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Gene expression profiling of MYC-driven tumor signatures in porcine liver stem cells by transcriptome sequencing

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World Journal of Gastroenterology 2015年第7期21卷 2011-2029页

作者： Rajagopal N Aravalli Neil C Talbot Clifford J Steer Department of Radiology University of Minnesota Medical School Minneapolis Beltsville Agricultural Research Center US Department of Agriculture departments of Medicine and Genetics Cell Biology and Development University of Minnesota

AIM:To identify the genes induced and regulated by the MYC protein in generating tumors from liver stem ***:In this study,we have used an immortal porcine liver stem cell line,PICM-19,to study the role of c-MYC in ***-19 cells were converted into cancer cells(PICM-19-CSCs)by overexpressing human *** identify MYC-driven differential gene expression,transcriptome sequencing was carried out by RNA sequencing,and genes identified by this method were validated using real-time *** vivo tumorigenicity studies were then conducted by injecting PICM-19-CSCs into the flanks of immunodeficient ***:Our results showed that MYC-overexpressing PICM-19 stem cells formed tumors in immunodeficient mice demonstrating that a single oncogene was sufficient to convert them into cancer cells(PICM-19-CSCs).By using comparative bioinformatics analyses,we have determined that>1000 genes were differentially expressed between PICM-19 and *** ontology analysis further showed that the MYCinduced,altered gene expression was primarily associated with various cellular processes,such as metabolism,cell adhesion,growth and proliferation,cell cycle,inflammation and ***,six genes expressed by PICM-19 cells(CDO1,C22orf39,DKK2,ENPEP,GPX6,SRPX2)were completely silenced after MYC-induction in PICM-19-CSCs,suggesting that the absence of these genes may be critical for ***:MYC-driven genes may serve as promising candidates for the development of hepatocellular carcinoma therapeutics that would not have deleterious effects on other cell types in the liver.

关键词： Hepatocellular carcinoma MYC Stem cells Gene expre

Safety Assessment of Aconitum-Derived Bulleyaconitine A: A 91-Day Oral Toxicity Study and a Tissue Accumulation Study in Rats

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World Journal of Traditional Chinese Medicine 2021年第2期7卷 217-226页

作者： Shi-Liang Yin Feng Xu Hao Wu Fei Li Ge Jin Zu-Qian Wu Ran Meng Si-Man Ma Fan Zhou Peter Breslin Chun-Fu Wu Hong Zhang Department of pharmacology School of PharmacyShenyang Medical College Department of pharmacology School of Life Science and BiopharmaceuticsShenyang Pharmaceutical UniversityShenyang State Key Laboratory of Medicinal Chemical biology College of PharmacyNankai UniversityTianjin Department of Pharmaceutical Analysis School of PharmacyShenyang Pharmaceutical UniversityShenyang Department of Hematology General Hospital of Northern Theater CommandShenyangChina Department of biology and Molecular cellular Physiology Loyola University ChicagoChicagoIllinoisUSA

Background:Bulleyaconitine A(BLA)is a diterpenoid alkaloid from the rhizomes of Aconitum bulleyanum Diels and has been clinically used for chronic pain treatment in China for many ***,the newly reported adverse events of BLA indicated that BLA still has potential safety *** and Methods:To assess the safety of BLA,analgesic tests,acute toxicity studies,repeated-dose oral toxicity studies,and tissue distribution studies after single and repeated administration of BLA were carried ***:Administration of 0.14 mg/kg BLA showed potent analgesic effects in both analgesic *** acute toxicity study,the LD50 value of BLA was calculated to be 3.4434 mg/*** the subchronic toxicity study,the no observed adverse effect level was 0.25 mg/kg,and the lowest observed adverse effect level was 0.5 mg/*** spleen,liver,and kidneys are newly identified target organs of BLA toxicity after long-term ***,unlike a single BLA administration,repeated administration showed BLA redistribution from organs with an abundant blood supply to immune and metabolic ***:These results suggested that BLA itself would be nontoxic at a dosage of 0.25 mg/kg in rats and should be carefully used when combining BLA with medications that can cause spleen,liver,or kidney injury.

关键词： Adverse reaction bulleyaconitine A repeated-dose(91-day)toxicity tissue distribution

G protein controls stress readiness by modulating transcriptional and metabolic homeostasis in Arabidopsis thaliana and Marchantia polymorpha

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Molecular Plant 2022年第12期15卷 1889-1907页

作者： Ting-Ying Wu Shalini Krishnamoorthi Kulaporn Boonyaves Isam Al-Darabsah Richalynn Leong Alan M.Jones Kimitsune Ishizaki Kang-Ling Liao Daisuke Urano Temasek Life Sciences Laboratory SingaporeSingapore Department of Mathematics University of ManitobaWinnipegMBCanada Singapore-MIT Alliance for Research and Technology SingaporeSingapore Department of Biological Sciences National University of SingaporeSingapore 117558Singapore departments of biology and pharmacology University of North CarolinaChapel HillNCUSA Graduate School of Science Kobe UniversityKobeHyogo 657-8501Japan

The core G protein signaling module,which consists of Gαand extra-large Gα(XLG)subunits coupled with the Gβγdimer,is a master regulator of various stress *** this study,we compared the basal and salt stress-induced transcriptomic,metabolomic and phenotypic profiles in Gα,Gβ,and XLG-null mutants of two plant species,Arabidopsis thaliana and Marchantia polymorpha,and showed that G protein mediates the shift of transcriptional and metabolic homeostasis to stress readiness *** demonstrated that such stress readiness serves as an intrinsic protection mechanism against further stressors through enhancing the phenylpropanoid pathway and abscisic acid ***,WRKY transcription factors were identified as key intermediates of G protein-mediated homeostatic *** and mathematical model comparisons between *** and *** revealed evolutionary conservation of transcriptional and metabolic networks over land plant evolution,whereas divergence has occurred in the function of plant-specific atypical XLG *** together,our results indicate that the shifts in transcriptional and metabolic homeostasis at least partially act as the mechanisms of G protein-coupled stress responses that are conserved between two distantly related plants.

关键词： homeostatic adjustments transcriptional regulation metabolic regulation heterotrimeric G protein evolutionary conservation

Regulation of pancreatic cancer metastasis through the Gli2-YAP1 axis via regulation of anoikis

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Genes & Diseases 2022年第6期9卷 1427-1430页

作者： Beiqin Yu Dongsheng Gu Xiaoli Zhang Bingya Liu Jingwu Xie Department of General Surgery Shanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025PR China departments of Pediatrics Biochemistry and Molecular BiologyPharmacology and ToxicologyThe Wells Center for Pediatrics ResearchIndiana University School of MedicineIndianapolisIN 46202USA

Pancreatic cancer,mostly pancreatic ductal adenocarcinoma(PDAC),is often metastatic upon the initial diagnosis,and has a high mortality ***,the primary and the matched metastatic cancers often share the same driver gene mutations.1,2 Gene expression comparison between primary and metastatic PDAC tissues revealed high expression of Gli2 and YAP1 in the metastatic ***2 is an important player in non-canonical hedgehog signaling,and YAP1 is an essential cell polarity *** this study,we investigated the effects of Gli2 and YAP1 on pancreatic cancer cell function in 3D culture and in mouse *** further determined the relationship between Gli2 and *** studies further our understanding of pancreatic cancer metastasis.

关键词： YAP1 Gli2 metastasis

Interactome Mapping: Using Protein Microarray Technology to Reconstruct Diverse Protein Networks

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Genomics, Proteomics & Bioinformatics 2013年第1期11卷 18-28页

作者： Ijeoma Uzoma Heng Zhu Department of pharmacology and Molecular Sciences The Johns Hopkins University School of Medicine The Center for High-Throughput biology The Johns Hopkins University School of Medicine

A major focus of systems biology is to characterize interactions between cellular compo- nents, in order to develop an accurate picture of the intricate networks within biological systems. Over the past decade, protein microarrays have greatly contributed to advances in proteomics and are becoming an important platform for systems biology. Protein microarrays are highly flex- ible, ranging from large-scale proteome microarrays to smaller customizable microarrays, making the technology amenable for detection of a broad spectrum of biochemical properties of proteins. In this article, we will focus on the numerous studies that have utilized protein microarrays to recon- struct biological networks including protein-DNA interactions, posttranslational protein modifica- tions （PTMs）, lectin glycan recognition, pathogen-host interactions and hierarchical signaling cascades. The diversity in applications allows for integration of interaction data from numerous molecular classes and cellular states, providing insight into the structure of complex biological sys- tems. We will also discuss emerging applications and future directions of protein microarray tech- nology in the global frontier.

关键词： Protein mieroarray Protein networker Interaetome Serum profiling Systems biology

Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma

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World Journal of Gastroenterology 2013年第47期19卷 8880-8886页

作者： Chia-Chi Hsu Hsin-Chen Lee Yau-Huei Wei Institute of pharmacology School of MedicineNational Yang-Ming University Department of Biochemistry and Molecular biology National Yang-Ming University Department of Medicine Mackay Medical College

Hepatocellular carcinoma(HCC)is one of the most common malignancies and is ranked third in mortality among cancer-related *** are intracellular organelles that are responsible for energy metabolism and cellular homeostasis,and mitochondrial dysfunction has been regarded as a hallmark of *** the past decades,several types of mitochondrial DNA(mtDNA)alterations have been identified in human cancers,including ***,the role of these mtDNA alterations in cancer progression is *** this review,we summarize the recent findings on the somatic mtDNA alterations identified in HCC and their relationships with the clinicopathological features of *** advances in understanding the potential roles of somatic mtDNA alterations in the progression of HCC are also *** suggest that somatic mtDNA mutations and a decrease in the mtDNA copy number are common events in HCC and that a mitochondrial dysfunction-activated signaling cascade may play an important role in the progression of *** of the retrograde signaling pathways in HCC and the quest for strategies to block some of these pathways will be instrumental for the development of novel treatments for this and other malignancies.

关键词： Hepatocellular carcinoma Somatic mitochondrial DNA mutations Mitochondrial dysfunction

Essential role of the iron-sulfur cluster binding domain of the primase regulatory subunit Pri2 in DNA replication initiation

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Protein & Cell 2015年第3期6卷 194-210页

作者： Lili Liu Mingxia Huang Department of pharmacology and Chemical biology University of Pittsburgh School of Medicine Pittsburgh PA 15213 USA Department of Biochemistry and Molecular Genetics University of Colorado School of Medicine Aurora CO 80045 USA

DNA primase catalyzes de novo synthesis of a short RNA primer that is further extended by replicative DNA polymerases during initiation of DNA replication. The eukaryotic primase is a heterodimeric enzyme comprising a catalytic subunit Pril and a regulatory subunit Pri2. Pri2 is responsible for facilitating optimal RNA primer synthesis by Pril and mediating interaction between Pril and DNA polymerase o for transition from RNA synthesis to DNA elongation. All eukaryotic Pri2 proteins contain a conserved C-terminal iron-sulfur （Fe-S） cluster-binding domain that is critical for primase catalytic activity in vitro. Here we show that mutations at conserved cysteine ligands for the Pri2 Fe-S cluster markedly decrease the protein stability, thereby causing S phase arrest at the restrictive temperature. Furthermore, Pri2 cysteine mutants are defective in loading of the entire DNA pol α-primase complex onto early replication origins resulting in defective initiation. Importantly, assembly of the Fe-S cluster in Pri2 is impaired not only by mutations at the conserved cysteine ligands but also by increased oxidative stress in the sodlA mutant lacking the Cu/Zn superoxide dismutase. Together these findings highlight the critical role of Pri2＇s Fe-S cluster domain in replication initiation in vivo and suggest a molecular basis for how DNA replication can be influenced by changes in cellular redox state.

关键词： pdmase Pri2 iron-sulfur cluster,replication initiation

Mechanistic insights into cancer immunity and immunotherapy

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cellular & Molecular Immunology 2018年第5期15卷 419-420页

作者： Weiping Zou departments of Surgery and Pathology The University of Michigan Comprehensive Cancer CenterGraduate Programs in Immunology and Cancer BiologyUniversity of Michigan School of MedicineAnn ArborMI 48109USA

While immunotherapy has had an important impact on cancer treatment,only approximately a quarter of patients respond to these *** does it work in some patients but not in other patients?How can we improve the therapeutic efficacy of current immunotherapy?Are there potential new strategies to tackle this problem?The answers to these questions may rely on our in-depth understanding of the basic mechanisms of the cancer immune response,immunotherapeutic efficacy,and resistance.

关键词： immunotherapy immunity cancer

Leukocyte-derived biomimetic nanoparticulate drug delivery systems for cancer therapy

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Acta Pharmaceutica Sinica B 2018年第1期8卷 4-13页

作者： Yukun Huang Xiaoling Gao Jun Chen Key Laboratory of Smart Drug Delivery Ministry of Education School of Pharmacy Fudan University Department of pharmacology and Chemical biology Faculty of Basic Medicine Shanghai Jiao Tong University School of Medicine

Precise drug delivery to tumors with low system toxicity is one of the most important and challenging tasks for pharmaceutical researchers. Despite progress in the field of nanotherapeutics, the use of artificially synthesized nanocarriers still faces several challenges, including rapid clearance from blood circulation and limited capability of overcoming multiple physiological barriers, which hamper the clinical application of nanoparticle-based therapies. Since leukocytes(including monocytes/macrophages,neutrophils, dendritic cells and lymphocytes) target tumors and can migrate across physiological barriers,leukocytes are increasing utilized as carriers to transfer nanoparticles to tumors. In this review we specifically focus on the molecular and cellular mechanisms of leukocytes that can be exploited as a vehicle to deliver nanoparticles to tumors and summarize the latest research on how leukocytes can be harnessed to improve therapeutic end-points. We also discuss the challenges and opportunities of this leukocyte-derived nanoparticle drug delivery system.

关键词： Leukocytes Tumor Biomimetic carrier Nanoparticulate drug delivery systems Nanotherapeutics Cancer therapy