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Crispr/cas9 hepatitis

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https://www.readbyqxmd.com/read/28627393/the-potential-and-challenges-of-crispr-cas-in-eradication-of-hepatitis-b-virus-covalently-closed-circular-dna
#1
REVIEW
Hung-Chih Yang, Pei-Jer Chen
Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection, primarily because of the persistence of covalently closed circular DNA (cccDNA). Although nucleos(t)ide analogues (NAs) can inhibit the reverse transcriptase of HBV and suppress its replication to levels below the detection limit, viremia often rebounds after cessation of therapy. Nuclear cccDNA serves as the HBV replicative template and exhibits extraordinary stability, and is not affected by NAs. Therefore, curing chronic hepatitis B (CHB) requires novel therapy for purging cccDNA from patients...
June 13, 2017: Virus Research
https://www.readbyqxmd.com/read/28584302/crispr-cas9-mediated-p53-and-pten-dual-mutation-accelerates-hepatocarcinogenesis-in-adult-hepatitis-b-virus-transgenic-mice
#2
Yongzhen Liu, Xuewei Qi, Zhenzhen Zeng, Lu Wang, Jie Wang, Ting Zhang, Qiang Xu, Congle Shen, Guangde Zhou, Shaomin Yang, Xiangmei Chen, Fengmin Lu
The p53 mutation and altered Pten expression are two most common genetic events in Hepatitis B virus (HBV) infection related hepatocellular carcinoma (HCC). To confirm the causative role of p53 and Pten somatic mutation in HCC development, we established CRISPR/Cas9-mediated somatic gene disruption via hydrodynamic tail vein injection, allowing for in vivo targeting p53 and Pten simultaneously in adult HBV transgenic mice. Here we demonstrated that the utility of this approach resulted in macroscopic liver tumors as early as 4 months' post injection and most tumors harbored both p53 and Pten loss-of-function alterations...
June 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28574502/hepatitis-b-virus-x-protein-promotes-creb-mediated-activation-of-mir-3188-and-notch-signaling-in-hepatocellular-carcinoma
#3
Shao-Jun Zhou, Yue-Ling Deng, Hui-Fang Liang, Jonathan C Jaoude, Fu-Yao Liu
Familiar clustering of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been frequently reported. However, limited information is available about the underlying molecular mechanisms in HBV-related HCC patients with family history of HCC. In our previous study, Agilent miRNA Base 16.0 microarray showed miRNA profiles of the plasma of HBV-related HCC patients who had a family history of HCC. This study aims to explore the expression, function, and mechanisms of miR-3188 in HCC that might provide novel insights into the role of family history on the risk of HCC...
June 2, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28557353/generation-of-carbamoyl-phosphate-synthetase-1-reporter-cell-lines-for-the-assessment-of-ammonia-metabolism
#4
Yi Wang, Le Chang, Jiahui Zhai, Qiao Wu, Donggen Wang, Yunfang Wang
Both primary hepatocytes and stem cells-derived hepatocyte-like cells (HLCs) are major sources for bioartificial liver (BAL). Maintenance of hepatocellular functions and induction of functional maturity of HLCs are critical for BAL's support effect. It remains difficult to assess and improve detoxification functions inherent to hepatocytes, including ammonia clearance. Here, we aim to assess ammonia metabolism and identify ammonia detoxification enhancer by developing an imaging strategy. In hepatoma cell line HepG2, and immortalized hepatic cell line LO2, carbamoyl phosphate synthetase 1 (CPS1) gene, the first enzyme of ammonia-eliminating urea cycle, was labelled with fluorescence protein via CRISPR/Cas9 system...
May 30, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28513320/crispr-cas9-based-pten-knock-out-and-sleeping-beauty-transposon-mediated-nras-knock-in-induces-hepatocellular-carcinoma-and-hepatic-lipid-accumulation-in-mice
#5
Mingming Gao, Dexi Liu
Both Pten and Nras are downstream mediators of receptor tyrosine kinase activation that plays important roles in controlling cell survival and proliferation. Here, we investigated whether and how Pten loss cross-talks with Nras activation in driving liver cancer development in mice. Somatic disruption of hepatic Pten and overexpression of Nras were achieved in out-bred immunocompetent CD-1 mice through a hydrodynamic delivery of plasmids carrying Sleeping Beauty transposon-based integration of Nras and the CRISPR/Cas9-mediated Pten knock-out system...
May 17, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28442604/hepatitis-c-virus-indirectly-disrupts-dna-damage-induced-p53-responses-by-activating-protein-kinase-r
#6
Jonathan K Mitchell, Bentley R Midkiff, Benjamin Israelow, Matthew J Evans, Robert E Lanford, Christopher M Walker, Stanley M Lemon, David R McGivern
Many DNA tumor viruses promote cellular transformation by inactivating the critically important tumor suppressor protein p53. In contrast, it is not known whether p53 function is disrupted by hepatitis C virus (HCV), a unique, oncogenic RNA virus that is the leading infectious cause of liver cancer in many regions of the world. Here we show that HCV-permissive, liver-derived HepG2 cells engineered to constitutively express microRNA-122 (HepG2/miR-122 cells) have normal p53-mediated responses to DNA damage and that HCV replication in these cells potently suppresses p53 responses to etoposide, an inducer of DNA damage, or nutlin-3, an inhibitor of p53 degradation pathways...
April 25, 2017: MBio
https://www.readbyqxmd.com/read/28404852/attachment-and-post-attachment-receptors-important-for-hepatitis-c-virus-infection-and-cell-to-cell-transmission
#7
Huahao Fan, Luhua Qiao, Kyung-Don Kang, Junfen Fan, Wensheng Wei, Guangxiang Luo
Hepatitis C virus (HCV) infection requires multiple receptors for its attachment and entry to the cell. Our previous studies found that human syndecan-1 (SDC-1), SDC-2, and T cell immunoglobulin and mucin domain-containing protein 1 (TIM-1) are HCV attachment receptors. Other cell surface molecules such as CD81, CLDN1, OCLN, SR-BI, and LDLR mainly function at post-attachment steps, which are considered post-attachment receptors. The underlying molecular mechanisms of different receptors in HCV cell-free and cell-to-cell transmission remain elusive...
April 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28382278/removal-of-integrated-hepatitis-b-virus-dna-using-crispr-cas9
#8
Hao Li, Chunyu Sheng, Shan Wang, Lang Yang, Yuan Liang, Yong Huang, Hongbo Liu, Peng Li, Chaojie Yang, Xiaoxia Yang, Leili Jia, Jing Xie, Ligui Wang, Rongzhang Hao, Xinying Du, Dongping Xu, Jianjun Zhou, Mingzhen Li, Yansong Sun, Yigang Tong, Qiao Li, Shaofu Qiu, Hongbin Song
The presence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and the permanent integration of HBV DNA into the host genome confers the risk of viral reactivation and hepatocellular carcinoma. Nucleoside/nucleotide analogs alone have little or no capacity to eliminate replicative HBV templates consisting of cccDNA or integrated HBV DNA. Recently, CRISPR/Cas9 technology has been widely applied as a promising genome-editing tool, and HBV-specific CRISPR-Cas9 systems were shown to effectively mediate HBV cccDNA disruption...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28300165/somatic-genome-editing-with-crispr-cas9-generates-and-corrects-a-metabolic-disease
#9
Kelsey E Jarrett, Ciaran M Lee, Yi-Hsien Yeh, Rachel H Hsu, Rajat Gupta, Min Zhang, Perla J Rodriguez, Chang Seok Lee, Baiba K Gillard, Karl-Dimiter Bissig, Henry J Pownall, James F Martin, Gang Bao, William R Lagor
Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28282856/hepatitis-b-virus-x-protein-stimulates-proliferation-wound-closure-and-inhibits-apoptosis-of-huh-7-cells-via-cdc42
#10
Yongru Xu, Yingzi Qi, Jing Luo, Jing Yang, Qi Xie, Chen Deng, Na Su, Wei Wei, Deshun Shi, Feng Xu, Xiangping Li, Ping Xu
Chronic hepatitis B virus (HBV) infection has been considered as the major cause of hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) has been reported to be oncogenic. The underlying mechanisms of HBV-related HCC are not fully understood, and the role played by the HBx protein in HBV induced carcinogenesis remains controversial. CDC42, a member of the Rho GTPase family, has been reported to be overexpressed in several different cancers, including HBV-related HCC. However, the specific role of CDC42 in HCC development remains unclear...
March 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28087399/advances-with-using-crispr-cas-mediated-gene-editing-to-treat-infections-with-hepatitis-b-virus-and-hepatitis-c-virus
#11
REVIEW
Buhle Moyo, Kristie Bloom, Tristan Scott, Abdullah Ely, Patrick Arbuthnot
Chronic infections with hepatitis B and hepatitis C viruses (HBV and HCV) account for the majority of cases of cirrhosis and hepatocellular carcinoma. Current therapies for the infections have limitations and improved efficacy is necessary to prevent complications in carriers of the viruses. In the case of HBV persistence, the replication intermediate comprising covalently closed circular DNA (cccDNA) is particularly problematic. Licensed therapies have little effect on cccDNA and HBV replication relapses following treatment withdrawal...
January 10, 2017: Virus Research
https://www.readbyqxmd.com/read/27935189/epigenetic-regulation-of-the-glucose-transporter-gene-slc2a1-by-%C3%AE-hydroxybutyrate-underlies-preferential-glucose-supply-to-the-brain-of-fasted-mice
#12
Kosuke Tanegashima, Yukiko Sato-Miyata, Masabumi Funakoshi, Yasumasa Nishito, Toshiro Aigaki, Takahiko Hara
We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body β-hydroxybutyrate (β-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification...
January 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/27929099/stat1-is-essential-for-the-inhibition-of-hepatitis-c-virus-replication-by-interferon-%C3%AE-but-not-by-interferon-%C3%AE
#13
Shota Yamauchi, Kenji Takeuchi, Kazuyasu Chihara, Chisato Honjoh, Yuji Kato, Hatsumi Yoshiki, Hak Hotta, Kiyonao Sada
Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27917363/future-therapy-for-hepatitis-b-virus-role-of-immunomodulators
#14
REVIEW
Edward A Pham, Ryan B Perumpail, Benjamin J Fram, Jeffrey S Glenn, Aijaz Ahmed, Robert G Gish
Although currently available therapies for chronic hepatitis B virus infection can suppress viremia and provide long-term benefits for patients, they do not lead to a functional cure for most patients. Advances in our understanding of the virus-host interaction and the recent remarkable success of immunotherapy in cancer offer new and promising strategies for developing immune modulators that may become important components of a total therapeutic approach to hepatitis B, some of which are now in clinical development...
2016: Current Hepatology Reports
https://www.readbyqxmd.com/read/27860197/crispr-cas9-the-ultimate-weapon-to-battle-infectious-diseases
#15
REVIEW
M Doerflinger, W Forsyth, G Ebert, M Pellegrini, M J Herold
Infectious diseases are a leading cause of death worldwide. Novel therapeutics are urgently required to treat multidrug-resistant organisms such as Mycobacterium tuberculosis and to mitigate morbidity and mortality caused by acute infections such as malaria and dengue fever virus as well as chronic infections such as human immunodeficiency virus-1 and hepatitis B virus. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, which has revolutionized biomedical research, holds great promise for the identification and validation of novel drug targets...
November 16, 2016: Cellular Microbiology
https://www.readbyqxmd.com/read/27783675/dna-polymerase-%C3%AE%C2%BA-is-a-key-cellular-factor-for-the-formation-of-covalently-closed-circular-dna-of-hepatitis-b-virus
#16
Yonghe Qi, Zhenchao Gao, Guangwei Xu, Bo Peng, Chenxuan Liu, Huan Yan, Qiyan Yao, Guoliang Sun, Yang Liu, Dingbin Tang, Zilin Song, Wenhui He, Yinyan Sun, Ju-Tao Guo, Wenhui Li
Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27708159/insulin-resistance-and-diabetes-caused-by-genetic-or-diet-induced-kbtbd2-deficiency-in-mice
#17
Zhao Zhang, Emre Turer, Xiaohong Li, Xiaoming Zhan, Mihwa Choi, Miao Tang, Amanda Press, Steven R Smith, Adeline Divoux, Eva Marie Y Moresco, Bruce Beutler
We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27659023/highly-multiplexed-crispr-cas9-nuclease-and-cas9-nickase-vectors-for-inactivation-of-hepatitis-b-virus
#18
Tetsushi Sakuma, Keiichi Masaki, Hiromi Abe-Chayama, Keiji Mochida, Takashi Yamamoto, Kazuaki Chayama
CRISPR-Cas9-mediated genome-editing technology contributes not only to basic genomic studies but also to clinical studies such as genetic correction and virus inactivation. Hepatitis B virus (HBV) is a major target for potential application of CRISPR-Cas9 in eliminating viral DNA from human cells. However, the high stability of covalently closed circular DNA (cccDNA) makes it difficult to completely clear HBV infection. Here, we report highly multiplexed CRISPR-Cas9-nuclease and Cas9-nickase vector systems that simultaneously target three critical domains of the HBV genome...
November 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/27614072/talen-crispr-mediated-engineering-of-a-promoterless-anti-viral-rnai-hairpin-into-an-endogenous-mirna-locus
#19
Elena Senís, Stefan Mockenhaupt, Daniel Rupp, Tobias Bauer, Nagarajan Paramasivam, Bettina Knapp, Jan Gronych, Stefanie Grosse, Marc P Windisch, Florian Schmidt, Fabian J Theis, Roland Eils, Peter Lichter, Matthias Schlesner, Ralf Bartenschlager, Dirk Grimm
Successful RNAi applications depend on strategies allowing robust and persistent expression of minimal gene silencing triggers without perturbing endogenous gene expression. Here, we propose a novel avenue which is integration of a promoterless shmiRNA, i.e. a shRNA embedded in a micro-RNA (miRNA) scaffold, into an engineered genomic miRNA locus. For proof-of-concept, we used TALE or CRISPR/Cas9 nucleases to site-specifically integrate an anti-hepatitis C virus (HCV) shmiRNA into the liver-specific miR-122/hcr locus in hepatoma cells, with the aim to obtain cellular clones that are genetically protected against HCV infection...
January 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27585307/crispr-cas9-technology-targeting-fas-gene-protects-mice-from-concanavalin-a-induced-fulminant-hepatic-failure
#20
Wei-Cheng Liang, Pu-Ping Liang, Cheuk-Wa Wong, Tzi-Bun Ng, Jun-Jiu Huang, Jin-Fang Zhang, Mary Miu-Yee Waye, Wei-Ming Fu
Fulminant hepatic failure is a life-threatening disease which occurs in patients without preexisting liver disease. Nowadays, there is no ideal therapeutic tool in the treatment of fulminant hepatic failure. Recent studies suggested that a novel technology termed CRISPR/Cas9 may be a promising approach for the treatment of fulminant hepatic failure. In this project, we have designed single chimeric guide RNAs specifically targeting the genomic regions of mouse Fas gene. The in vitro and in vivo effects of sgRNAs on the production of Fas protein were examined in cultured mouse cells and in a hydrodynamic injection-based mouse model, respectively...
September 1, 2016: Journal of Cellular Biochemistry
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