclear. This study intends to explore the role of MA in MIRI. In vitro, MA had no obvious cytotoxic effects on H9C2 cells, and significantly improved the impaired cell viability caused by hypoxia reoxygenation (HR). In vivo, MA significantly alleviated ischemia reperfusion (IR)-induced left ventricular myocardial tissue injury, downregulated creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels in serum as well as reducing infarct size. Moreover, MA inhibited HR-induced mitochondrial apoptosis and necroptosis in vitro and in vivo. Of interest, MA interacts with lysosome-associated membrane protein 2 (LAMP2). MA protected LAMP2 from IR and promoting autophagic flux to inhibit apoptosis and necroptosis, whereas these effects were reversed by co-treatment with lysosomal inhibitor BarfA1. In conclusion, MA can inhibit MIRI-induced apoptosis and necroptosis by promoting autophagic flux. These results support that MA is a potential agent to ameliorate MIRI.
{"title":"Maslinic Acid Inhibits Myocardial Ischemia-Reperfusion Injury-Induced Apoptosis and Necroptosis via Promoting Autophagic Flux.","authors":"Lin Li, Lei Lin, S. Lei, Si Shi, Chun Chen, Z. Xia","doi":"10.1089/dna.2021.0918","DOIUrl":"https://doi.org/10.1089/dna.2021.0918","url":null,"abstract":"Apoptosis, necroptosis, and autophagy are the major programmed cell death in myocardial ischemia-reperfusion injury (MIRI). Maslinic acid (MA) has been found to regulate pathophysiological processes that mediate programmed cell death in MIRI, such as inflammation and oxidative stress. However, its effects on MIRI remain unclear. This study intends to explore the role of MA in MIRI. In vitro, MA had no obvious cytotoxic effects on H9C2 cells, and significantly improved the impaired cell viability caused by hypoxia reoxygenation (HR). In vivo, MA significantly alleviated ischemia reperfusion (IR)-induced left ventricular myocardial tissue injury, downregulated creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels in serum as well as reducing infarct size. Moreover, MA inhibited HR-induced mitochondrial apoptosis and necroptosis in vitro and in vivo. Of interest, MA interacts with lysosome-associated membrane protein 2 (LAMP2). MA protected LAMP2 from IR and promoting autophagic flux to inhibit apoptosis and necroptosis, whereas these effects were reversed by co-treatment with lysosomal inhibitor BarfA1. In conclusion, MA can inhibit MIRI-induced apoptosis and necroptosis by promoting autophagic flux. These results support that MA is a potential agent to ameliorate MIRI.","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2022-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48059430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li Cao, C. Ren, Guochun Zhang, Xuerui Li, Bo Chen, Kai Li, Cheukfai Li, H. Mok, Yulei N. Wang, L. Wen, M. Jia, Guangnan Wei, Jiali Lin, N. Liao
MYC amplification is detected in ∼15% of breast tumors and is associated with poor prognosis by mediating acquired resistance to anticancer therapies. This study aimed to determine the prevalence of MYC amplifications in Chinese women with breast cancer (BRCA) and investigate the correlation between MYC amplification and clinicopathological and molecular characteristics and its clinical implications. We analyzed MYC alterations in tissue specimens from 410 women diagnosed with BRCA in our hospital from June 1, 2017 to September 27, 2018. We compared our results with publicly available data from The Cancer Genome Atlas (TCGA) BRCA cohort (n = 1079). MYC amplification was identified in 12.4% (51/410) of our cohort, with mean copy number (CN) of 4.42 (range: 2.84-11.27). In TCGA cohort, MYC amplification was identified in 21.2% (229/1079) and was associated with age, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 (HER2) status, and molecular subtype, whereas in our cohort, MYC amplification was associated with smaller tumor size (T1-2, p = 0.023) and higher Ki-67 levels (≥20%; p = 0.031). Analysis of molecular profiles revealed that MYC-amplified breast tumors had significantly more concurrent CN variations compared with MYC nonamplified BRCA in both Guangdong Provincial People's Hospital (GDPH) and TCGA cohorts (p < 0.001). Pathway mapping analysis demonstrated that MYC-amplified tumors had more mutations involved in 15 different but interrelated pathways critical in DNA repair, cell cycle, and cell proliferation. Patients in TCGA cohort with MYC-amplified hormone receptor (HR)-positive/HER2-positive BRCA (p = 0.038) and MYC nonamplified triple-negative BRCA (p = 0.027) had significantly shorter overall survival. In conclusion, this study contributes to a better understanding that MYC-amplified breast tumors had distinct clinicopathological and molecular features compared with MYC nonamplified breast tumors. Further research with a larger sample size is necessary to further elucidate the clinical and survival implications of MYC amplifications.
{"title":"Characteristics of MYC Amplification and Their Association with Clinicopathological and Molecular Factors in Patients with Breast Cancer.","authors":"Li Cao, C. Ren, Guochun Zhang, Xuerui Li, Bo Chen, Kai Li, Cheukfai Li, H. Mok, Yulei N. Wang, L. Wen, M. Jia, Guangnan Wei, Jiali Lin, N. Liao","doi":"10.1089/dna.2020.6487","DOIUrl":"https://doi.org/10.1089/dna.2020.6487","url":null,"abstract":"MYC amplification is detected in ∼15% of breast tumors and is associated with poor prognosis by mediating acquired resistance to anticancer therapies. This study aimed to determine the prevalence of MYC amplifications in Chinese women with breast cancer (BRCA) and investigate the correlation between MYC amplification and clinicopathological and molecular characteristics and its clinical implications. We analyzed MYC alterations in tissue specimens from 410 women diagnosed with BRCA in our hospital from June 1, 2017 to September 27, 2018. We compared our results with publicly available data from The Cancer Genome Atlas (TCGA) BRCA cohort (n = 1079). MYC amplification was identified in 12.4% (51/410) of our cohort, with mean copy number (CN) of 4.42 (range: 2.84-11.27). In TCGA cohort, MYC amplification was identified in 21.2% (229/1079) and was associated with age, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 (HER2) status, and molecular subtype, whereas in our cohort, MYC amplification was associated with smaller tumor size (T1-2, p = 0.023) and higher Ki-67 levels (≥20%; p = 0.031). Analysis of molecular profiles revealed that MYC-amplified breast tumors had significantly more concurrent CN variations compared with MYC nonamplified BRCA in both Guangdong Provincial People's Hospital (GDPH) and TCGA cohorts (p < 0.001). Pathway mapping analysis demonstrated that MYC-amplified tumors had more mutations involved in 15 different but interrelated pathways critical in DNA repair, cell cycle, and cell proliferation. Patients in TCGA cohort with MYC-amplified hormone receptor (HR)-positive/HER2-positive BRCA (p = 0.038) and MYC nonamplified triple-negative BRCA (p = 0.027) had significantly shorter overall survival. In conclusion, this study contributes to a better understanding that MYC-amplified breast tumors had distinct clinicopathological and molecular features compared with MYC nonamplified breast tumors. Further research with a larger sample size is necessary to further elucidate the clinical and survival implications of MYC amplifications.","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2022-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43741745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Calorie restriction (CR) if planned properly with regular exercise at different ages can result in healthy weight loss. CR can also have different beneficial effects on improving lifespan and decreasing the age-associated diseases by regulating physiological, biochemical, and molecular markers. The different pathways regulated by CR include:(1) AMP-activated protein kinase (AMPK), which involves PGC-1α, SIRT1, and SIRT3. AMPK also effects myocyte enhancer factor 2 (MEF2), peroxisome proliferator-activated receptor delta, and peroxisome proliferator-activated receptor alpha, which are involved in mitochondrial biogenesis and lipid oxidation; (2) Forkhead box transcription factor's signaling is related to the DNA repair, lipid metabolism, protection of protein structure, autophagy, and resistance to oxidative stress; (3) Mammalian target of rapamycin (mTOR) signaling, which involves key factors, such as S6 protein kinase-1 (S6K1), mTOR complex-1 (mTORC1), and 4E-binding protein (4E-BP). Under CR conditions, AMPK activation and mTOR inhibition helps in the activation of Ulk1 complex along with the acetyltransferase Mec-17, which is necessary for autophagy; (4) Insulin-like growth factor-1 (IGF-1) pathway downregulation protects against cancer and slows the aging process; (5) Nuclear factor kappa B pathway downregulation decreases the inflammation; and (6) c-Jun N-terminal kinase and p38 kinase regulation as a response to the stress. The acute and chronic CR both shows antidepression and anxiolytic action by effecting ghrelin/GHS-R1a signaling. CR also regulates GSK3β kinase and protects against age-related brain atrophy. CR at young age may show many deleterious effects by effecting different mechanisms. Parental CR before or during conception will also affect the health and development of the offspring by causing many epigenetic modifications that show transgenerational transmission. Maternal CR is associated with intrauterine growth retardation effecting the offspring in their adulthood by developing different metabolic syndromes. The epigenetic changes with response to paternal food supply also linked to offspring health. CR at middle and old age provides a significant preventive impact against the development of age-associated diseases.
如果在不同的年龄进行适当的计划和有规律的运动，热量限制(CR)可以达到健康的减肥效果。CR还可以通过调节生理、生化和分子标记，对延长寿命和减少与年龄相关的疾病产生不同的有益影响。CR调节的不同途径包括:(1)amp活化蛋白激酶(AMPK)，涉及PGC-1α、SIRT1和SIRT3。AMPK还影响心肌细胞增强因子2 (MEF2)、过氧化物酶体增殖物激活受体δ和过氧化物酶体增殖物激活受体α，它们参与线粒体生物发生和脂质氧化;(2)叉头盒转录因子的信号转导与DNA修复、脂质代谢、蛋白质结构保护、自噬、抗氧化应激等有关;(3)哺乳动物雷帕霉素(mTOR)信号通路靶点，涉及S6蛋白激酶-1 (S6K1)、mTOR复合物-1 (mTORC1)、4e结合蛋白(4E-BP)等关键因子。在CR条件下，AMPK激活和mTOR抑制有助于Ulk1复合物和乙酰转移酶Mec-17的激活，这是自噬所必需的;(4)胰岛素样生长因子-1 (IGF-1)通路下调具有抗癌和延缓衰老作用;(5)核因子κ B通路下调可减轻炎症反应;(6) c-Jun n -末端激酶和p38激酶的调控对胁迫的响应。急性和慢性CR均通过影响ghrelin/GHS-R1a信号通路表现出抗抑郁和抗焦虑作用。CR还调节GSK3β激酶，并防止与年龄相关的脑萎缩。幼年期CR可能通过不同的机制表现出许多有害的影响。父母在受孕前或怀孕期间的CR也会影响后代的健康和发育，导致许多表现为跨代遗传的表观遗传修饰。母体CR与宫内生长迟缓有关，通过发展不同的代谢综合征影响后代成年期。表观遗传变化对父亲食物供应的反应也与后代健康有关。中老年CR对老年相关疾病的发展具有重要的预防作用。
{"title":"Calorie Restriction-Regulated Molecular Pathways and Its Impact on Various Age Groups: An Overview.","authors":"Anuradha Rachakatla, Rajender Rao Kalashikam","doi":"10.1089/dna.2021.0922","DOIUrl":"https://doi.org/10.1089/dna.2021.0922","url":null,"abstract":"Calorie restriction (CR) if planned properly with regular exercise at different ages can result in healthy weight loss. CR can also have different beneficial effects on improving lifespan and decreasing the age-associated diseases by regulating physiological, biochemical, and molecular markers. The different pathways regulated by CR include:(1) AMP-activated protein kinase (AMPK), which involves PGC-1α, SIRT1, and SIRT3. AMPK also effects myocyte enhancer factor 2 (MEF2), peroxisome proliferator-activated receptor delta, and peroxisome proliferator-activated receptor alpha, which are involved in mitochondrial biogenesis and lipid oxidation; (2) Forkhead box transcription factor's signaling is related to the DNA repair, lipid metabolism, protection of protein structure, autophagy, and resistance to oxidative stress; (3) Mammalian target of rapamycin (mTOR) signaling, which involves key factors, such as S6 protein kinase-1 (S6K1), mTOR complex-1 (mTORC1), and 4E-binding protein (4E-BP). Under CR conditions, AMPK activation and mTOR inhibition helps in the activation of Ulk1 complex along with the acetyltransferase Mec-17, which is necessary for autophagy; (4) Insulin-like growth factor-1 (IGF-1) pathway downregulation protects against cancer and slows the aging process; (5) Nuclear factor kappa B pathway downregulation decreases the inflammation; and (6) c-Jun N-terminal kinase and p38 kinase regulation as a response to the stress. The acute and chronic CR both shows antidepression and anxiolytic action by effecting ghrelin/GHS-R1a signaling. CR also regulates GSK3β kinase and protects against age-related brain atrophy. CR at young age may show many deleterious effects by effecting different mechanisms. Parental CR before or during conception will also affect the health and development of the offspring by causing many epigenetic modifications that show transgenerational transmission. Maternal CR is associated with intrauterine growth retardation effecting the offspring in their adulthood by developing different metabolic syndromes. The epigenetic changes with response to paternal food supply also linked to offspring health. CR at middle and old age provides a significant preventive impact against the development of age-associated diseases.","PeriodicalId":11248,"journal":{"name":"DNA and cell biology","volume":"1 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60970081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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