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ANTIHYPERLIPIDEMIA AGENTS Plasma lipids Transported in bloodstream in form of macromolecular complexes of lipid and known as lipoproteins Two major clinical importance/sequelae of high lipid Acute pancreatitis atherosclerosis Hyperlipoproteinemia Hyperlipidemia Lipoprotein disorders Primary hypertriglyceridemias Primary chylomicronemia Familial hypertriglyceridemia Familial combined hyperlipoproteinemia Familial dysbetalipoproteinemia Primary hypercholesterolemias Famimial hypercholesterolemia Familial ligan-defective apolipoprotein B Familial combine hyperlipoproteinemia Lp(a) hyperlipoproteinemia Secondary hyperlipoproteinemia Lipid-lowering drugs Several drugs are used To decrease plasma LDL-cholesterol Drug therapy is only one approach Dietary measures are the first [...] | 19th January, 2010 | More News
Resveratrol …an Investment against Influenza A Virus protection?
Introduction
Influenza A Virus
Influenza viruses are enveloped viruses with segmented, single‐stranded, negative‐sense RNA genomes. Every year, influenza epidemics cause numerous deaths and millions of hospitalizations, but the most frightening effects are seen when new strains of the virus emerge, causing worldwide outbreaks of infection. Recent reports of direct avian‐to‐human transmission of influenza make the prospect of a new pandemic particularly alarming. The replication of influenza virus has been studied in depth, and several antiviral compounds have been developed, but their long‐term efficacy is often limited by toxicity and the almost inevitable selection of drug‐resistant viral mutants.Influenza A virus strains are categorized according to two proteins found on the surface of the virus: hemagglutinin (H) and neuraminidase (N). All influenza A viruses contain hemagglutinin and neuraminidase, but the structure of these proteins differ from strain to strain due to rapid genetic mutation in the viral genome.
Influenza A virus strains are assigned an H number and an N number based on which forms of these two proteins the strain contains. There are 16 H and 9 N subtypes known in birds, but only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.
Resveratrol
Resveratrol (RV; 3,5,4′‐trihydroxy‐trans‐stilbene) is a polyphenol that is synthesized by at least 72 plant species, including grapes (50–100 μg/g of RV) and other fruits, in response to physiological stimuli and environmental stress. Its health benefits include cardio‐ and neuroprotective effects and anticarcinogenic activity. Some researchers have reported that RV also inhibits the replication of herpes simplex virus and synergistically enhances the effects of known anti‐HIV drugs, but the mechanisms underlying these actions remain obscure. RV appears to be capable of interfering with several intracellular signaling pathways, including those activated by protein kinase C (PKC) and by mitogen‐activated protein kinases (MAPKs). It has documented antioxidant activity , and its cardioprotective effects have been related to its inhibition of lipid peroxidation and the oxidation of low‐density lipoproteins .
Discussion
There is increasing evidence that the oxidoreductive (redox) balance of cells is involved in viral infections and that certain antioxidant molecules exert potent antiviral activities in vitro and in vivo.According to a study by Dr Anna T. Palamara,on her paper>Inhibition of Influenza A Virus Replication by Resveratrol
Anna T. Palamara,1 Lucia Nencioni,1 Katia Aquilano,2 Giovanna De Chiara,3 Leyanis Hernandez,3 Federico Cozzolino,4 Maria R. Ciriolo,2 and Enrico Garaci3
They have previously demonstrated that RNA and DNA viruses can deplete host‐cell levels of the antioxidant glutathione (GSH) and that the administration of exogenous GSH inhibits viral replication in several experimental systems. These observations prompted them to investigate RV’s potential for inhibiting the replication of influenza virus and the possible mechanisms underlying these effects. They found that RV strongly inhibits the replication of influenza A virus in vitro but that this effect did not seem to be directly related to GSH‐mediated antioxidant activity. Instead, it appeared to involve the blockade of nuclear‐cytoplasmic translocation of viral ribonucleoproteins (vRNPs) and reduced expression of late viral proteins, and these effects were related to the inhibition of PKC activity and its dependent pathways. In in vivo studies, RV also improved survival and decreased pulmonary viral titers in influenza virus–infected mice.
Its is also shown that RV, a natural polyphenol whose concentration in red wine is 1.5–3.0 mg/L, can inhibit the in vitro and in vivo replication of influenza A virus without producing any significant toxicity. The drug’s effects involved blockade of the nuclear‐cytoplasmic translocation of vRNP complexes, decreased expression of late viral proteins, and an inhibition of cellular PKC activity and its dependent pathways.
Depletion of host‐cell GSH is a direct consequence of several viral infections, and various antioxidant substances display strong antiviral activities. RV has been characterized as a potent free‐radical scavenger, and it has reportedly increased GSH levels in different experimental models. Therefore, their in vitro findings of decreased GSH levels in uninfected cells treated with RV and its mild effect in restoring the GSH depletion provoked by viral infection were somewhat unexpected. However, natural phenols can produce in vivo antioxidant or pro‐oxidant effects, depending on their own oxidative status, which, in turn, reflects the specific redox potential in the microenvironment. Thus, although RV can quench reactive free radicals by donating hydrogen atoms, this process also generates phenoxyl radicals that can oxidize GSH to GS•. Moreover, the oxidation of the RV‐phenoxyl radical produces an RV‐quinone form, which can alkylate GSH and further diminish intracellular concentrations of free GSH. Our findings suggest that RV’s inhibition of PR8 replication involves mechanisms other than a GSH‐mediated modulation of the cell redox state, although they cannot exclude the possibility that the RV quinone is involved in the drug’s inhibition of virus growth.
RV had little effect on early viral protein expression, but it dose‐dependently inhibited the expression of M1 and HA. That mRNA for these late viral proteins was efficiently transcribed in the presence of RV suggests that the drug acts on posttranscriptional phases of the viral life cycle. This hypothesis was confirmed by immunofluorescence data that showed an RV‐induced blockade of the nucleocytoplasmic translocation of vRNPs. Inhibition of influenza virus replication, with decreased production of HA and M1 and nuclear retention of vRNPs, is also produced by the broad‐spectrum kinase inhibitor H7, and this similarity suggests that kinase inhibition might be involved in RV’s antiviral effects.
Influenza A virus infection causes the activation of various MAPK pathways , including the p38MAPK and JNK pathways (which are thought to play roles in the inflammatory and apoptotic responses and the Raf/MEK/ERK cascade. Blockade of the latter pathway with the ERK inhibitor U0126 results in nuclear retention of vRNPs and diminished virus production but has no effect on the expression of late viral protein. Phosphorylation events also seem to play crucial roles in other steps of the influenza virus life cycle, such as cell penetration and budding.
The influenza A virus has 6 phosphorylated proteins, including NP . That both H7 and U0126 block the export of vRNPs to the cytosol strongly suggests that a phosphorylation event is required for efficient nuclear export of NP, but the specific kinase responsible for this event has not been identified .Pleschka et al reported that NP phosphorylation is not directly affected by the ERK inhibitor U0126 and suggested that vRNP export might even depend on the phosphorylation of a cellular factor.
RV reportedly interferes with signaling cascades by modulating the activities of kinases and other enzymes—for example, the inhibition of PKC activity. It also exerts modulatory effects on MAPK pathways as a consequence of the inhibition of PKC activity. In the present study, RV efficiently inhibited the PR8‐ and TPA‐induced phosphorylation of PKD, a downstream effector of PKC, as well as that of p38MAPK and JNK. That ERK activation was not affected by RV is consistent with previous observations and suggests that (1) different PKC isoenzymes can be involved in the activation of different MAPK pathways and (2) the functional outcome is both isoenzyme and cell‐type specific. Their data strongly suggest that RV’s antiviral effects are related to the inhibition of PKC activity and its dependent pathways. Studies are already under way to identify the cellular and/or viral substrates of RV‐inhibited kinases and their specific roles in the PR8 life cycle.
RV’s in vitro antiviral effects were mirrored in a murine model of influenza. Treatment of PR8‐infected mice markedly improved their survival, decreased pulmonary virus titers, and caused no significant toxicity. The latter finding is consistent with the results of previous in vivo studies, including some in which RV was administered at doses higher than the ones that they have used . Different mechanisms might underlie the in vivo efficacy of RV documented in their study. RV inhibits several cell‐signaling pathways that are involved in the inflammatory airway damage that is characteristic of influenza disease. This finding raises the possibility that the survival benefits of RV observed in their study involved a dual mechanism: inhibition of both viral replication and NF‐κB–induced inflammation. Studies under way in their laboratory of inflammatory‐cytokine levels in PR8‐infected mice treated with RV should shed more light on this hypothesis.
All currently approved anti‐influenza drugs target essential viral functions and/or structures, and the major drawback of this approach is that the virus will eventually adapt to the selective pressure exerted by the drug . Inactivation of host‐cell functions that are essential for virus replication, which seems to be the mechanism of RV’s anti‐influenza activity, offers 2 important advantages: not only it is more difficult for the virus to adapt to, but it can also be expected to affect viral replication independently of the invader’s type, strain, and antigenic properties. For these reasons, RV merits further investigation as a potential weapon for combating the growing threat of influenza.
Good info, but need to put up some studies/researches from other fields (other than medicine and science) in order to get more viewers.