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1دورية أكاديمية
المؤلفون: Shouyan Wu, Henglei Lu, Wenjie Wang, Limei Song, Meng Li, Yuhan Cao, Xinming Qi, Jianhua Sun, Likun Gong
مصطلحات موضوعية: Pharmacological Effects of Licorice Roots, Pharmacology, Pharmacology, Toxicology and Pharmaceutics, Life Sciences, Cellular Response to Osmotic Stress and Metabolism, Cell Biology, Biochemistry, Genetics and Molecular Biology, Molecular Mechanisms and Medical Applications of Ginseng, Molecular Biology, Hepatoprotective, Autophagy, Lysosome, Autophagosome, Pregnane X receptor, Cell biology, Hepatocyte, ATG12, Biology, Apoptosis, Chemistry, Liver injury, Programmed cell death, ATG5, Biochemistry, Gene, Nuclear receptor, Transcription factor, Enzyme, In vitro
الوصف: Acute liver injury (ALI) has multiple causes and results in liver dysfunction. Severe or persistent liver injury eventually leads to liver failure and even death. Pregnane X receptor (PXR)-null mice present more severe liver damage and lower rates of autophagy. 18β-glycyrrhetinic acid (GA) has been proposed as a promising hepatoprotective agent. We hypothesized that GA significantly alleivates D-GalN/LPS-induced ALI, which involved in PXR-mediated autophagy and lysosome biogenesis. We found that GA can significantly decrease hepatocyte apoptosis and increase the hepatic autophagy marker LC3-B. Ad-mCherry-GFP-LC3 tandem fluorescence, RNA-seq and real-time PCR indicated that GA may stabilize autophagosomes and lysosomes and inhibit autophagosome-lysosome fusion. Simultaneously, GA markedly activates PXR, even reversing the D-GalN/LPS-induced reduction of PXR and its downstream genes. In contrast, GA has a weak protective effect in pharmacological inhibition of PXR and PXR-null mice, which significantly ... : إصابة الكبد الحادة (ALI) لها أسباب متعددة وتؤدي إلى خلل وظيفي في الكبد. تؤدي إصابة الكبد الشديدة أو المستمرة في النهاية إلى فشل الكبد وحتى الموت. مستقبلات بريجنان إكس (PXR) - تظهر الفئران الفارغة تلفًا شديدًا في الكبد ومعدلات أقل من الالتهام الذاتي. تم اقتراح حمض 18 β - glycyrrhetinic (GA) كعامل واعد لحماية الكبد. افترضنا أن التخدير العام ينشط بشكل كبير ALI الذي يسببه D - GalN/LPS، والذي يشارك في الالتهام الذاتي بواسطة PXR والتكوين الحيوي للليزوزوم. وجدنا أن التخدير العام يمكن أن يقلل بشكل كبير من موت الخلايا المبرمج للكبد ويزيد من علامة الالتهام الذاتي الكبدي LC3 - B. أشار كل من التألق الترادفي Ad - mCherry - GFP - LC3 و RNA - seq و PCR في الوقت الفعلي إلى أن التخدير العام قد يستقر في البلعمة الذاتية والليزوزومات ويثبط اندماج البلعمة الذاتية والليزوزوم. في الوقت نفسه، ينشط GA بشكل ملحوظ PXR، حتى عكس الانخفاض الناجم عن D - GalN/LPS لـ PXR وجيناته النهائية. على النقيض من ذلك، فإن التخدير العام له تأثير وقائي ضعيف في التثبيط الدوائي لفئران PXR و PXR - null، مما أثر بشكل كبير على الجينات المرتبطة بالموت المبرمج ...
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المؤلفون: Jiahui Mou, Meijun Huang, Feifei Wang, Xiaoding Xu, Hanqi Xie, Henglei Lu, Mingyang Li, Yu Li, Weiwen Kong, Jing Chen, Ying Xiao, Yiding Chen, Chaochen Wang, Jin Ren
المصدر: Molecular cancer research : MCR. 20(12)
مصطلحات موضوعية: STAT3 Transcription Factor, Cancer Research, Carcinogenesis, Apoptosis, Breast Neoplasms, Chromatin, Mice, Oncology, Cell Line, Tumor, Trans-Activators, Humans, Animals, HMGN Proteins, Female, Molecular Biology, Cell Proliferation
الوصف: Cancer progression is highly dependent on the ability of cancer cell tumor formation, in which epigenetic modulation plays an essential role. However, the epigenetic factors promoting breast tumor formation are less known. Screened from three-dimensional (3D)-sphere tumor formation model, HMGN5 that regulates chromatin structures became the candidate therapeutic target in breast cancer, though its role is obscure. HMGN5 is highly expressed in 3D-spheres of breast cancer cells and clinical tumors, also an unfavorable prognostic marker in patients. Furthermore, HMGN5 controls tumor formation and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape the oncogenic chromatin landscape and transcriptional program. More importantly, interference of HMGN5 by nanovehicle-packaged siRNA effectively inhibits tumor growth in breast cancer cell–derived xenograft mice model. Implications: Our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic target in STAT3-hyperactive breast cancer.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::930b126ca65d60b9b259018821b928b9Test
https://pubmed.ncbi.nlm.nih.gov/36066963Test -
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المؤلفون: Rongrong, Tan, Jiayang, Li, Lu, Liu, Qian, Wu, Lei, Fan, Ningning, Ma, Chuwei, Yu, Henglei, Lu, Xuemei, Zhang, Jing, Chen, Likun, Gong, Jin, Ren
المصدر: International Journal of Molecular Sciences; Volume 23; Issue 24; Pages: 15931
مصطلحات موضوعية: Inorganic Chemistry, Organic Chemistry, NAFLD, CSAD, obesity, liver damage, fatty acid β-oxidation, mitochondrial damage, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
الوصف: Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic disease manifested in hepatic steatosis, inflammation, fibrosis, etc., which affects over one-quarter of the population around the world. Since no effective therapeutic drugs are available to cope with this widespread epidemic, the functional research of genes with altered expression during NAFLD helps understand the pathogenesis of this disease and the development of new potential therapeutic targets for drugs. In the current work, we discovered via the analysis of the Gene Expression Omnibus (GEO) dataset that cysteine sulfinic acid decarboxylase (CSAD) decreased significantly in NAFLD patients, which was also confirmed in multiple NAFLD mouse models (HFD-fed C57BL/6J, db/db and HFHFrHC-fed C57BL/6J mice). Next, CSAD’s function in the progression of NAFLD was explored using AAV-mediated liver-directed gene overexpression in an HFD-fed mouse model, where the overexpression of CSAD in the liver could alleviate NAFLD-associated pathologies, including body weight, liver/body weight ratio, hepatic triglyceride and total cholesterol, and the degree of steatosis. Mechanically, we found that the overexpression of CSAD could increase the expression of some genes related to fatty acid β-oxidation (Acad1, Ppara, and Acox1). Furthermore, we also detected that CSAD could improve mitochondrial injury in vitro and in vivo. Finally, we proposed that the effect of CSAD on lipid accumulation might be independent of the taurine pathway. In conclusion, we demonstrated that CSAD is involved in the development of NAFLD as a protective factor, which suggested that CSAD has the potential to become a new target for drug discovery in NAFLD.
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8f6279be78b213b4077a1aaaaa9d130bTest
https://doi.org/10.3390/ijms232415931Test -
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المؤلفون: Huibiao Zhang, Jin Ren, Chao Peng, Yizheng Wang, Ruimin Huang, Liting Zhao, Zhouteng Tao, Yuxiang Chen, Henglei Lu, Jiahui Mou, Yue Yin, Lei Fan, Jing Chen, Xinming Qi, Yu Li
المصدر: Oncogene. 39:3473-3488
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Lung Neoplasms, Motility, Adenocarcinoma of Lung, Biology, Permeability, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Neoplasm Invasiveness, RNA, Neoplasm, Lung cancer, Molecular Biology, A549 cell, Cadherin, HEK 293 cells, Endothelial Cells, Cadherins, medicine.disease, Neoplasm Proteins, Endothelial stem cell, MicroRNAs, HEK293 Cells, 030104 developmental biology, A549 Cells, 030220 oncology & carcinogenesis, Cancer research, Adenocarcinoma
الوصف: Tumor invasion underlies further metastasis, the leading cause for cancer-related deaths. Deregulation of microRNAs has been identified associated with the malignant behavior of various cancers, including lung adenocarcinoma (LUAD), the major subtype of lung cancer. Here, we showed the significantly positive correlation between miR-629-5p level and tumor invasion in LUAD specimens (n = 49). In a human LUAD metastasis mouse model, H1650 cells (high level of miR-629-5p) were more aggressive than A549 cells (low level of miR-629-5p) in vivo, including higher incidence of vascular invasion and pulmonary colonization. Ectopic expression of miR-629-5p in A549 cells also increased their invasive capability. Then we identified that miR-629-5p promotes LUAD invasion in a mode of dual regulation via tumor cells invasion and endothelial cells permeability, respectively. In tumor cells, miR-629-5p enhanced motility and invasiveness of tumor cells by directly targeting PPWD1 (a cyclophilin), which clinically related to tumor invasion in LUAD specimens. Restoring PPWD1 protein significantly attenuated the invasion-promoting effects of miR-629-5p. Besides, exosomal-miR-629-5p secreted from tumor cells could be transferred to endothelial cells and increased endothelial monolayers permeability by suppressing CELSR1 (a nonclassic-type cadherin), which had a low level in the endothelial cells of invasive LUAD specimens. Activating the expression of CELSR1 in endothelial cells markedly blocked the effect of miR-629-5p. Our study suggests the dual roles of miR-629-5p in tumor cells and endothelial cells for LUAD invasion, implying a therapeutic option to targeting miR-629-5p using the "one stone, two birds" strategy in LUAD.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2bac28b136404a7c86681a178cd9da9cTest
https://doi.org/10.1038/s41388-020-1228-1Test -
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المؤلفون: Guanghui Wang, Huijie Guo, Jin Ren, Ruimin Huang, Zhouteng Tao, Xinming Qi, Jing Chen, Mei Pu, Yusi Tai, Yuxiang Chen, Junwen Qiao, Henglei Lu
المصدر: Cell Death Differ
مصطلحات موضوعية: 0301 basic medicine, Male, Cellular homeostasis, Article, 03 medical and health sciences, Transactivation, Mice, 0302 clinical medicine, Transcription (biology), Lysosome, medicine, Autophagy, Animals, Humans, Molecular Biology, Transcription factor, Cell Nucleus, Chemistry, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Biology, Cell biology, Mice, Inbred C57BL, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, HEK293 Cells, 030220 oncology & carcinogenesis, TFEB, Lysosomes, Biogenesis, HeLa Cells
الوصف: Lysosome is a crucial organelle in charge of degrading proteins and damaged organelles to maintain cellular homeostasis. Transcription factor EB (TFEB) is the master transcription factor regulating lysosomal biogenesis and autophagy. Under external stimuli such as starvation, dephosphorylated TFEB transports into the nucleus to specifically recognize and bind to the coordinated lysosomal expression and regulation (CLEAR) elements at the promotors of autophagy and lysosomal biogenesis-related genes. The function of TFEB in the nucleus is fine regulated but the molecular mechanism is not fully elucidated. In this study, we discovered that miR-30b-5p, a small RNA which is known to regulate a series of genes through posttranscriptional regulation in the cytoplasm, was translocated into the nucleus, bound to the CLEAR elements, suppressed the transcription of TFEB-dependent downstream genes, and further inhibited the lysosomal biogenesis and the autophagic flux; meanwhile, knocking out the endogenous miR-30b-5p by CRISPR/Cas9 technique significantly increased the TFEB-mediated transactivation, resulting in the increased expression of autophagy and lysosomal biogenesis-related genes. Overexpressing miR-30b-5p in mice livers showed a decrease in lysosomal biogenesis and autophagy. These in vitro and in vivo data indicate that miR-30b-5p may inhibit the TFEB-dependent transactivation by binding to the CLEAR elements in the nucleus to regulate the lysosomal biogenesis and autophagy. This novel mechanism of nuclear miRNA regulating gene transcription is conducive to further elucidating the roles of miRNAs in the lysosomal physiological functions and helps to understand the pathogenesis of abnormal autophagy-related diseases.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3cbde0e19579ce3f63be87703c456de9Test
https://pubmed.ncbi.nlm.nih.gov/32764647Test -
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المؤلفون: Qian Li, Yiting Zhang, Bingshun Wang, Zonghai Li, Jin Ren, Yongzhen Liu, Hua Jiang, Hualiang Jiang, Henglei Lu, Likun Gong, Huamao Wang, Wei Wan, Jianhua Sun, Minjia Tan
المصدر: Molecular Therapy. 26:1457-1470
مصطلحات موضوعية: Male, 0301 basic medicine, genetic structures, medicine.drug_class, Protein subunit, Integrin, Integrin alpha2, Pharmacology, Monoclonal antibody, 03 medical and health sciences, Drug Discovery, Genetics, medicine, Animals, Humans, Platelet, Epidermal growth factor receptor, Molecular Biology, biology, business.industry, Integrin beta3, Antibodies, Monoclonal, Thrombocytopenia, Rats, Macaca fascicularis, 030104 developmental biology, Drug development, Monoclonal antibody CH12, Toxicity, biology.protein, Molecular Medicine, Original Article, Female, business
الوصف: CH12 is a novel humanized monoclonal antibody against epidermal growth factor receptor variant III (EGFRvIII) for cancer treatment. Unfortunately, in pre-clinical safety evaluation studies, acute thrombocytopenia was observed after administration of CH12 in cynomolgus monkeys, but not rats. More importantly, in vitro experiments found that CH12 can bind and activate platelets in cynomolgus monkey, but not human peripheral blood samples. Cynomolgus monkey-specific thrombocytopenia has been reported previously; however, the underlying mechanism remains unclear. Here, we first showed that CH12 induced thrombocytopenia in cynomolgus monkeys through off-target platelet binding and activation, resulting in platelet destruction. We subsequently found that integrin αIIbβ3 (which is expressed on platelets) contributed to this off-target toxicity. Furthermore, three-dimensional structural modeling of the αIIbβ3 molecules in cynomolgus monkeys, humans, and rats suggested that an additional unique loop exists in the ligand-binding pocket of the αIIb subunit in cynomolgus monkeys, which may explain why CH12 binds to platelets only in cynomolgus monkeys. Moreover, this study supported the hypothesis that the minor differences between cynomolgus monkeys and humans can confuse human risk assessments and suggests that species differences can help the prediction of human risks and avoid losses in drug development.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4b6e6706940dabe05c0ac22e20630b2cTest
https://doi.org/10.1016/j.ymthe.2018.04.005Test
