scholarly journals Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication

2018 ◽  
Author(s):  
André C. Ferreira ◽  
Patrícia A. Reis ◽  
Caroline S. de Freitas ◽  
Carolina Q. Sacramento ◽  
Lucas Villas Bôas Hoelz ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Chikungunya Virus ◽  
Therapeutic Option ◽  
Antiviral Drug ◽  
Specific Treatment ◽  
Public Health Problem ◽  
Hepatoma Cells ◽  
Dependent Manner ◽  
Mice Model ◽  
Human Hepatoma Cells

AbstractChikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is a consolidated public health problem, in tropical and subtropical regions of the world, where control of CHIKV vector, mosquitos of theAedesgenus, failed. Since there is no vaccine or specific treatment against CHIKV, infected patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. Recently, the structure and activity of CHIKV RNA polymerase was partially resolved, revealing similar aspects with the enzyme counterparner on other positive sense RNA viruses, such as members of the Flaviviridae family. We then evaluated if sofosbuvir, clinically approved against hepatitis C virus RNA polymerase, which also aims to dengue, Zika and yellow fever viruses replication, would inhibit CHIKV replication. Indeed, sofosbuvir was 5-times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell (iPS)-derived astrocytes was less sensitive to sofosbuvir’s, compared to hepatoma cells – this drug still impaired virus production and cell death in a MOI-dependent manner. Sofosbuvir also exhibited antiviral activityin vivo, by preventing CHIKV-induced paw oedeme in adult mice, at 20 mg/kg/day, and mortality on neonate mice model, at 40 and 80 mg/kg/day. Our data demonstrates that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. Since this is a clinically approved drug, it could pave the way to become a therapeutic option against CF.

scholarly journals Beyond Members of theFlaviviridaeFamily, Sofosbuvir Also Inhibits Chikungunya Virus Replication

2018 ◽  
Vol 63 (2) ◽  
pp. e01389-18 ◽  
Author(s):  
André C. Ferreira ◽  
Patrícia A. Reis ◽  
Caroline S. de Freitas ◽  
Carolina Q. Sacramento ◽  
Lucas Villas Bôas Hoelz ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Virus Replication ◽  
Chikungunya Virus ◽  
Yellow Fever Virus ◽  
Therapeutic Option ◽  
Antiviral Drug ◽  
Specific Treatment ◽  
Public Health Problem ◽  
Hepatoma Cells ◽  
Dependent Manner

ABSTRACTChikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector,Aedesmosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of theFlaviviridaefamily. Among theFlaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell-derived astrocytes was less susceptible to sofosbuvir than were hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection-dependent manner. Sofosbuvir also exhibited antiviral activityin vivoby preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg of body weight/day and prevented mortality in a neonate mouse model at 40- and 80-mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

The KLF6 Super Enhancer Modulates Cell Proliferation via MiR-1301 in Human Hepatoma Cells

MicroRNA ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 64-69 ◽  
Author(s):  
KumChol Ri ◽  
Chol Kim ◽  
CholJin Pak ◽  
PhyongChol Ri ◽  
HyonChol Om
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Hepatoma Cells ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Over Expression ◽  
Super Enhancer ◽  
Engineering Changes

Background: Recent studies have attempted to elucidate the function of super enhancers by means of microRNAs. Although the functional outcomes of miR-1301 have become clearer, the pathways that regulate the expressions of miR-1301 remain unclear. Objective: The objective of this paper was to consider the pathway regulating expression of miR- 1301 and miR-1301 signaling pathways with the inhibition of cell proliferation. Methods: In this study, we prepared the cell clones that the KLF6 super enhancer was deleted by means of the CRISPR/Cas9 system-mediated genetic engineering. Changes in miR-1301 expression after the deletion of the KLF6 super enhancer were evaluated by RT-PCR analysis, and the signal pathway of miR-1301 with inhibition of the cell proliferation was examined using RNA interference technology. Results: The results showed that miR-1301 expression was significantly increased after the deletion of the KLF6 super enhancer. Over-expression of miR-1301 induced by deletion of the KLF6 super enhancer also regulated the expression of p21 and p53 in human hepatoma cells. functional modeling of findings using siRNA specific to miR-1301 showed that expression level changes had direct biological effects on cellular proliferation in Human hepatoma cells. Furthermore, cellular proliferation assay was shown to be directly associated with miR-1301 levels. Conclusion: As a result, it was demonstrated that the over-expression of miR-1301 induced by the disruption of the KLF6 super enhancer leads to a significant inhibition of proliferation in HepG2 cells. Moreover, it was demonstrated that the KLF6 super enhancer regulates the cell-proliferative effects which are mediated, at least in part, by the induction of p21and p53 in a p53-dependent manner. Our results provide the functional significance of miR-1301 in understanding the transcriptional regulation mechanism of the KLF6 super enhancer.

Inhibitory Effects of Lycopene on the Adhesion, Invasion, and Migration of SK-Hep1 Human Hepatoma Cells

2006 ◽  
Vol 231 (3) ◽  
pp. 322-327 ◽  
Author(s):  
Eun-Sun Hwang ◽  
Hyong Joo Lee
Keyword(s):  
Cell Growth ◽  
Hepatoma Cell ◽  
Hepatoma Cells ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Human Hepatoma Cell ◽  
Invasion And Migration ◽  
And Migration

Lycopene, which is the predominant carotenoid in tomatoes and tomato-based foods, may protect humans against various cancers. Effects of lycopene on the adhesion, invasion, migration, and growth of the SK-Hep1 human hepatoma cell line were investigated. Lycopene inhibited cell growth in dose-dependent manners, with growth inhibition rates of 5% and 40% at 0.1 μM and 50 μM lycopene, respectively, after 24 hrs of incubation. Similarly, after 48 hrs of incubation, lycopene at 5 μM and 10 μM decreased the cell numbers by 30% and 40%, respectively. Lycopene decreased the gelatinolytic activities of both matrix metalloproteinase (MMP)-2 and MMP-9, which were secreted from the SK-Hep1 cells. Incubation of SK-Hep1 cells with 110 μM of lycopene for 60 mins significantly inhibited cell adhesion to the Matrigel-coated substrate in a concentration-dependent manner. To study invasion, SK-Hep1 cells were grown either on Matrigel-coated Transwell membranes or in 24-well plates. The cells were treated sequentially for 24 hrs with lycopene before the start of the invasion assays. Cell growth and death were assessed under the same conditions. The invasion of SK-Hep1 cells treated with lycopene was significantly reduced to 28.3% and 61.9% of the control levels at 5 μM and 10 μM lycopene, respectively (P < 0.05). In the migration assay, lycopene-treated cells showed lower levels of migration than untreated cells. These results demonstrate the antimetastatic properties of lycopene in inhibiting the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells.

Hepcidin regulation by innate immune and infectious stimuli

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4129-4139 ◽  
Author(s):  
Andrew E. Armitage ◽  
Lucy A. Eddowes ◽  
Uzi Gileadi ◽  
Suzanne Cole ◽  
Natasha Spottiswoode ◽  
...  
Keyword(s):  
Influenza A ◽  
Acute Infection ◽  
Transferrin Saturation ◽  
Hepatoma Cells ◽  
Innate Immune ◽  
Dependent Manner ◽  
Human Hepatoma Cells ◽  
Hepcidin Expression

Abstract Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6–independent hepcidin up-regulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin up-regulation that was augmented by TGF-β1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6–dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6–independent, but partially TGF-β–dependent. In a murine acute systemic candidiasis model, C albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was up-regulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis.

Computational Drug-repositioning Approach Identifying Sirolimus as a Potential Therapeutic Option for Inflammatory Dilated Cardiomyopathy

Drug Research ◽  
2019 ◽  
Vol 69 (10) ◽  
pp. 565-571 ◽  
Author(s):  
Kyoko Shibata ◽  
Toshinori Endo ◽  
Yoshikazu Kuribayashi
Keyword(s):  
Gene Expression ◽  
Dilated Cardiomyopathy ◽  
Drug Repositioning ◽  
Expression Profiles ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Specific Treatment ◽  
Gene Expression Profiles ◽  
Connectivity Map

Abstract Objective The aim of this study was to determine promising treatment options for human inflammatory dilated cardiomyopathy using a computational drug-repositioning approach (repurposing established drug compounds for new therapeutic indications). Background If the myocardial tissue is detected to be infiltrated with inflammatory cells, primarily of lymphocytes, and if the virus is confirmed using genetic examination (PCR) or immunostaining, the infection is suspected. However, there is no specific treatment (i. e., an antiviral drug) even if the virus is identified; therefore, we used Connectivity Map to identify compounds showing inverse drug–disease signatures, indicating activity against inflammatory dilated cardiomyopathy. Results Potential drug-repositioning candidates for the treatment of inflammatory dilated cardiomyopathy were explored through a systematic comparison of the gene expression profiles induced by drugs using Gene Expression Omnibus and Connectivity Map databases. Conclusion Using a computational drug-repositioning approach based on the integration of publicly available gene expression signatures of drugs and diseases, sirolimus was suggested as a novel therapeutic option for inflammatory dilated cardiomyopathy.

Baculovirus Mediated Production of Infectious Hepatitis C Virus in Human Hepatoma Cells Stably Expressing T7 RNA Polymerase

2008 ◽  
Vol 40 (2) ◽  
pp. 186-194 ◽  
Author(s):  
Xiangjie Yao ◽  
Qingxia Han ◽  
Jianhua Song ◽  
Changyong Liang ◽  
Takaji Wakita ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Hepatoma Cells ◽  
Infectious Hepatitis ◽  
T7 Rna Polymerase ◽  
Human Hepatoma ◽  
Human Hepatoma Cells

scholarly journals The clinically approved antiviral drug sofosbuvir impairs brazilian zika virus replication

2016 ◽  
Author(s):  
Caroline Q. Sacramento ◽  
Gabrielle R. de Melo ◽  
Natasha Rocha ◽  
Lucas Villas Bôas Hoelz ◽  
Milene Mesquita ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Zika Virus ◽  
Antiviral Drug ◽  
Time Frame ◽  
Polymerase Activity ◽  
Antiviral Drugs ◽  
South American ◽  
Dependent Manner ◽  
Amino Acid Residues ◽  
Uridine Nucleotide

SummaryZika virus (ZIKV) is a member of Flaviviridae family, as other agents of clinical significance, such as dengue (DENV) and hepatitis C (HCV) viruses. ZIKV spread from Africa to Pacific and South American territories, emerging as an etiological pathogen of neurological disorders, during fetal development and in adulthood. Therefore, antiviral drugs able to inhibit ZIKV replication are necessary. Broad spectrum antivirals, such as interferon, ribavirin and favipiravir, are harmful for pregnant animal models and women. The clinically approved uridine nucleotide analog anti-HCV drug, sofosbuvir, has not been affiliated to teratogenicity. Sofosbuvir target the most conserved protein over the members of the Flaviviridae family, the viral RNA polymerase. We thus studied ZIKV susceptibility to sofosbovir. We initially characterized a Brazilian ZIKV strain for use in experimental assays. Sofosbuvir inhibits the Brazilian ZIKV replication in a dose-dependent manner, both in BHK-21 cells and SH-Sy5y, by targeting ZIKV RNA polymerase activity, with the involvement of conserved amino acid residues over the members of Flaviviridae family. The identification of clinically approved antiviral drugs endowed with anti-ZIKV could reduce the time frame in pre-clinical development. Altogether, our data indicates that sofosbuvir chemical structure is endowed with anti-ZIKV activity.

scholarly journals The Involvement of HAb18G/CD147 in Regulation of Store-operated Calcium Entry and Metastasis of Human Hepatoma Cells

2001 ◽  
Vol 276 (50) ◽  
pp. 46870-46877 ◽  
Author(s):  
Jian Li Jiang ◽  
Qing Zhou ◽  
Mei Kuen Yu ◽  
Lok Sze Ho ◽  
Zhi Nan Chen ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Hepatoma Cells ◽  
Inhibitory Response ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Concentration Dependent Manner ◽  
No Donor ◽  
Store Operated Calcium Entry ◽  
The Difference

The present study examined the effect of hepatoma-associated antigen HAb18G (homologous to CD147) expression on the NO/cGMP-regulated Ca2+mobilization and metastatic process of human hepatoma cells. HAb18G/CD147 cDNA was transfected into human 7721 hepatoma cells to obtain a cell line stably expressing HAb18G/CD147, T7721, as demonstrated by Northern blot and immunocytochemical studies. 8-Bromo-cGMP (cGMP) inhibited the thapsigargin-induced Ca2+entry in a concentration-dependent manner in 7721 cells. The cGMP-induced inhibition was abolished by an inhibitor of protein kinase G, KT5823 (1 μm). However, expression of HAb18G/CD147 in T7721 cells decreased the inhibitory response to cGMP. A similar concentration-dependent inhibitory effect on the Ca2+entry was observed in 7721 cells in response to a NO donor, (±)-S-nitroso-N-acetylpenicillamine (SNAP). The inhibitory effect of SNAP on the thapsigargin-induced Ca2+entry was significantly reduced in HAb18G/CD147-expressing T7721 cells, indicating a role for HAb18G/CD147 in NO/cGMP-regulated Ca2+entry. Experiments investigating metastatic potentials demonstrated that HAb18G/CD147-expressing T7721 cells attached to the Matrigel-coated culture plates and invaded through Matrigel-coated permeable filters at the rate significantly greater than that observed in 7721 cells. Both the attachment and invasion rates could be suppressed by SNAP, and the inhibitory effect of SNAP could be reversed by NO inhibitor,NG-nitro-l-arginine methyl ester. The sensitivity of the attachment and invasion rates to cGMP was significantly reduced in T7721 cells as compared with 7721 cells when cells were pretreated with thapsigargin. The difference in the sensitivity between the two cells could be abolished by a Ca2+channel blocker, Ni2+(3 mm). These results suggest that HAb18G/CD147 enhances metastatic potentials in human hepatoma cells by disrupting the regulation of store-operated Ca2+entry by NO/cGMP.

scholarly journals TiO2 particles induce ER stress and apoptosis in human hepatoma cells, HepG2, in a particle size-dependent manner

2019 ◽  
Vol 28 (6) ◽  
pp. 1907-1917 ◽  
Author(s):  
Ha Na Song ◽  
Su Kyung Jang ◽  
Ok Kyung Hwang ◽  
Hong Jin Lee ◽  
Hyang Sook Chun
Keyword(s):  
Particle Size ◽  
Er Stress ◽  
Hepatoma Cells ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Size Dependent ◽  
Tio2 Particles

scholarly journals Renoprotective Effect of Laminaria japonica Polysaccharide in Adenine-Induced Chronic Renal Failure

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1491 ◽  
Author(s):  
Miao Long ◽  
Qiang-Ming Li ◽  
Qing Fang ◽  
Li-Hua Pan ◽  
Xue-Qiang Zha ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Chronic Renal Failure ◽  
Public Health Problem ◽  
Laminaria Japonica ◽  
Major Public Health Problem ◽  
Dependent Manner ◽  
Mice Model ◽  
Reduce Weight Loss ◽  
Dose Dependent

Chronic renal failure (CRF) is a major public health problem worldwide. In this work, we investigated the effects of a purified Laminaria japonica polysaccharide (LJP61A) on renal function using an adenine-induced CRF mice model. Results exhibited that adenine treatment caused serious renal pathological damages and elevation of serum creatinine and blood urea nitrogen of mice. However, these changes could be significantly reversed by the administration of LJP61A in a dose-dependent manner. Additionally, LJP61A could dramatically reduce weight loss, improve the urine biochemical index, and regulate the electrolyte disturbance of CRF mice. These results suggest that the renal function of adenine-induced CRF mice can be improved by LJP61A, which might be developed into a potential therapeutic agent for CRF patients.

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