REVIEW | doi:10.20944/preprints202201.0468.v1
Subject: Life Sciences, Virology Keywords: Flavivirus; NS2B-NS3; ZIKA Virus; Dengue Virus; West Nile Virus; Inhibitors
Online: 31 January 2022 (13:46:44 CET)
Flaviviruses cause a significant amount of mortality and morbidity, especially in the area where they are endemic. A recent example is the outbreak of Zika virus though out the world. Development of antiviral drugs against different viral targets is as important as development of vaccine. During viral replication, the flavivirus genome is translated as a single polyprotein precursor, which must be cleaved into individual proteins by a complex of the viral protease, NS3, and its cofactor, NS2B. Flavivirus protease is the most attractive target for development of therapeutic antivirals because it is essential for processing of viral polyprotein precursor and generation of functional viral proteins. In this review, we have summarized recent development in drug discovery targeting NS3-NS2B protease of flaviviruses, especially Zika, dengue and West Nile virus.
Subject: Biology, Anatomy & Morphology Keywords: RSV; BRD4; AP-MS; PPI; AP1; Wnt; Innate Immune Response
Online: 26 February 2021 (09:26:24 CET)
Respiratory Syncytial Virus (RSV) causes severe inflammation and airway pathology in children and the elderly by infecting the epithelial cells of the upper and lower respiratory tract. RSV replication is sensed by intracellular pattern recognition receptors upstream of the IRF and NF-B transcription factors. These proteins coordinate an innate inflammatory response via Bromodomain containing protein 4 (BRD4), a protein that functions as a scaffold for unknown transcriptional regulators. To better understand the pleiotropic regulatory function of BRD4, we examine the BRD4 interactome and identify how RSV infection dynamically alters it. To accomplish these goals, we leverage native immunoprecipitation and Parallel Accumulation – Serial Fragmentation (PASEF) mass spectrometry to examine BRD4 complexes isolated from human alveolar epithelial cells in the absence or presence of RSV infection. In addition, we explore the role of BRD4’s acetyl-lysine binding bromodomains in mediating these interactions by using a highly selective competitive bromodomain inhibitor. We identify 101 proteins that are significantly enriched in the BRD4 complex and are responsive to both RSV-infection and BRD4 inhibition. These proteins are highly enriched in transcription factors and transcriptional coactivators. Among them, we identify members of the AP1 transcription factor complex, a complex important in innate signaling and cell stress responses. We independently confirm the BRD4/AP1 interaction in primary human small airway epithelial cells. We conclude that BRD4 recruits multiple transcription factors during RSV infection in a manner dependent on acetyl-lysine binding domain interactions. This data suggests that BRD4 recruits transcription factors to target its RNA processing complex to regulate gene expression in innate immunity and inflammation.
ARTICLE | doi:10.20944/preprints201901.0041.v1
Subject: Biology, Physiology Keywords: nonalcoholic fatty liver disease; high fat-sucrose diet; metabolomics; HPLC-QTOF-MS; quercetin
Online: 4 January 2019 (14:04:13 CET)
As metabolomics is widely used in the study of disease mechanisms, more and more studies have found that metabolites play an important role in the occurrence of diseases. The aim of this study is to investigate the effects and mechanisms of quercetin in high-fat-sucrose diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) development using nontargeted metabolomics. A rat model of NAFLD was established by feeding with a HFD for 30 and 50 days. Results indicated quercetin exhibited hepatoprotective activity in HFD-induced NAFLD rats in 30 days by regulating fatty acids related metabolites (adrenic acid, etc.), inflammation related metabolites (arachidonic acid, etc.), oxidative stress related metabolites (2-hydroxybutyric acid) and other differential metabolites (citric acid, etc.). However, quercetin couldn’t improve NAFLD in 50 days maybe it couldn’t reverse the inflammation condition induced by long-term high-fat diet. These data indicate that dietary quercetin may be beneficial to NAFLD at early stages. Furthermore, combining metabolomics and experimental approaches opens up avenues of effects and mechanisms of drugs for complex diseases.