Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-l-homocysteine hydrolase inhibitor

Bray, Mike; Driscoll, John S.; Huggins, John W.

doi:10.1016/s0166-3542(00)00066-8

Cited by 146 publications

(111 citation statements)

References 31 publications

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“…As previously observed, serum viral titers of mice treated on day 0 or 1 were 10-100 000 times lower than placebo controls on days 3 and 4 ( Fig. 2B; Bray et al, 2000). Serum IFN-a levels of placebo-treated mice did not become elevated until day 3, when all of the animals were already losing weight and were visibly ill (Fig.…”

Section: Efficacy Of Pre-and Postchallenge Treatmentsupporting

confidence: 80%

“…We previously reported that one s.c. injection of 1 mg/kg of c 3 -Npc A on day 0, 1 or 2 postinfection prevented death in mice infected with 10 pfu (300 LD 50 ) of mouse-adapted EBO-Z (Bray et al, 2000). No toxicity was observed with single doses of up to 10 mg/kg.…”

Section: Efficacy Of Pre-and Postchallenge Treatmentmentioning

confidence: 91%

“…However, a number of synthetic analogues of adenosine that have broad-spectrum antiviral activity against both RNA and DNA viruses are potent inhibitors of EBO-Z replication (Huggins et al, , 1999Bray and Paragas, 2002). A single dose of one such compound, 3-deazaneplanocin A (c 3 -Npc A), prevented illness and death in mice infected with a mouse-adapted variant of EBO-Z (Bray et al, 2000). c 3 -Npc A and related substances inhibit a host cell enzyme, S-adenosylhomocysteine (SAH) hydrolase, which breaks down the SAH produced from S-adenosylmethionine (SAM) in the course of cellular methylation reactions (De Clercq, 1987, 1998De Clercq et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

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3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

et al. 2002

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3-Deazaneplanocin A, an analog of adenosine, is a potent inhibitor of Ebola virus replication. A single dose early in infection prevents illness and death in Ebola virus-infected mice. The ability of this and similar compounds to block both RNA and DNA viruses has been attributed to the inhibition of a cellular enzyme, S-adenosylhomocysteine hydrolase (SAH), indirectly resulting in reduced methylation of the 5% cap of viral messenger RNA. However, we found that the protective effect of the drug resulted from massively increased production of interferon-a in Ebola-infected, but not uninfected mice. Peak interferon levels increased with the extent of disease at the time of treatment, indicating that production was boosted only in virus-infected cells. Ebola virus has been shown to suppress innate antiviral mechanisms of the type I interferon response. 3-Deazaneplanocin A appears to reverse such suppression, restricting viral dissemination. Further development should focus on identifying adenosine analogues that produce a similar effect in Ebola virus-infected primates. Published by Elsevier Science B.V.

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Section: Efficacy Of Pre-and Postchallenge Treatmentsupporting

confidence: 80%

Section: Efficacy Of Pre-and Postchallenge Treatmentmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

et al. 2002

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“…Animals were inoculated subcutaneously into the posterior flanks with RH30 cell suspensions in PBS (5 Â 10 6 cells) and, when the tumors became palpable, intraperitoneally injected (5 mice/group) either with DZNep (2.5 mg/kg) or normal saline (vehicle) or with MC1945 (2.5 mg/kg) or DMSO (vehicle) twice daily, 3 days per week for 3 weeks when mice were killed with no visible signs of toxicity. 34,72 Tumor volume was measured as reported. 6 Sections from paraffin-embedded excised xenografts were stained with hematoxylin/ eosin or immunohistochemically stained for EZH2 and Ki67 expression with antibodies and detection/acquisition methods reported below.…”

Section: Ezh2 Inhibitory Assaymentioning

confidence: 99%

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

et al. 2013

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The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.Oncogene ( Keywords: EZH2; FBXO32; histone methyltransferases; PAX3-FOXO1; rhabdomyosarcoma; Polycomb proteins INTRODUCTION Rhabdomyosarcomas (RMS) are heterogeneous highly malignant tumors, which account for 7-8% of all pediatric malignancies and over half of the soft-tissue sarcomas in children. RMS are classically subdivided in two major histotypes: embryonal (around 70-80%) and alveolar (around 20-30%), the latter often metastatic at diagnosis and showing a high risk of recurrence. 1 In 70% of cases, alveolar RMS is characterized by the chromosomal translocation t(2;13) or t(1;13), resulting in

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“…[5,15] However, the treatment to protect rodents from lethal fever has not been active. [16,17] The outbreak is occurring on a periodic basis. Therefore, technical inhibits to deliver the vaccination ought to overcome at the earliest.…”

Section: Introductionmentioning

confidence: 99%

Ebola Virus: A Scientometric Study of World Research Publications

Bhardwaj¹

2016

J. Scientomet Res.

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The virus of Ebola belongs to the filovirus family. The hemorrhagic fever occurs due to Ebola virus and is highly transmittable. The study covers a scientometric analysis of publications on Ebola virus worldwide. It revealed that 2446 papers have been published on Ebola virus in 159 journals, originating from 84 countries till December 31, 2013. These publications have received 69,960 citations until March 1, 2015. The maximum literature on this deadly virus is published in the form of articles and review, 2040 (83.40%). The highest number of papers was published in 2012, i.e., 198 (8.1%). Eighty-four countries have contributed in Ebola research with at least one publication. Top ten countries produced 2124 (86.8%) of the total research publications on Ebola virus. The United States is the leading country with 1146 (46.9%) in research outcome. The average citation per publication on papers in the area is ~28.6 citations per paper. The majority of papers is published in English language, 2149 (87.9%). Overall, 157 journals produced the Ebola virus research and "Journal of Virology" has published 257 (10.5%) of the papers. In addition, the world over 160 institutions contributed in Ebola virus research, and National Center for Infectious Diseases (~3.3) has recorded highest relative citation impact. Feldmann from the University of Manitoba is the leading author in the field with 129 (5.3%) papers.

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Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-l-homocysteine hydrolase inhibitor

Cited by 146 publications

References 31 publications

3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

Ebola Virus: A Scientometric Study of World Research Publications

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