scholarly journals Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra-O-Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Teresa Merino-Ramos ◽  
Nereida Jiménez de Oya ◽  
Juan-Carlos Saiz ◽  
Miguel A. Martín-Acebes
Keyword(s):  
Lipid Metabolism ◽  
West Nile Virus ◽  
Zika Virus ◽  
Regulatory Element ◽  
Antiviral Agents ◽  
Nordihydroguaiaretic Acid ◽  
Antiviral Effect ◽  
West Nile ◽  
Sterol Regulatory Element ◽  
Positive Strand Rna

ABSTRACT Flaviviruses are positive-strand RNA viruses distributed all over the world that infect millions of people every year and for which no specific antiviral agents have been approved. These viruses include the mosquito-borne West Nile virus (WNV), which is responsible for outbreaks of meningitis and encephalitis. Considering that nordihydroguaiaretic acid (NDGA) has been previously shown to inhibit the multiplication of the related dengue virus and hepatitis C virus, we have evaluated the effect of NDGA, and its methylated derivative tetra-O-methyl nordihydroguaiaretic acid (M4N), on the infection of WNV. Both compounds inhibited the infection of WNV, likely by impairing viral replication. Since flavivirus multiplication is highly dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the sterol regulatory element-binding proteins (SREBP) pathway. Remarkably, we observed that other structurally unrelated inhibitors of the SREBP pathway, such as PF-429242 and fatostatin, also reduced WNV multiplication, supporting that the SREBP pathway may constitute a druggable target suitable for antiviral intervention against flavivirus infection. Moreover, treatment with NDGA, M4N, PF-429242, and fatostatin also inhibited the multiplication of the mosquito-borne flavivirus Zika virus (ZIKV), which has been recently associated with birth defects (microcephaly) and neurological disorders. Our results point to SREBP inhibitors, such as NDGA and M4N, as potential candidates for further antiviral development against medically relevant flaviviruses.

scholarly journals First report of antiviral activity of nordihydroguaiaretic acid against Fort Sherman-like virus (Orthobunyavirus)

2020 ◽  
Author(s):  
Florencia Martinez ◽  
María Laura Mugas ◽  
Juan Javier Aguilar ◽  
Juliana Marioni ◽  
Marta Silvia Contigiani ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Antiviral Activity ◽  
Biochemical Study ◽  
Regulatory Element ◽  
Antiviral Treatment ◽  
Nordihydroguaiaretic Acid ◽  
Antiviral Effect ◽  
Virus Multiplication ◽  
Human Infection

AbstractThe genus Orthobunyavirus are a group of viruses within arbovirus, with a zoonotic cycle, some of which could lead to human infection. A characteristic of these viruses is their lack of antiviral treatment or vaccine for its prevention. The objective of this work was to study the in vitro antiviral activity of nordihydroguaiaretic acid (NDGA), the most important active compound of Larrea divaricata Cav. (Zigophyllaceae), against Fort Sherman-like virus (FSV-like) as a model of Orthobunyavirus genus. At the same time, the effect of NDGA as a lipolytic agent on the cell cycle of this viral model was assessed. The method of reducing plaque forming units on LLC-MK2 cells was used to detect the action of NDGA on CbaAr426 and SFCrEq231 isolates of FSV-like. NDGA did not show virucidal effect, but it had antiviral activity with a similar inhibition in both isolates, which was dose dependent. It was established that the NDGA has a better inhibition one-hour post infection (p.i.), showing a different behavior in each isolate, which was dependent upon the time p.i. Since virus multiplication is dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the sterol regulatory element-binding proteins (SREBP) pathway and the 5-lipoxigenase (5-LOX). We determined by using caffeic acid, a 5-LOX inhibitor, that the inhibition of this enzyme negatively affected the FSV-like replication; and by the use of resveratrol, a SREBP1 inhibitor, it was showed that the negative regulation of this pathway only had action on the SFCrEq231 reduction. In addition, it was proved that the NDGA acts intracellularly, since it showed the ability to incorporate into LLC-MK2 cells. The information provided in this work converts the NDGA in a good antiviral candidate, especially for Orthobunyavirus infections, and a useful tool for the biochemical study of FSV-like that causes an infection poorly studied and potentially dangerous.

Simultaneous detection of Dengue virus, Chikungunya virus, Zika virus, Yellow fever virus and West Nile virus

2019 ◽  
Vol 268 ◽  
pp. 53-55 ◽  
Author(s):  
José A. Boga ◽  
Marta E. Alvarez-Arguelles ◽  
Susana Rojo-Alba ◽  
Mercedes Rodríguez ◽  
María de Oña ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Dengue Virus ◽  
Yellow Fever ◽  
Zika Virus ◽  
Chikungunya Virus ◽  
Yellow Fever Virus ◽  
Simultaneous Detection ◽  
Fever Virus ◽  
West Nile ◽  
Virus Zika

scholarly journals Tissue-Specific Effects of Central Leptin on the Expression of Genes Involved in Lipid Metabolism in Liver and White Adipose Tissue

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5604-5610 ◽  
Author(s):  
Nilda Gallardo ◽  
Elena Bonzón-Kulichenko ◽  
Teresa Fernández-Agulló ◽  
Eduardo Moltó ◽  
Sergio Gómez-Alonso ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
White Adipose Tissue ◽  
Binding Protein ◽  
Regulatory Element ◽  
Epididymal Adipose Tissue ◽  
Key Enzymes ◽  
Specific Effects ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 d did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue, and plasma. In both tissues this treatment markedly decreased the expression of key enzymes of the de novo fatty acid (FA) synthesis such as acetyl-coenzyme A-carboxylase, FA synthase, and stearoyl-coenzyme A desaturase-1, in parallel with a reduction in mRNA expression of sterol regulatory element binding protein-1c in liver and carbohydrate regulatory element binding protein in adipose tissue. In addition, leptin also decreased phosphoenol-pyruvate carboxykinase-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down-regulates delta-6-desaturase expression in liver and adipose tissue, in parallel with the decrease of the expression of sterol regulatory element binding protein-1c in liver and peroxisome proliferator activated receptor α in adipose tissue. Finally, leptin treatment, by regulating adipose triglyceride lipase/hormone sensitive lipase/diacylglycerol transferase 1 expression, also established a new partitioning in the FA-triacylglyceride cycling in adipose tissue, increasing lipolysis and probably the FA efflux from this tissue, and favoring in parallel the FA uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in nonadipose tissues, preventing the development of obesity and type 2 diabetes.

scholarly journals Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier

2015 ◽  
Vol 7 (284) ◽  
pp. 284ra59-284ra59 ◽  
Author(s):  
Helen M. Lazear ◽  
Brian P. Daniels ◽  
Amelia K. Pinto ◽  
Albert C. Huang ◽  
Sarah C. Vick ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Blood Brain Barrier ◽  
West Nile Virus Infection ◽  
Antiviral Effect ◽  
Brain Barrier ◽  
West Nile ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Brain ◽  
Interferon Λ

Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1−/− mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1−/− mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1−/− mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis– and signal transducer and activator of transcription 1 (STAT1)–independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis.

scholarly journals Novel infectious diseases in europe

2017 ◽  
Vol 70 (11-12) ◽  
pp. 385-390
Author(s):  
Dajana Lendak ◽  
Tomislav Preveden ◽  
Nadica Kovacevic ◽  
Slavica Tomic ◽  
Maja Ruzic ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Infectious Diseases ◽  
Zika Virus ◽  
Ebola Virus ◽  
Cost Effective ◽  
Hepatitis E ◽  
West Nile ◽  
Human Contact ◽  
Fast Spreading ◽  
Virus Zika

Introduction. The end of 20th and beginning of 21st century is marked by the discovery of new, supercontagious and fast spreading viral diseases. Since 1967, more than 40 new agents have been identified, including human immunodeficiency virus, Ebola, Marburg fever, severe acute respiratory syndrome, hepatitis C, hepatitis E viruses and Zika virus. Modern lifestyle, availability and speed of air traffic, migrations, as well as climate changes, enable faster spreading of infectious diseases from the regions that were hardly reachable. We selected a few diseases that raised the greatest attention among experts and public in general. Ebola. Ebola virus raises anxiety due to high mortality and fast spreading by using inter-human contact. Zika virus. Zika virus, that most often causes mild symptoms, is potentially responsible for microcephaly in neonates. Dengue. Dengue virus is an ?old story?, but in last decades incidence has multiplied by 30. West Nile virus. Although discovered in 1937, West Nile virus has been found exclusively in rural parts of Africa, while nowadays it represents one of the most important etiological factors of viral meningo-encephalitis all over the world. Hepatitis E. Today it is well-known that hepatitis E virus can cause not only acute viral hepatitis but also potentially blood-transmitted chronic hepatitis in immunocompromised, as well as some neurological disorders. Conclusion. One of the scientific challenges in the future will certainly be the discovery of available and cost-effective diagnostic tests, as well as efficient and safe vaccines for these diseases. Up to now, efficient prophylaxis is available only for Denga virus.

scholarly journals Viral RNA-Dependent RNA Polymerase Inhibitor 7-Deaza-2′-C-Methyladenosine Prevents Death in a Mouse Model of West Nile Virus Infection

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Luděk Eyer ◽  
Martina Fojtíková ◽  
Radim Nencka ◽  
Ivo Rudolf ◽  
Zdeněk Hubálek ◽  
...  
Keyword(s):  
West Nile Virus ◽  
West Nile Virus Infection ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Modified Nucleosides ◽  
West Nile ◽  
Brain Infection ◽  
Highly Effective ◽  
Time Of Infection

ABSTRACTWest Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans and against which no approved antiviral therapy is currently available. In this study, we demonstrate that 2′-C-methyl- or 4′-azido-modified nucleosides are highly effective inhibitors of WNV replication, showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. One representative ofC2′-methylated nucleosides, 7-deaza-2′-C-methyladenosine, significantly protected WNV-infected mice from disease progression and mortality. Twice daily treatment at 25 mg/kg starting at the time of infection resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days postinfection, at the time of a peak of viremia, which resulted in a 90% survival rate. However, the antiviral effect of 7-deaza-2′-C-methyladenosine was absent or negligible when the treatment was started 8 days postinfection (i.e., at the time of extensive brain infection). The 4′-azido moiety appears to be another important determinant for highly efficient inhibition of WNV replicationin vitro. However, the strong anti-WNV effect of 4′-azidocytidine and 4′-azido-aracytidine was cell type dependent and observed predominantly in porcine kidney stable (PS) cells. The effect was much less pronounced in Vero cells. Our results indicate that 2′-C-methylated or 4′-azidated nucleosides merit further investigation as potential therapeutic agents for treating WNV infections as well as infections caused by other medically important flaviviruses.

scholarly journals Lipid Metabolism as a Source of Druggable Targets for Antiviral Discovery against Zika and Other Flaviviruses

2019 ◽  
Vol 12 (2) ◽  
pp. 97 ◽  
Author(s):  
Miguel A. Martín-Acebes ◽  
Nereida Jiménez de Oya ◽  
Juan-Carlos Saiz
Keyword(s):  
Lipid Metabolism ◽  
Regulatory Element ◽  
Antiviral Treatment ◽  
Adenosine Monophosphate ◽  
Sphingolipid Metabolism ◽  
Pharmacological Intervention ◽  
Complex Interactions ◽  
Novel Host ◽  
Sterol Regulatory Element ◽  
Cellular Pathways

The Zika virus (ZIKV) is a mosquito-borne flavivirus that can lead to birth defects (microcephaly), ocular lesions and neurological disorders (Guillain-Barré syndrome). There is no licensed vaccine or antiviral treatment against ZIKV infection. The effort to understand the complex interactions of ZIKV with cellular networks contributes to the identification of novel host-directed antiviral (HDA) candidates. Among the cellular pathways involved in infection, lipid metabolism gains attention. In ZIKV-infected cells lipid metabolism attributed to intracellular membrane remodeling, virion morphogenesis, autophagy modulation, innate immunity and inflammation. The key roles played by the cellular structures associated with lipid metabolism, such as peroxisomes and lipid droplets, are starting to be deciphered. Consequently, there is a wide variety of lipid-related antiviral strategies that are currently under consideration, which include an inhibition of sterol regulatory element-binding proteins (SREBP), the activation of adenosine-monophosphate activated kinase (AMPK), an inhibition of acetyl-Coenzyme A carboxylase (ACC), interference with sphingolipid metabolism, blockage of intracellular cholesterol trafficking, or a treatment with cholesterol derivatives. Remarkably, most of the HDAs identified in these studies are also effective against flaviviruses other than ZIKV (West Nile virus and dengue virus), supporting their broad-spectrum effect. Considering that lipid metabolism is one of the main cellular pathways suitable for pharmacological intervention, the idea of repositioning drugs targeting lipid metabolism as antiviral candidates is gaining force.

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