• Ankrd1
• Cardiac repair
• Cardiomyocyte proliferation
• Cyclin D1

• Animals
• Regeneration
• Myocytes, Cardiac/metabolism
• Mice
• Cyclin D1/metabolism
• Cyclin D1/genetics
• Cell Proliferation
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Myocardial Infarction/physiopathology
• Myocardial Infarction/metabolism
• Myocardial Infarction/pathology
• Myocardial Infarction/genetics
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism
• Heart/physiology
• Heart/physiopathology
• Animals, Newborn
• Mice, Inbred C57BL
• Muscle Proteins/genetics
• Muscle Proteins/metabolism
• Male

• Animals
• MAP Kinase Kinase Kinase 5/antagonists & inhibitors
• MAP Kinase Kinase Kinase 5/metabolism
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Mice
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/pathology
• Liver Cirrhosis/metabolism
• Disease Progression
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• p38 Mitogen-Activated Protein Kinases/metabolism
• p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
• Mice, Inbred BALB C
• Male
• Thioacetamide/toxicity
• Mitochondria/drug effects
• Mitochondria/metabolism
• Disease Models, Animal

• R01 DK139288 NIDDK NIH HHS

• HCV diagnosis biomarker
• machine learning algorithms
• molecular docking
• therapeutic target

• UMO-2020/37/B/NZ7/01466 National Science Centre, Cracow, Poland
• 002/RID/2018/19 Minister of Science and Higher Education "Regional Initiative of Excellence" in 2019-2022

The Chinese patent drug Yinzhihuang granule (YZHG) is used to treat hepatitis B. This research is aimed at exploring the multicomponent synergistic mechanism of YZHG in the treatment of inflammation-cancer transformation of hepar and at providing new evidence and insights for its clinical application.

To retrieve the components and targets of Yinzhihuang granules. The differentially expressed genes (DEGs) of hepar inflammation-cancer transformation were obtained from TTD, PharmGKB, and GEO databases. Construct the compound-prediction target network and the key module network using Cytoscape 3.7.1.

The results show that hepatitis B and hepatitis C shared a common target, MMP2. CDK1 and TOP2A may play an important role in the treatment with YZHG in hepatitis B inflammatory cancer transformation. KEGG pathway enrichment showed that key genes of modules 1, 2, and 4 were mainly enriched in the progesterone-mediated oocyte maturation signaling pathway and oocyte meiosis signaling pathway.

The multicomponent, multitarget, and multichannel pharmacological benefits of YZHG in the therapy of inflammation-cancer transition of hepar are directly demonstrated by network pharmacology, providing a scientific basis for its mechanism.

Cyclin‐dependent kinases (CDKs) are protein kinases that play a key role in cell division and transcriptional regulation. Recent studies have demonstrated the critical roles of CDKs in various viral infections. However, the molecular processes underpinning CDKs' roles in viral infection and host antiviral defense are unknown. This minireview briefly overviews CDKs' functions and highlights the most recent discoveries of CDKs' emerging roles during viral infections, thereby providing a scientific and theoretical foundation for antiviral regulation and shedding light on developing novel drug targets and therapeutic strategies against viral infection.

• CDKs
• DNA viruses
• RNA viruses
• viral infection

• Bronchial epithelial cells
• COVID-19
• Cytokine storm
• Gene ontology
• Immunological regulations
• Reactome pathways
• SARS-CoV-2
• Severe acute respiratory syndrome
• Signaling pathways
• Transcriptomics

The P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in CVB3-induced diseases. We previously demonstrated microRNA-21 has potential inhibitory effect on the MAP2K3 which locates upstream of P38 MAPK and was upregulated in mouse hearts upon CVB3 infection. However, the effect and underlying mechanism of miRNA-21 on CVB3 infection remain unclear.

We detected continuous changes of cellular miRNA-21 and P38 MAPK proteins expression profiling post CVB3 infection in vitro within 12 h. P38 MAPK signaling was inhibited by the specific inhibitor, small interfering RNA and miRNA-21 mimic in vitro, CVB3 replication, cell apoptosis rate and proliferation were detected. Viral load in the mice heart, cardiomyocyte apoptosis rate and histological of the heart were also detected in the mice model of viral myocarditis pretreated with miRNA-21-lentivirus.

We observed significant upregulation of miRNA-21 expression followed by suppression of the MAP2K3/P38 MAPK signaling in CVB3-infected Hela cells. The inactivation of the MAP2K3/P38 MAPK signaling by P38 MAPK specific inhibitor, small interfering RNA against MAP2K3, or miRNA-21 overexpression significantly inhibited viral progeny release from CVB3-infected cells. Mechanistically, when compared with control miRNA, miRNA-21 showed no effect on capsid protein VP1 expression and viral load within host cells, while significantly reversing CVB3-induced caspase-3 activation and cell apoptosis rate, further promoting proliferation of infected cells, which indicates the inhibitory effect of miRNA-21 on CVB3 progeny release. In the in vivo study, when compared with control miRNA, miRNA-21 pretreatment remarkably inactivated the MAP2K3/P38 MAPK signaling in mice and protected them against CVB3 infection as evidenced by significantly alleviated cell apoptosis rate, reduced viral titers, necrosis in the heart as well as by remarkably prolonged survival time.

miRNA-21 were reverse correlated with P38 MAPK activation post CVB3 infection, miRNA-21 overexpression significantly inhibited viral progeny release and decreased myocytes apoptosis rate in vitro and in vivo, suggesting that miRNA-21 may serve as a potential therapeutic agent against CVB3 infection through targeting the MAP2K3/P38 MAPK signaling.

• CVB3
• P38 MAPK
• Viral release
• miRNA-21

Hepatocellular carcinoma (HCC) is sexually disparate in humans, with a significantly increased prevalence in males. The molecular mechanisms by which the inhibition or development of liver cancer are facilitated require further investigation with regard to sex factors affecting disease progression. In the present study, functional signatures of differentially expressed genes (DEGs) were screened in female and male tumors via bioinformatics analysis. The following gene chip expression profiles were downloaded from the Gene Expression Omnibus: GSE19665, GSE23342 and GSE9843. They comprised cancerous and non-cancerous tissue from patients with HCC and included critical sex features. Further evaluation of selected DEGs in the two sexual groups was performed via hierarchical clustering analysis. Venn diagram and functional protein-protein interaction (PPI) network analyses were performed. Survival analysis of patients with differences in gene expression levels was subsequently performed using the Kaplan-Meier Plotter database. Certain identified DEGs were common in female and male tumor samples, whereas others exhibited a sexually-biased expression profile. Gene Ontology revealed that the cell cycle module ‘biological process’ was enriched in tumors derived from both sexes, whereas the metabolic pathways and drug metabolism modules were only significantly enriched in cancer tissues from male subjects. A number of hub DEGs in the cell cycle and p53 signaling pathways were involved in significant protein-protein interaction (PPI) modules, including CDK1 and CCNB1. These DEGs were upregulated in tumors derived from female subjects compared with those derived from male subjects, and could be used as markers of poor prognosis in male patients. Other genes, such as CYP3A4 and SERPINA4, were identified in metabolic pathways, and were downregulated in male compared with female subjects. These genes were associated with a decreased survival rate. The data demonstrated that sex differences in physiology may regulate the levels of gene expression and/or activity, including gene function associated with oncogenesis and the outcomes of liver cancer. Additional surveys are required to explore in detail the molecular mechanisms underlying the differences in gene expression between the two sexes during the development of liver cancer.

• Acetylation
• HDAC4
• Phosphorylation
• STAT1
• VSV
• Virotherapy

• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/virology
• Cell Line, Tumor
• Down-Regulation
• Hepatitis C/metabolism
• Histone Deacetylases/metabolism
• Humans
• Oncolytic Virotherapy/methods
• Oncolytic Viruses/physiology
• Repressor Proteins/metabolism
• Treatment Outcome
• Vesicular Stomatitis/virology
• Vesiculovirus/physiology
• Viral Core Proteins/metabolism

Fuzheng-Huayu (FZHY) tablet was formulated based on Chinese medicine theory in treating liver fibrosis. A clinical trial has indicated that FZHY can against hepatitis B-caused liver cirrhosis (HBC), but the underlying mechanism of FZHY efficacy is unclear. Here, we report that miRNA expression levels are remarkably changed when FZHY formula was used in HBC patient's treatment as a paradigm of trials. Then, we functionally characterize the significant impact of potential kernel miRNAs by miRNA-target network analysis. Enrichment analysis show that the FZHY formula dramatically effecting the molecular regulated module in HBC. Thus, we infer that FZHY plays a critical function in HBC treatment process and directly regulated many important pathways, including but not limited to cell cycle, p53 signaling pathway, and TGF-β signaling pathway, suggesting a new strategy for investigating the molecular mechanism of FZHY treatment.

Enterovirus 71 (EV71) is one of the major etiological pathogens of hand, foot and mouth disease (HFMD) and can cause severe cerebral and pulmonary complications and even fatality. MicroRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing various physiological and pathological processes. Increasing evidence suggests that miRNAs act as key effector molecules in the complicated pathogen-host interactions. However, the roles of miRNAs in EV71 infection and pathogenesis are not well understood.

To identify special miRNAs involved in EV71 infection, a microarray assay was performed to study the expression pattern of miRNAs in EV71-infected human rhabdomyosarcoma cells (RD cells) and uninfected RD cells. We further predicted the putative target genes for the dysregulated miRNAs using the online bioinformatic algorithms (TargetScan, miRanda and PicTar) and carried out functional annotation including GO enrichment and KEGG pathway analysis for miRNA predicted targets. Then, the results of microarray were further confirmed by quantitative RT-PCR.

Totally, 45 differentially expressed miRNAs ware identified by microarray, among which 36 miRNAs were up-regulated and 9 were down-regulated. 7166 predicted target genes for the dysregulated miRNAs were revealed by using TargetScan in conjunction with miRanda and PicTar. The GO annotation suggested that predicted targets of miRNAs were enriched into the category of signal transduction, regulation of transcription, metabolic process, protein phosphorylation, apoptotic process and immune response. KEGG pathway analysis suggested that these predicted target genes were involved in many important pathways, mainly including endocytosis and focal adhesion, MAPK signaling pathway, hypertrophic cardiomyopathy, melanogenesis and ErbB signaling pathway. The expression levels of 8 most differentially up-regulated miRNAs and 3 most differentially down-regulated miRNAs were confirmed by qRT-PCR. The expressions of hsa-miR-4530, hsa-miR-4492, hsa-miR-6125, hsa-miR-494-3p, hsa-miR-638, hsa-miR-6743-5p, hsa-miR-4459 and hsa-miR-4443 detected by qRT-PCR were consistent with the microarray data.

These results might extend our understanding to the regulatory mechanism of miRNAs underlying the pathogenesis of EV71 infection, thus strengthening the preventative and therapeutic strategies of HFMD caused by EV71.

• HEK293T cells
• SCYL1-BP1
• knockdown
• microRNA
• network

• BRCA2 Protein/genetics
• BRCA2 Protein/metabolism
• Bone Morphogenetic Protein Receptors, Type II/genetics
• Bone Morphogenetic Protein Receptors, Type II/metabolism
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Knockdown Techniques
• Golgi Matrix Proteins
• HEK293 Cells
• Humans
• MicroRNAs
• RNA Interference
• Reproducibility of Results
• Vesicular Transport Proteins/genetics
• Vesicular Transport Proteins/metabolism

• enterovirus 71
• viral replication
• jnk1/2
• p38 mapk
• dendritic cells

• Cells, Cultured
• Cytokines/metabolism
• Dendritic Cells/virology
• Enterovirus A, Human/physiology
• Host-Pathogen Interactions
• Humans
• Mitogen-Activated Protein Kinase 8/metabolism
• Mitogen-Activated Protein Kinase 9/metabolism
• Signal Transduction
• Virus Replication
• p38 Mitogen-Activated Protein Kinases/metabolism

• HCV persistence
• autophagy
• innate immunity

Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for many diseases. In this study, the characteristics among excessive, excessive-deficient, and deficient syndromes of Hepatocellular carcinoma (HCC) were studied using miRNA array data. We first calculated the differentially expressed miRNAs based on random module t-test and classified three TCM syndromes of HCC using SVM method. Then, the weighted miRNA-target networks were constructed for different TCM syndromes using predicted miRNA targets. Subsequently, the prioritized target genes of upexpression network of TCM syndromes were analyzed using DAVID online analysis. The results showed that there are distinctly different hierarchical cluster and network structure of TCM syndromes in HCC, but the excessive-deficient combination syndrome is extrinsically close to deficient syndrome. GO and pathway analysis revealed that the molecular mechanisms of excessive-deficient and deficient syndromes of HCC are more complex than excessive syndrome. Furthermore, although excessive-deficient and deficient syndromes have similar complex mechanisms, excessive-deficient syndrome is more involved than deficient syndrome in development of cancer process. This study suggested that miRNAs might be important mediators involved in the changing process from excessive to deficient syndromes and could be potential molecular markers for the diagnosis of TCM syndromes in HCC.

Host cell lipid droplets (LD) are essential in the hepatitis C virus (HCV) life cycle and are targeted by the viral capsid core protein. Core-coated LDs accumulate in the perinuclear region and facilitate viral particle assembly, but it is unclear how mobility of these LDs is directed by core. Herein we used two-photon fluorescence, differential interference contrast imaging, and coherent anti-Stokes Raman scattering microscopies, to reveal novel core-mediated changes to LD dynamics. Expression of core protein’s lipid binding domain II (DII-core) induced slower LD speeds, but did not affect directionality of movement on microtubules. Modulating the LD binding strength of DII-core further impacted LD mobility, revealing the temporal effects of LD-bound DII-core. These results for DII-core coated LDs support a model for core-mediated LD localization that involves core slowing down the rate of movement of LDs until localization at the perinuclear region is accomplished where LD movement ceases. The guided localization of LDs by HCV core protein not only is essential to the viral life cycle but also poses an interesting target for the development of antiviral strategies against HCV.

• Biological Transport
• Cell Line, Tumor
• Hepacivirus/physiology
• Host-Pathogen Interactions
• Humans
• Lipid Metabolism
• Organelle Size
• Organelles/metabolism
• Organelles/virology
• Protein Binding
• Viral Core Proteins/metabolism
• Virus Assembly

• MC_UU_12014/1 Medical Research Council
• CIHR

Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for chronic hepatitis B (CHB), which requires a traditional diagnosis method to distinguish the TCM syndrome. In this study, we study the differences and similarities among excessive, excessive-deficient, and deficient syndromes, by an integrative and comparative analysis of weighted miRNA expression or miRNA-target network in CHB patients. We first calculated the differential expressed miRNAs based on random module t-test and classified three CHB TCM syndromes using SVM method. Then, miRNA target genes were obtained by validated database and predicted programs subsequently, the weighted miRNA-target networks were constructed for different TCM syndromes. Furthermore, prioritize target genes of networks of CHB TCM syndromes progression analyzed using DAVID online analysis. The results have shown that the difference between TCM syndromes is distinctly based on hierarchical cluster and network structure. GO and pathway analysis implicated that three CHB syndromes more likely have different molecular mechanisms, while the excessive-deficient and deficient syndromes are more dangerous than excessive syndrome in the process of tumorigenesis. This study suggested that miRNAs are important mediators for TCM syndromes classification as well as CHB development progression and therefore could be potential diagnosis and therapeutic molecular markers.

Hepatitis C virus (HCV), a hepatotropic virus, is a single stranded-positive RNA virus of ~9,600 nt. length belonging to the Flaviviridae family. HCV infection causes acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that HCV-coding proteins interact with host-cell factors that are involved in cell cycle regulation, transcriptional regulation, cell proliferation and apoptosis. Severe inflammation and advanced liver fibrosis in the liver background are also associated with the incidence of HCV-related HCC. In this review, we discuss the mechanism of hepatocarcinogenesis in HCV-related liver diseases.

• Carcinogenesis
• Cirrhosis
• Fibrosis
• Hepatitis C virus
• Hepatocellular carcinoma
• Inflammation

• Cell Cycle Checkpoints
• Cell Line
• Gene Expression Regulation
• Genotype
• Hepacivirus/physiology
• Humans
• Viral Load
• Virus Replication

The double-stranded RNA-dependent protein kinase PKR plays multiple roles in cells, in response to different stress situations. As a member of the interferon (IFN)‑Stimulated Genes, PKR was initially recognized as an actor in the antiviral action of IFN, due to its ability to control translation, through phosphorylation, of the alpha subunit of eukaryotic initiation factor 2 (eIF2α). As such, PKR participates in the generation of stress granules, or autophagy and a number of viruses have designed strategies to inhibit its action. However, PKR deficient mice resist most viral infections, indicating that PKR may play other roles in the cell other than just acting as an antiviral agent. Indeed, PKR regulates several signaling pathways, either as an adapter protein and/or using its kinase activity. Here we review the role of PKR as an eIF2α kinase, its participation in the regulation of the NF-κB, p38MAPK and insulin pathways, and we focus on its role during infection with the hepatitis C virus (HCV). PKR binds the HCV IRES RNA, cooperates with some functions of the HCV core protein and may represent a target for NS5A or E2. Novel data points out for a role of PKR as a pro-HCV agent, both as an adapter protein and as an eIF2α-kinase, and in cooperation with the di-ubiquitin-like protein ISG15. Developing pharmaceutical inhibitors of PKR may help in resolving some viral infections as well as stress-related damages.

• Animals
• Enzyme Activation
• Hepatitis C/genetics
• Hepatitis C/immunology
• Hepatitis C/metabolism
• Humans
• Protein Transport
• RNA, Double-Stranded/metabolism
• Signal Transduction
• Stress, Physiological
• eIF-2 Kinase/genetics
• eIF-2 Kinase/metabolism

• Actin Depolymerizing Factors/metabolism
• Breast/cytology
• Breast/enzymology
• Breast/pathology
• Breast Neoplasms/enzymology
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Membrane/enzymology
• Cell Membrane/pathology
• Cell Movement
• Enzyme Activation
• Female
• Humans
• Intracellular Signaling Peptides and Proteins/metabolism
• Lim Kinases/metabolism
• Protein Serine-Threonine Kinases/metabolism
• Signal Transduction
• eIF-2 Kinase/metabolism
• p38 Mitogen-Activated Protein Kinases/metabolism

• R01 AA015407 NIAAA NIH HHS
• R01 AA017226 NIAAA NIH HHS
• AA017226 NIAAA NIH HHS

Hepatitis C virus (HCV) is a significant health problem facing the world. This virus infects more than 170 million people worldwide and is considered the major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Although the sexual behavior is considered as a high risk factor for HCV infection, the transmission of HCV infection through sexual means, is less frequently. Currently, the available treatment for patients with chronic HCV infection is interferon based therapies alone or in combination with ribavirin and protease inhibitors. Although a sustained virological response of patients to the applied therapy, a great portion of patients did not show any response. HCV infection is mostly associated with progressive liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Although the focus of many patients and clinicians is sometimes limited to that problem, the natural history of HCV infection (HCV) is also associated with the development of several extrahepatic manifestations including dermatologic, rheumatologic, neurologic, and nephrologic complications, diabetes, arterial hypertension, autoantibodies and cryglobulins. Despite the notion that HCV-mediated extrahepatic manifestations are credible, the mechanism of their modulation is not fully described in detail. Therefore, the understanding of the molecular mechanisms of HCV-induced alteration of intracellular signal transduction pathways, during the course of HCV infection, may offer novel therapeutic targets for HCV-associated both hepatic and extrahepatic manifestations. This review will elaborate the etiopathogenesis of HCV-host interactions and summarize the current knowledge of HCV-associated diseases and their possible therapeutic strategies.

• Hepatitis C virus
• Hepatocellular carcinoma
• Extrahepatic
• Signalling
• Therapy

Incidence of hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) has been increasing in the United States and Europe during recent years. Although HCV-associated HCC shares many pathological characteristics with other types of HCC, its molecular mechanisms of progression remain elusive.

To investigate the underlying pathology, we developed a systematic approach to identify deregulated biological networks in HCC by integrating gene expression profiles with high-throughput protein-protein interaction data. We examined five stages including normal (control) liver, cirrhotic liver, dysplasia, early HCC and advanced HCC.

Among the five consecutive pathological stages, we identified four networks including precancerous networks (Normal-Cirrhosis and Cirrhosis-Dysplasia) and cancerous networks (Dysplasia-Early HCC, Early-Advanced HCC). We found little overlap between precancerous and cancerous networks, opposite to a substantial overlap within precancerous or cancerous networks. We further found that the hub proteins interacted with HCV proteins, suggesting direct interventions of these networks by the virus. The functional annotation of each network demonstrates a high degree of consistency with current knowledge in HCC. By assembling these functions into a module map, we could depict the stepwise biological functions that are deregulated in HCV-induced hepatocarcinogenesis. Additionally, these networks enable us to identify important genes and pathways by developmental stage, such as LCK signalling pathways in cirrhosis, MMP genes and TIMP genes in dysplastic liver, and CDC2-mediated cell cycle signalling in early and advanced HCC. CDC2 (alternative symbol CDK1), a cell cycle regulatory gene, is particularly interesting due to its topological position in temporally deregulated networks.

Our study uncovers a temporal spectrum of functional deregulation and prioritizes key genes and pathways in the progression of HCV induced HCC. These findings present a wealth of information for further investigation.

LZAP (Cdk5rap3, C53) is a putative tumor suppressor that inhibits RelA, Chk1 and Chk2 and activates p53. LZAP is lost in a portion of human head and neck squamous cell carcinoma and experimental loss of LZAP expression is associated with enhanced invasion, xenograft tumor growth and angiogenesis. p38 MAPK can increase or decrease proliferation and cell death depending on cellular context. LZAP has no known enzymatic activity, implying that its biological functions are likely mediated by its protein-protein interactions. To gain further insight into LZAP activities, we searched for LZAP-associated proteins (LAPs). Here we show that the LZAP binds p38, alters p38 cellular localization, and inhibits basal and cytokine-stimulated p38 activity. Expression of LZAP inhibits p38 phosphorylation in a dose-dependent fashion while loss of LZAP enhances phosphorylation and activation with resultant phosphorylation of p38 downstream targets. Mechanistically, the ability of LZAP to alter p38 phosphorylation depended, at least partially, on the p38 phosphatase, Wip1. Expression of LZAP increased both LZAP and Wip1 binding to p38. Taken together, these data suggest that LZAP activity includes inhibition of p38 phosphorylation and activation.

• Cell Compartmentation
• Cell Cycle Proteins
• Humans
• Intracellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/physiology
• Nerve Tissue Proteins/metabolism
• Nerve Tissue Proteins/physiology
• Phosphoprotein Phosphatases/metabolism
• Phosphorylation
• Protein Binding/physiology
• Protein Phosphatase 2C
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Proteins
• p38 Mitogen-Activated Protein Kinases/analysis
• p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
• p38 Mitogen-Activated Protein Kinases/metabolism

• R01 DE013173 NIDCR NIH HHS
• R56 DE013173 NIDCR NIH HHS
• 2R56 DE013173-10 NIDCR NIH HHS
• # 2R01 DE013173 NIDCR NIH HHS

Severe acute respiratory syndrome (SARS) is a respiratory illness with variable symptoms that was recognized as the first near-pandemic infectious disease of the twenty-first century. A novel human coronavirus, named SARS coronavirus (SARS-CoV), derived from SARS patients was reported as the etiologic agent of SARS. Studying the signaling pathways of SARS-infected cells is key to understanding the molecular mechanism of SARS viral infection. Cell death is observed in cultured Vero E6 cells after SARS-CoV infection. From SARS-CoV infection to cell death, p38 mitogen-activated protein kinase (MAPK) is a key participant in the determination of cell death and survival. Two signaling pathways comprising signal transducer and activator of transcription 3 (STAT3) and p90 ribosomal S6 kinase (p90RSK) are downstream of p38 MAPK. AKT and JNK (Jun NH₂-terminal kinase) signaling pathways are important to establish persistent infection of SARS-CoV in Vero E6 cells. Expression studies of SARS-CoV proteins indicate that the viral proteins are able to activate signaling pathways of host cells. The study of signaling pathways in SARS-CoV patients is difficult to perform compared with in vitro studies due to the effects of the human immune system. This review highlights recent progress in characterizing signal transduction pathways in SARS-CoV-infected cells in vitro and in vivo.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Studies indicate that the development of HCC is related to signal transduction of Ras-MAPK.P38MAPK, an important member of the family of mitogen-activated protein kinases. P38MAPK participates in cell proliferation, apoptosis and differentiation and plays a key role in cell apoptosis. P38MAPK is closely related with carcinogenesis, rapid generation and infinite growth of liver cancer and plays a role in the occurrence and development of liver cancer induced by organics, HBV and HCV. Drugs exert their anti-tumor effects through p38MAPK which also takes part in the formation of drug resistance to HCC. This paper reviews the advances in studies on p38MAPK-related HCC.

• Hepatocellular carcinoma
• Mitogen-activated protein kinases
• p38 mitogen-activated protein kinase

• Animals
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Cell Proliferation
• Clofibrate/pharmacology
• DNA Damage
• Fatty Acids/metabolism
• Fatty Liver/pathology
• Fatty Liver/virology
• Hepatitis C, Chronic/complications
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Heterozygote
• Homozygote
• Hypolipidemic Agents/pharmacology
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Mice
• Mice, Transgenic
• Mitochondria, Liver/metabolism
• Oxidation-Reduction
• Oxidative Stress
• PPAR alpha/agonists
• PPAR alpha/genetics
• PPAR alpha/metabolism
• Triglycerides/metabolism
• Viral Core Proteins/genetics
• Viral Core Proteins/metabolism

• Adenocarcinoma/drug therapy
• Adenocarcinoma/metabolism
• Adenosine Diphosphate/pharmacology
• Adenosine Triphosphate/analogs & derivatives
• Adenosine Triphosphate/pharmacology
• Antineoplastic Agents/pharmacology
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Drug Synergism
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Mitogen-Activated Protein Kinases/metabolism
• NF-kappa B p50 Subunit/metabolism
• Receptors, Purinergic P2/metabolism
• Signal Transduction/drug effects
• Up-Regulation/drug effects