The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a data set of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean of 5.5 to 9.5 nucleotide differences from each other, consistent with a midrange coronavirus substitution rate of 3 × 10−4 substitutions/site/year. Almost one-half of sequence changes were C→U transitions, with an 8-fold base frequency normalized directional asymmetry between C→U and U→C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV, Middle East respiratory syndrome [MERS]-CoV), and decreasing ratios were observed in other human coronaviruses (HCoV-NL63, -OC43, -229E, and -HKU1) proportionate to their increasing divergence. C→U transitions underpinned almost one-half of the amino acid differences between SARS-CoV-2 variants and occurred preferentially in both 5′ U/A and 3′ U/A flanking sequence contexts comparable to favored motifs of human APOBEC3 proteins. Marked base asymmetries observed in nonpandemic human coronaviruses (U ≫ A > G ≫ C) and low G+C contents may represent long-term effects of prolonged C→U hypermutation in their hosts. The evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short- and long-term evolution. Repeated cycles of mutation and reversion in favored mutational hot spots and the widespread occurrence of amino acid changes with no adaptive value for the virus represent a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks and are not incorporated by standard models used in molecular epidemiology investigations. IMPORTANCE The wealth of accurately curated sequence data for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its long genome, and its low substitution rate provides a relatively blank canvas with which to investigate effects of mutational and editing processes imposed by the host cell. The finding that a large proportion of sequence change in SARS-CoV-2 in the initial months of the pandemic comprised C→U mutations in a host APOBEC-like context provides evidence for a potent host-driven antiviral editing mechanism against coronaviruses more often associated with antiretroviral defense. In evolutionary terms, the contribution of biased, convergent, and context-dependent mutations to sequence change in SARS-CoV-2 is substantial, and these processes are not incorporated by standard models used in molecular epidemiology investigations.

https://msphere.asm.org/content/msph/5/3/e00408-20.full.pdf

Rampant C→U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short- and Long-Term Evolutionary Trajectories.

Context: Coptidis rhizome (CR), also known as Huanglian in Chinese, is the rhizome of Coptis chinensis Franch., C. deltoidea C.Y. Cheng et Hsiao, or C. teeta Wall (Ranunculaceae). It has been widel...

Coptidis Rhizoma: a comprehensive review of its traditional uses, botany, phytochemistry, pharmacology and toxicology

Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways

Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidant response element- (ARE-) driven cytoprotective protein expression. The activation of Nrf2 signaling plays an essential role in preventing cells and tissues from injury induced by oxidative stress. Under the unstressed conditions, natural inhibitor of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), traps Nrf2 in the cytoplasm and promotes the degradation of Nrf2 by the 26S proteasome. Nevertheless, stresses including highly oxidative microenvironments, impair the ability of Keap1 to target Nrf2 for ubiquitination and degradation, and induce newly synthesized Nrf2 to translocate to the nucleus to bind with ARE. Due to constant exposure to external environments, including diverse pollutants and other oxidants, the redox balance maintained by Nrf2 is fairly important to the airways. To date, researchers have discovered that Nrf2 deletion results in high susceptibility and severity of insults in various models of respiratory diseases, including bronchopulmonary dysplasia (BPD), respiratory infections, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and lung cancer. Conversely, Nrf2 activation confers protective effects on these lung disorders. In the present review, we summarize Nrf2 involvement in the pathogenesis of the above respiratory diseases that have been identified by experimental models and human studies and describe the protective effects of Nrf2 inducers on these diseases.

https://downloads.hindawi.com/journals/omcl/2019/7090534.pdf

Role of Nrf2 and Its Activators in Respiratory Diseases.

SARS-CoV-2 (2019-nCoV) emerged in 2019 and proliferated rapidly across the globe Scientists are attempting to investigate antivirals specific to COVID-19 treatment The 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease (Mpro)COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral candidates So the objective and purpose of this work was to investigate the plants with reported potential antiviral activity With the aid of in silico techniques such as molecular docking and druggability studies, we have proposed several natural active compounds including glycyrrhizin, bicylogermecrene, tryptanthrine, β-sitosterol, indirubin, indican, indigo, hesperetin, crysophanic acid, rhein, berberine and β-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against SARS-CoV-2 Promising docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease

/pdf/recognition-of-natural-products-as-potential-inhibitors-of-15dtoznrk3.pdf

Recognition of Natural Products as Potential Inhibitors of COVID-19 Main Protease (Mpro): In-Silico Evidences.

Influenza is an acute transmissible respiratory infectious disease in humans and animals with high morbidity and mortality. It was reported that luteolin, extracted from Chinese herbs, could potently inhibit influenza virus replication in vitro. To assess the effect and explore the fundamental mechanism of luteolin, we infected several cell lines with two subtypes of influenza A virus (IAV), including A/Jiangxi/312/2006 (H3N2) and A/Fort Monmouth/1/1947 (H1N1) and demonstrated that luteolin suppressed the replication of IAV by cytopathic effect reduction method, qRT-PCR, immunofluorescence and Western blot assays. A time-of-addition assay indicated that this compound interfered with viral replication at the early stage of infection. In addition, we found that luteolin suppressed coat protein I complex expression, which was related to influenza virus entry and endocytic pathway. Overall, our findings demonstrated the antiviral effect of luteolin against IAV and its novel antiviral mechanism.

/pdf/luteolin-decreases-the-yield-of-influenza-a-virus-in-vitro-3igtoj3hhp.pdf

Luteolin decreases the yield of influenza A virus in vitro by interfering with the coat protein I complex expression.

The MEK-ERK signaling pathway and autophagy play an important role for enterovirus71(EV71) replication. Inhibition of MEK-ERK signaling pathway and autophagy is shown to impair EV71 replication. Berberine (BBR), an isoquinoline alkaloid isolated from Berberis vulgaris L., has been reported to have ability to regulate this signaling pathway and autophagy. Herein, we want to determine whether berberine can inhibit EV71 infection by downregulating the MEK/ERK signaling pathway and autophagy. The antiviral effect of berberine was determined by cytopathic effect (CPE) assay, western blotting assay and qRT-PCR assay. The mechanism of BBR anti-virus was determined by western blotting assay and immunofluorescence assay. We showed that berberine does-dependently reduced EV71 RNA and protein synthesis, which was, at least in part, the result of inhibition of activation of MEK/ERK signaling pathway. Furthermore, we found that berberine suppressed the EV71-induced autophagy by activating AKT protein and inhibiting the phosphorylation of JNK and PI3KIII. BBR inhibited EV71 replication by downregulating autophagy and MEK/ERK signaling pathway. These findings suggest that BBR may be a potential agent or supplement against EV71 infection.

/pdf/berberine-inhibits-enterovirus-71-replication-by-5b3ss05dhm.pdf

Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy.

Artemisia scoparia Waldst and Kit is a famous traditional Chinese medicine widely distributed in Xinjiang, China. Flavonoids extracted from it exhibits inhibitory activities against several influenza virus strains. Despite this fact, the antiviral properties of CST, one of such flavonoids, against the influenza virus has not been reported. Thus, the aim of this study is to investigate the anti-influenza virus efficacy and antiviral mechanism of CST. The inhibitory activity of CST against influenza viruses was assessed by using viral titers and performing Western blot, qRT-PCR, and immunofluorescence assays in Madin–Darby canine kidney (MDCK) cells and a human monocytic cell line (THP-1). The mechanism of CST against influenza virus was analyzed by hemagglutination inhibition (HI) assay, neuraminidase (NA) inhibition assay, and Western blot. CST reduced viral titers and influenza A virus (IAV) RNA and protein synthesis in a dose-dependent manner. Mechanistically, CST had no inhibitory effect on the attachment and release processes of the viral life cycle, as indicated by the HI and NA assays. Conversely, the CST-mediated inhibition of IAV is possibly linked to the inactivation of the NF-κB/p65 signal pathway. CST also suppressed the activation of JNK MAPK and P38 MAPK in vitro. In line with NF-κB/p65 inhibition, the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-8, and IL-10) and the inflammation-related protein COX-2 were downregulated by CST. CST inhibited IAV replication by downregulating the NF-κB signal transduction pathway. CST may be a potential agent or supplement against IAV infection.

/pdf/cirsimaritin-inhibits-influenza-a-virus-replication-by-1t1rl11avj.pdf

Shuo Wu

Papers

Luteolin decreases the yield of influenza A virus in vitro by interfering with the coat protein I complex expression.

Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy.

Cirsimaritin inhibits influenza A virus replication by downregulating the NF-κB signal transduction pathway

Rupestonic acid derivative YZH-106 suppresses influenza virus replication by activation of heme oxygenase-1-mediated interferon response

Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety.