• Humans
• Benzoquinones/pharmacology
• Virus Replication/drug effects
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Hep G2 Cells
• Interferon-alpha/metabolism
• Interferon-alpha/genetics
• Signal Transduction/drug effects
• Proto-Oncogene Proteins c-raf/metabolism
• Proto-Oncogene Proteins c-raf/genetics
• Antiviral Agents/pharmacology
• Molecular Docking Simulation
• Cell Survival/drug effects
• Viral Nonstructural Proteins/metabolism
• Viral Nonstructural Proteins/genetics
• RNA-Dependent RNA Polymerase

• COVID-19
• ERK
• MAPK
• MEK
• PLA
• RAF
• Sepsis

• Humans
• COVID-19/mortality
• COVID-19/complications
• Sepsis/mortality
• Sepsis/virology
• Sepsis/metabolism
• Male
• Female
• Middle Aged
• Aged
• SARS-CoV-2
• MAP Kinase Signaling System
• Prospective Studies
• Phosphorylation
• Cohort Studies

• Land Nordrhein-Westfalen
• Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH (8943)

• JNK
• combination therapy
• microtubule-targeting agents
• oncolytic virus

• Animals
• Humans
• Antineoplastic Agents/therapeutic use
• Combined Modality Therapy
• Oncolytic Virotherapy
• Oncolytic Viruses/physiology
• Taxoids/therapeutic use
• Tubulin Modulators/therapeutic use
• Neoplasms/therapy
• Neoplasms/virology

• 1966/18 Israel Science Foundation

• KRAS
• LKB1
• interferon signaling pathway
• lung cancer
• p53

• Animals
• Lung Neoplasms/genetics
• Lung Neoplasms/immunology
• Lung Neoplasms/pathology
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Mice
• Interferon Type I/metabolism
• Interferon Type I/genetics
• Humans
• Signal Transduction
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/pharmacology
• Mutation
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• AMP-Activated Protein Kinase Kinases
• Cell Line, Tumor
• Tumor Microenvironment/immunology
• Tumor Microenvironment/genetics
• AMP-Activated Protein Kinases

• RTI2018-094664-B-I00 Spanish Ministry of Science, Innovation and Universities
• PID2021-122797OB-I00 Spanish Ministry of Science, Innovation and Universities

• Newcastle disease virus
• antiviral
• canthin-6-one
• viral entry

• Animals
• Antiviral Agents/pharmacology
• Carbolines/pharmacology
• Carbolines/chemistry
• Cell Line
• Indole Alkaloids/pharmacology
• MAP Kinase Signaling System/drug effects
• Newcastle disease virus/drug effects
• Newcastle disease virus/physiology
• Proto-Oncogene Proteins c-akt/metabolism
• Virus Replication/drug effects
• Humans

• Animals
• Humans
• Macaca arctoides
• Thailand
• Parasites
• Chromatography, Liquid
• Proteomics
• Tandem Mass Spectrometry
• Malaria/veterinary
• Malaria/parasitology

• Kasetsart University Research and Development Institute

• Humans
• Educational Personnel

• Antiviral activity
• BVDV
• IFN-α
• Interferon-stimulated gene
• Molecular characteristic

The mitogen-activated protein kinase (MEK) inhibitor zapnometinib is in development to treat acute viral infections like COVID-19 and influenza. While the antiviral efficacy of zapnometinib is well documented, further data on target engagement/pharmacodynamics (PD) and pharmacokinetics (PK) are needed. Here, we report zapnometinib PK and PD parameters in mice, hamsters, dogs, and healthy human volunteers. Mice received 25 mg/kg/day zapnometinib (12.5 mg/kg p. o. twice daily, 8 h interval). Syrian hamsters received 30 mg/kg (15 mg/kg twice daily) or 60 mg/kg/day once daily. Beagle dogs were administered 300 mg/kg/day, and healthy human volunteers were administered 100, 300, 600 and 900 mg zapnometinib (once daily p. o.). Regardless of species or formulation, zapnometinib maximum plasma concentration (C_max) was reached between 2–4 h after administration with an elimination half-life of 4–5 h in dogs, 8 h in mice or hamsters and 19 h in human subjects. Doses were sufficient to cause up to 80% MEK inhibition. Across all species approximately 10 μg/ml zapnometinib was appropriate to inhibit 50% of peripheral blood mononuclear cells (PBMC) MEK activity. In mice, a 50%–80% reduction of MEK activity was sufficient to reduce influenza virus titer in the lungs by more than 90%. In general, while >50% MEK inhibition was reached in vivo at most doses, 80% inhibition in PBMCs required significantly higher doses and appeared to be the practical maximal level obtained in vivo. However, the period of reduced phosphorylated extracellular-signal regulated kinase (pERK), a measure of MEK inhibition, was maintained even after elimination of zapnometinib from plasma, suggesting a sustained effect on MEK consistent with regulatory effects or a slow off-rate. These data suggest a target plasma C_max of at least 10 μg/ml zapnometinib in further clinical studies.

The COVID-19 pandemic, caused by the rapidly spreading SARS-CoV-2 virus, led to the unprecedented mobilization of scientists, resulting in the rapid development of vaccines and potential pharmaceuticals. Although COVID-19 symptoms are moderately severe in most people, in some cases the disease can result in pneumonia and acute respiratory failure as well as can be fatal. The severe course of COVID-19 is associated with a hyperinflammatory state called a cytokine storm. One of the key cytokines creating a proinflammatory environment is IL-6, which is secreted mainly by monocytes and macrophages. Therefore, this cytokine has become a target for some therapies that inhibit its biological action; however, these therapies are expensive, and their availability is limited in poorer countries. Thus, new cheaper drugs that can overcome the severe infections of COVID-19 are needed. Here, we show that chlorpromazine inhibits the expression and secretion of IL-6 by monocytes activated by SARS-CoV-2 virus nucleocapsid protein and affects the activity of NF-κB and MEK/ERK signaling. Our results, including others, indicate that chlorpromazine, which has been used for several decades as a neuroleptic, exerts antiviral and immunomodulatory activity, is safe and inexpensive, and might be a desirable drug to support the therapy of patients with COVID-19.

• COVID-19
• Interleukin 6
• SARS-CoV-2
• chlorpromazine
• cytokine storm
• monocytes

Nucleic acid-based therapeutics have demonstrated their efficacy in the treatment of various diseases and vaccine development. Antisense oligonucleotide (ASO) technology exploits a single-strand short oligonucleotide to either cause target RNA degradation or sterically block the binding of cellular factors or machineries to the target RNA. Chemical modification or bioconjugation of ASOs can enhance both its pharmacokinetic and pharmacodynamic performance, and it enables customization for a specific clinical purpose. ASO-based therapies have been used for treatment of genetic disorders, cancer and viral infections. In particular, ASOs can be rapidly developed for newly emerging virus and their reemerging variants. This review discusses ASO modifications and delivery options as well as the design of antiviral ASOs. A better understanding of the viral life cycle and virus-host interactions as well as advances in oligonucleotide technology will benefit the development of ASO-based antiviral therapies.

• RNA therapeutics
• antisense oligonucleotide
• drug delivery
• virus
• virus-host interaction

• SREBP (sterol regulatory element-binding protein) pathway
• Zika virus
• autophagy
• dengue virus
• hepatitis C virus
• lipid droplets

• Animals
• Autophagy
• Cell Nucleus/metabolism
• Dengue Virus/metabolism
• Dengue Virus/pathogenicity
• Extracellular Space/metabolism
• Flaviviridae/metabolism
• Flaviviridae/pathogenicity
• Hepacivirus/metabolism
• Hepacivirus/pathogenicity
• Humans
• Lipid Droplets/metabolism
• Lipid Droplets/virology
• Viral Proteins/metabolism
• Zika Virus/metabolism
• Zika Virus/pathogenicity

• PJT-153434 CIHR
• VR3-172639 CIHR

• COVID-19
• RNA viruses
• Raf/MEK/ERK signaling
• Viral life cycle
• Viral survival

• HCV
• Lipid metabolism
• hepatitis C virus
• microrna
• novel microRNA

• IFNAR1
• LINC00673
• cervical cancer
• miR-1231
• prognosis
• rs11655237

• E5
• EGFR
• STAT signaling
• TGFBR2
• innate immunity
• interferon kappa
• papillomavirus

• Chromosomal aberration
• Genetic damage
• Hepatitis C virus
• Lymphomagenesis
• Mixed cryoglobulinemia
• Non-Hodgkin B-lymphoma
• Oncogenic pathways
• Pathogenesis

• Acquired Immunodeficiency Syndrome/immunology
• Acquired Immunodeficiency Syndrome/virology
• Animals
• Clinical Trials as Topic
• HIV/immunology
• HIV Infections/immunology
• Host-Pathogen Interactions/immunology
• Humans
• Immunity, Innate
• Interferon Type I/immunology
• Mice
• Signal Transduction

• R15 AI138847 NIAID NIH HHS

• Caenorhabditis elegans
• Orsay virus
• drl-1

• Expression
• Fenneropenaeus chinensis
• Raf
• SNP
• White spot syndrome virus (WSSV)

• Amino Acid Sequence
• Animals
• Arthropod Proteins/genetics
• Base Sequence
• Cloning, Molecular
• DNA, Complementary/genetics
• Gills/metabolism
• Hepatopancreas/metabolism
• Muscles/metabolism
• Penaeidae/genetics
• Penaeidae/virology
• White spot syndrome virus 1
• raf Kinases/genetics

• cancer
• genomics
• global health
• global surgery
• low-income
• oncology
• precision medicine
• surgery

• Dengue virus infection
• Mitogen-activated protein kinase signaling
• Pathogenesis

• anticancer drug
• antiviral innate immunity
• chemokine
• transcriptome profiling
• tumor necrosis factor alpha

• PKA
• PKI 14-22
• Zika virus
• astrocytes
• endothelial cells
• inhibitor

• Animals
• Astrocytes/drug effects
• Astrocytes/virology
• Carrier Proteins/pharmacology
• Chlorocebus aethiops
• Endothelial Cells/drug effects
• Endothelial Cells/virology
• Humans
• Intracellular Signaling Peptides and Proteins/pharmacology
• MAP Kinase Signaling System
• Peptide Fragments/pharmacology
• Vero Cells
• Virus Replication/drug effects
• Zika Virus/drug effects
• Zika Virus Infection/drug therapy

• R01 CA197153 NCI NIH HHS
• R01 CA096512 NCI NIH HHS
• R21 AI129496 NIAID NIH HHS
• R01 DE025465 NIDCR NIH HHS
• R01 CA177377 NCI NIH HHS
• R01 CA132637 NCI NIH HHS
• R35 CA200422 NCI NIH HHS
• R01 CA124332 NCI NIH HHS
• R01 CA213275 NCI NIH HHS
• R01 AI100953 NIAID NIH HHS
• P01 CA180779 NCI NIH HHS
• HHS | NIH | National Cancer Institute (NCI)
• HHS | NIH | National Institute of Dental and Craniofacial Research (NIDCR)

Significant differences exist between the highly pathogenic (HP) porcine reproductive and respiratory syndrome virus (PRRSV) and its attenuated pathogenic (AP) strain in the ability to infect host cells. The mechanisms by which different virulent strains invade host cells remain relatively unknown. In this study, pulmonary alveolar macrophages (PAMs) are infected with HP‐PRRSV (HuN4) and AP‐PRRSV (HuN4‐F112) for 24 h, then harvested and subjected to label‐free quantitative MS. A total of 2849 proteins are identified, including 95 that are differentially expressed. Among them, 26 proteins are located on the membrane. The most differentially expressed proteins are involved in response to stimulus, metabolic process, and immune system process, which mainly have the function of binding and catalytic activity. Cluster of differentiation CD163, vimentin (VIM), and nmII as well as detected proteins are assessed together by string analysis, which elucidated a potentially different infection mechanism. According to the function annotations, PRRSV with different virulence may mainly differ in immunology, inflammation, immune evasion as well as cell apoptosis. This is the first attempt to explore the differential characteristics between HP‐PRRSV and its attenuated PRRSV infected PAMs focusing on membrane proteins which will be of great help to further understand the different infective mechanisms of HP‐PRRSV and AP‐PRRSV.

• attenuated
• highly pathogenic
• infection
• label-free quantitative proteomics
• membrane proteins

Hepatocellular carcinoma (HCC) is a complex disease with a multi-step carcinogenic process from preneoplastic lesions, including cirrhosis, low-grade dysplastic nodules (LGDNs), and high-grade dysplastic nodules (HGDNs) to HCC. There is only an elemental understanding of its molecular pathogenesis, for which a key problem is to identify when and how the critical transition happens during the HCC initiation period at a molecular level. In this work, for the first time, we revealed that LGDNs is the tipping point (i.e., pre-HCC state rather than HCC state) of hepatocarcinogenesis based on a series of gene expression profiles by a new mathematical model termed dynamic network biomarkers (DNB)—a group of dominant genes or molecules for the transition. Different from the conventional biomarkers based on the differential expressions of the observed genes (or molecules) for diagnosing a disease state, the DNB model exploits collective fluctuations and correlations of the observed genes, thereby predicting the imminent disease state or diagnosing the critical state. Our results show that DNB composed of 59 genes signals the tipping point of HCC (i.e., LGDNs). On the other hand, there are a large number of differentially expressed genes between cirrhosis and HGDNs, which highlighted the stark differences or drastic changes before and after the tipping point or LGDNs, implying the 59 DNB members serving as the early-warning signals of the upcoming drastic deterioration for HCC. We further identified the biological pathways responsible for this transition, such as the type I interferon signaling pathway, Janus kinase–signal transducers and activators of transcription (JAK–STAT) signaling pathway, transforming growth factor (TGF)-β signaling pathway, retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway, cell adhesion molecules, and cell cycle. In particular, pathways related to immune system reactions and cell adhesion were downregulated, and pathways related to cell growth and death were upregulated. Furthermore, DNB was validated as an effective predictor of prognosis for HCV-induced HCC patients by survival analysis on independent data, suggesting a potential clinical application of DNB. This work provides biological insights into the dynamic regulations of the critical transitions during multistep hepatocarcinogenesis.

• dynamic network biomarkers
• hepatocellular carcinoma
• low-grade dysplastic nodules
• tipping point

• hepatitis c virus (hcv)
• hepatoma cellular carcinoma (hcc)
• nore1a
• ras
• rna dependent rna polymerase (rdrp)
• cancer

Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) and Golgi protein 73 (GP73) is a serum biomarker for liver diseases and HCC. However, the mechanism underlying GP73 regulates HCV infection is largely unknown. Here, we revealed that GP73 acts as a novel negative regulator of host innate immunity to facilitate HCV infection. GP73 expression is activated and correlated with interferon-beta (IFN-β) production during HCV infection in patients’ serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase/extracellular regulated protein kinase (MEK/ERK) pathway. Detailed studies revealed that HCV infection activates MAVS that in turn recruits TRAF6 via TRAF-interacting-motifs (TIMs), and TRAF6 subsequently directly recruits GP73 to MAVS via coiled-coil domain. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation through proteasome-dependent pathway. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and nuclear factor κB (NF-κB) promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity. Finally, knock-down of GP73 down-regulates HCV infection and replication in Huh7-MAVSR cells and primary human hepatocytes (PHHs), but such repression is rescued by GP73m4 (a mutant GP73 resists to GP73-shRNA#4) in Huh7-MAVSR cells, suggesting that GP73 facilitates HCV infection. Taken together, we demonstrated that GP73 acts as a negative regulator of innate immunity to facilitate HCV infection by interacting with MAVS/TRAF6 and promoting MAVS/TRAF6 degradation. This study provides new insights into the mechanism of HCV infection and pathogenesis, and suggests that GP73 is a new potential antiviral target in the prevention and treatment of HCV associated diseases.

Golgi protein 73 (GP73) is a serum biomarker for liver diseases and hepatocellular carcinoma (HCC). In this study, the authors reveal that GP73 acts as a novel negative regulator of host innate immunity to facilitate hepatitis C virus (HCV) infection. GP73 expression is activated and correlated with IFN-β production during HCV infection in patients’ serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and MEK/ERK pathway. They further demonstrate that during viral infection, MAVS recruits TRAF6 that subsequently directly binds with GP73. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and NF-κB promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity and the facilitation of virus infection. These results reveal a novel mechanism by which GP73 acts as a novel negative regulator of host innate immunity to facilitate virus infection and also provide new insights into the therapeutic design of anti-HCV drugs.

• Adaptor Proteins, Signal Transducing/metabolism
• Antiviral Agents/metabolism
• Carcinoma, Hepatocellular/metabolism
• Cell Line
• Hepacivirus/isolation & purification
• Hepatitis C/metabolism
• Hepatitis C/virology
• Hepatocytes/virology
• Humans
• Interferon-beta/metabolism
• Interferons/metabolism
• Liver Neoplasms/metabolism
• Liver Neoplasms/virology
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• TNF Receptor-Associated Factor 6/metabolism
• Virus Replication/immunology

• Ministry of Science and Technology of the People's Republic of China
• National Natural Science Foundation of China
• National Health and Family Planning Commission of the People's Republic of China

• Cyclooxygenase-2
• Guanylate binding protein 5
• Influenza A virus
• Interferon signaling
• NF-κB-essential modulator

• hepatitis B virus
• interferon/Janus kinase/signal transducers and activators of transcription pathway
• matrix metalloproteinase 9
• type I IFN receptor 1

The mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK1/2/ERK1/2) cascade is involved in the replication of several members of the Flaviviridae family, including hepatitis C virus and dengue virus. The effects of the cascade on the replication of classical swine fever virus (CSFV), a fatal pestivirus of pigs, remain unknown. In this study, MEK2 was identified as a novel binding partner of the E2 protein of CSFV using yeast two-hybrid screening. The E2-MEK2 interaction was confirmed by glutathione S-transferase pulldown, coimmunoprecipitation, and laser confocal microscopy assays. The C termini of E2 (amino acids [aa] 890 to 1053) and MEK2 (aa 266 to 400) were mapped to be crucial for the interaction. Overexpression of MEK2 significantly promoted the replication of CSFV, whereas knockdown of MEK2 by lentivirus-mediated small hairpin RNAs dramatically inhibited CSFV replication. In addition, CSFV infection induced a biphasic activation of ERK1/2, the downstream signaling molecules of MEK2. Furthermore, the replication of CSFV was markedly inhibited in PK-15 cells treated with U0126, a specific inhibitor for MEK1/2/ERK1/2, whereas MEK2 did not affect CSFV replication after blocking the interferon-induced Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway by ruxolitinib, a JAK-STAT-specific inhibitor. Taken together, our results indicate that MEK2 positively regulates the replication of CSFV through inhibiting the JAK-STAT signaling pathway.

IMPORTANCE Mitogen-activated protein kinase kinase 2 (MEK2) is a kinase that operates immediately upstream of extracellular regulated kinase 1/2 (ERK1/2) and links to Raf and ERK via phosphorylation. Currently, little is known about the role of MEK2 in the replication of classical swine fever virus (CSFV), a devastating porcine pestivirus. Here, we investigated the roles of MEK2 and the MEK2/ERK1/2 cascade in the growth of CSFV for the first time. We show that MEK2 positively regulates CSFV replication. Notably, we demonstrate that MEK2 promotes CSFV replication through inhibiting the interferon-induced JAK-STAT signaling pathway, a key antiviral pathway involved in innate immunity. Our work reveals a novel role of MEK2 in CSFV infection and sheds light on the molecular basis by which pestiviruses interact with the host cell.

• Angiogenesis
• Cell-mediated immunity
• Epithelial–stromal interaction
• Fibroblast
• Growth factors
• Innate immunity
• Interferon
• Microenvironment
• Papillomavirus

• Animals
• Cellular Microenvironment
• Extracellular Matrix/metabolism
• Fibroblasts/pathology
• Fibroblasts/virology
• Humans
• Intercellular Signaling Peptides and Proteins/metabolism
• Papillomaviridae/physiology
• Stromal Cells/virology

• P30 GM110703 NIGMS NIH HHS
• R01 AI118904 NIAID NIH HHS

• PKR
• clinical trial
• interferon
• oncogenes
• viral oncolysis

• Antiviral activity
• Dengue virus infection
• ERK1/2
• Minocycline

• CYP4F12
• Hepatitis C virus
• Viral replication

• Gene regulation
• Hepatocarcinogenesis
• Hepatocellular carcinoma
• Human hepatoma cell growth
• Signaling pathway

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.

• direct-acting antiviral
• hepatitis C virus
• host-targeting agent
• viral resistance

• IFN/JAK/STAT pathway
• PKC/JNK/ERK/c-Jun cascade
• collagen triple helix repeat containing 1 (CTHRC1)
• hepatitis B virus
• immune evasion
• immune response

There is growing evidence that factors encoded by cytoplasmic replicating viruses functionally interact with components of the nucleocytoplasmic transport apparatus. They do so either to access the cell nucleus, thus affecting genes expression, or to interfere with nuclear transport functionality, hindering host immune response. Recent studies revealed that the hepatitis C virus (HCV) makes no exception, interacting with the host cell nuclear transport machinery at two different levels. On the one hand, small amounts of both core and NS5A localize within the host cell nucleus during productive infection, modulating gene expression and signaling functions to promote persistent infection. On the other hand, HCV infection causes a profound redistribution of certain nucleoproteins to the close proximity of endoplasmic reticulum membrane-derived viral replication factories, where viral RNA amplification occurs. These nucleoporins are believed to form nuclear pore complex-like structures, as suggested by their ability to recruit nuclear localization sequence-bearing proteins. Thus, both processes are linked to virus-induced persistence and pathogenesis, representing possible targets for the development of novel anti-HCV therapeutics.

• NPC
• Ran
• caspase
• exportin
• importin
• nuclear import
• nucleoporin
• replication factories