ABSTRACT
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Subject(s)
Animals , Humans , Mice , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Influenza A virus , Leflunomide , Pharmacology , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus ReplicationABSTRACT
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Subject(s)
Animals , Humans , Mice , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Influenza A virus , Leflunomide , Pharmacology , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus ReplicationABSTRACT
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Subject(s)
Animals , Humans , Mice , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Influenza A virus , Leflunomide , Pharmacology , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus ReplicationABSTRACT
To investigate the effects of different habitat processing methods of Salviae Miltiorrhizae Radix et Rhizoma on acute myocardial ischemia induced by pituitrin in rats. In this experiment, the tail vein injection of pituitrin was used to induce acute myocardial ischemia in rats. Electrocardiograph(ECG) heart rate and ΔST changes were recorded, and the levels of creatine kinase isoenzyme(CK-MB), lactate dehydrogenase(LDH), superoxide dismutase(SOD) and malondialdehyde(MDA) in serum of rats were detected to comprehensively evaluate the effects of six processing methods of Salviae Miltiorrhizae Radix et Rhizoma on serum biochemical indexes of rats with acute myocardial injury. The ECG results showed that the Salviae Miltiorrhizae Radix et Rhizoma dried in a drying oven had a good effect on the improvement of heart rate and ΔST of electrocardiogram after ischemia, and all the other groups had some protective effects to different degrees. The results of biochemical indexes in serum of each group after ischemia showed that the activity of CK-MB decreased most significantly in Salviae Miltiorrhizae Radix et Rhizoma high-dose group with drying in a drying oven after sweating and losing weight in a drying oven, high-dose group with drying in the shade and low-dose group with drying in the shade. The activity of LDH decreased most significantly in Salviae Miltiorrhizae Radix et Rhizoma high-dose group with drying in the shade and low-dose group of drying in the shade. The activity of SOD increased most significantly in Salviae Miltiorrhizae Radix et Rhizoma low-dose group with drying in sun, low-dose group with drying in sun after sweating and losing weight in sun, and low-dose group with drying in a drying oven. The activity of MDA decreased most significantly in Salviae Miltiorrhizae Radix et Rhizoma low-dose group with drying in sun. The comprehensive scoring results showed that the highest score was obtained in Salviae Miltiorrhizae Radix et Rhizoma high-dose group with drying in the shade while the scores of other treatment groups were higher than that of the model group. It could be seen that the Salviae Miltiorrhizae Radix et Rhizoma dried in a drying oven had a good improvement effect on electrocardiograph indexes after acute myocardial injury, the Salviae Miltiorrhizae Radix et Rhizoma dried in the shade had a good improvement effect on serum myocardial enzymes after acute myocardial injury, and the other processing methods had a certain protective effect on myocardial injury. The six processing methods evaluated by pharmacodynamics showed that the Salviae Miltiorrhizae Radix et Rhizoma dried in the shade and dried in a drying oven had good efficacy.
Subject(s)
Animals , Rats , Drugs, Chinese Herbal , Ecosystem , Myocardial Ischemia , Rhizome , Salvia miltiorrhizaABSTRACT
The metabonomics method was used to study the intervention effect of Psoraleae Fructus and Myristicae Semen in "Ershen pill" on the changes in serum endogenous metabolites in spleen-kidney Yang deficiency diarrhea rats before and after processing, screen out differentiated metabolites related to spleen-kidney Yang deficiency diarrhea and explore the metabolic patterns related to spleen-kidney Yang deficiency diarrhea and the processing synergy mechanism of Psoraleae Fructus and Myristicae Semen in "Ershen pill". Efforts were made to detect SOD and MDA of each group, test rat serum metabolic fingerprints in different stages by using GC-MS, analyze by PCA and PLS-DA methods and screen out potential biomarks through VIP and t test. The results revealed that "Ershen pill" could enhance the level of SOD and decrease the level of MDA and identified 10 differentiated metabolites related to spleen-kidney Yang deficiency diarrhea. Compared with the model group, all of metabolites recovered to varying levels after being intervened with "Ershen pill", with the best effect shown in the "Ershen pill" IV group (salt-processed Psoraleae Fructus + bran-roasted Myristicae Semen). It is speculated that that Psoraleae Fructus and Semen Myristicae in "Ershen pill" show a synergistic effect by inhibiting peroxide, improving aglucolipid, amino acids and energy metabolism, with multiple target sites.
Subject(s)
Animals , Humans , Male , Rats , Chemistry, Pharmaceutical , Diarrhea , Drug Therapy , Metabolism , Drugs, Chinese Herbal , Chemistry , Energy Metabolism , Kidney , Metabolism , Metabolomics , Myristicaceae , Chemistry , Psoralea , Chemistry , Rats, Sprague-Dawley , Spleen , Metabolism , Yang Deficiency , Drug Therapy , MetabolismABSTRACT
<p><b>OBJECTIVE</b>To assess the effect of Danshen on liver regeneration capacity of carbon tetrachloride-induced liver injury rats.</p><p><b>METHOD</b>Computer retrieval of data from CJFD, CBM, Chinese science & technology journal full-text database and Chinese medical association digital journals, and such foreign databases as PubMed, EMBASE and SCI was included in the randomized controlled trials (RCT) of rat liver injury induced by carbon tetrachloride,with the search as at May 2012. A Meta analysis was made using Rev-Man 5.1 software. Using the GRADE system to addess five outcomes in stuay.</p><p><b>RESULT</b>Two hundred and fourteen rats got involved in seven randomized trials. Meta analysis showed there were statistical differences between the Danshen group and the control group in alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-alpha) and hyaluronic acid (HA) after rat liver injury induced by carbon tetrachloride. When we used system to each outcome, because of serious limitations and indirect, they are all very low quality.</p><p><b>CONCLUSION</b>Danshen shows certain promoting effect to liver regeneration in carbon tetrachloride-induced liver injury rats.</p>