RESUMO
The pandemic outbreak of a new coronavirus (CoV), SARS-CoV-2, has captured the world's attention, demonstrating that CoVs represent a continuous global threat. As this is a highly contagious virus, it is imperative to understand RNA-dependent-RNA-polymerase (RdRp), the key component in virus replication. Although the SARS-CoV-2 genome shares 80% sequence identity with severe acute respiratory syndrome SARS-CoV, their RdRps and nucleotidyl-transferases (NiRAN) share 98.1% and 93.2% identity, respectively. Sequence alignment of six coronaviruses demonstrated higher identity among their RdRps (60.9%-98.1%) and lower identity among their Spike proteins (27%-77%). Thus, a 3D structural model of RdRp, NiRAN, non-structural protein 7 (nsp7), and nsp8 of SARS-CoV-2 was generated by modeling starting from the SARS counterpart structures. Furthermore, we demonstrate the binding poses of three viral RdRp inhibitors (Galidesivir, Favipiravir, and Penciclovir), which were recently reported to have clinical significance for SARS-CoV-2. The network of interactions established by these drug molecules affirms their efficacy to inhibit viral RNA replication and provides an insight into their structure-based rational optimization for SARS-CoV-2 inhibition.
Assuntos
Betacoronavirus/enzimologia , Nucleotidiltransferases/química , RNA Polimerase Dependente de RNA/química , Adenina/análogos & derivados , Adenina/química , Adenina/metabolismo , Adenosina/análogos & derivados , Amidas/química , Amidas/metabolismo , Antivirais/química , Antivirais/metabolismo , Betacoronavirus/isolamento & purificação , Sítios de Ligação , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Simulação de Acoplamento Molecular , Nucleotidiltransferases/metabolismo , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Estrutura Terciária de Proteína , Pirazinas/química , Pirazinas/metabolismo , Pirrolidinas/química , Pirrolidinas/metabolismo , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2RESUMO
Androgen receptor (AR) signaling is essential for prostate cancer (PC) progression and treatment. Experiments have demonstrated that the intratumoral androgen levels are not affected by circulating androgen levels, but rather modulated by local steroid-converting enzyme activities. The expression modulation status of human steroid-converting enzymes and nuclear receptors are of great promise to identify novel therapeutic targets. Meta-analysis was performed with 9 cohorts (1093 specimens) from Gene Expression Omnibus, 16 cohorts (933 specimens) from Oncomine and the TCGA cohort (550 specimens). We found significant up regulation of 5α-reductase type 1 and type 3 in both primary and metastatic PC, together with the down regulation of AKR1C2 in primary PC, contributing to the high intratumoral DHT levels. The expression of AR in metastatic PC was up regulated, indicating the importance of AR signaling in the progression of this cancer. The down regulations of HSD11B1 and NR3C1 in primary and metastatic PC may diminish the anti-inflammation and anti-proliferation effects of glucocorticoids signaling. Furthermore, the decrease of progesterone receptor (PGR) expression in primary and metastatic PC was also observed, relieving the suppression effect of PGR on PC proliferation. The clinical evidences of the remarkable expression modulation of steroid-converting enzymes and receptors in PC may indicate novel combined treatment against this highly incident cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Regulação para Baixo , Humanos , Hidroxiesteroide Desidrogenases/genética , Masculino , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores de Glucocorticoides/genética , Receptores de Progesterona/genética , Regulação para CimaRESUMO
Tomato fruit are especially susceptible to chilling injury (CI) when continuously exposed to temperatures below 12 °C. In this study, integrative comparative analyses of transcriptomics and metabolomics data were performed to uncover the regulatory network in CI tomato fruit. Metabolite profiling analysis found that 7 amino acids, 27 organic acids, 16 of sugars and 22 other compounds had a significantly different content while transcriptomics data showed 1735 differentially expressed genes (DEGs) were down-regulated and 1369 were up-regulated in cold-stored fruit. We found that the contents of citrate, cis-aconitate and succinate were increased, which were consistent with the expression of ATP-citrate synthase (ACS) and isocitrate dehydrogenase (IDH) genes in cold-treated tomato fruit. Cold stress promotes the expression of ACS and IDH which may increase the synthesis of citrate, cis-aconitate and succinate. Alanine and leucine had increased contents, which may result from alanine aminotransferase (ALT) and branched-chain amino acid aminotransferase (BcAT)'s high expression levels, respectively. Overall the transcriptomics and metabolomics data in our study explain the molecular mechanisms of the chilling injury and expands our understanding of the complex regulatory mechanisms of a metabolic network in response to chilling injury in tomato fruit.