Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states.

The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved in a chain of signal transduction events bringing signals from the external environment of a cell to specific sites in the genome. MSK1/2 phosphorylate histone H3 at multiple sites, resulting in chromatin remodeling at regulatory elements of target genes and the induction of gene expression. Several transcription factors (RELA of NF-κB and CREB) are also phosphorylated by MSK1/2 and contribute to induction of gene expression. In response to signal transduction pathways, MSK1/2 can stimulate genes involved in cell proliferation, inflammation, innate immunity, neuronal function, and neoplastic transformation. Abrogation of the MSK-involved signaling pathway is among the mechanisms by which pathogenic bacteria subdue the host's innate immunity. Depending on the signal transduction pathways in play and the MSK-targeted genes, MSK may promote or hinder metastasis. Thus, depending on the type of cancer and genes involved, MSK overexpression may be a good or poor prognostic factor. In this review, we focus on mechanisms by which MSK1/2 regulate gene expression, and recent studies on their roles in normal and diseased cells.

Identification of key candidate genes and pathways associated with colorectal aberrant crypt foci-to-adenoma-to-carcinoma progression.

AIM: The present study aimed to detect key candidate genes and pathways involved in colorectal aberrant crypt foci-to-adenoma-to-carcinoma progression. BACKGROUND: Although colorectal cancer (CRC) is the third most common type of cancer, the involved signaling pathways and driver-genes remain largely unclear. CRC begins with the malignant transformation of precancerous lesions including aberrant crypt foci (ACF) and benign adenomatous polyp or adenoma. METHODS: A list of formerly reported ACF, adenoma, and CRC-associated proteins was obtained from GeneCards, and then the data in online David Bioinformatics Resources was analyzed. The protein-protein interactions were surveyed utilizing String database and Cytoscape software. After hubs and bottlenecks were recognized, the key genes and pathways were identified through different bioinformatics analysis. RESULTS: The most important pathways associated with colorectal aberrant crypt foci-to-adenoma progression were attributed to "pathways in cancer" and "chemokine signaling pathway" and those in adenoma-to-carcinoma progression were related to "pathways in cancer," "chemokine signaling pathway," and "Ras signaling pathway." The genes participating in these pathways are key ones. Furthermore, PRKACB, CUL2, and GSK3B were significant as the seed in the clusters related to adenoma and GNB1, RALBP1, ROCK1, and IKBKG in the clusters related to cancer. CONCLUSION: The key candidate genes and pathways in progress CRC formed precursor lesions were identified by integrated bioinformatics analysis. The results could lead to a better understanding of the cause and underlying molecular events as well as detection of therapeutic targets for CRC.

Proteomic study of advanced cirrhosis based on HCV to reveal potential biomarkers.

AIM: We aimed to carry out proteomic assessment of long-term effects of hepatitis C on liver. BACKGROUND: Cirrhosis is a condition where liver is damaged and loses its efficiency, and has the high rate of mortality in the world. Proteome profiling may help to identify important proteins and find the pathogenesis Cirrhosis is a condition where liver is damaged and loses its efficiency, and has the high rate of mortality in the world. Proteome profiling may help to identify important proteins and find the pathogenesis. METHODS: Here, by the application of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), combined with (MALDI-TOF-TOF MS), proteome profile of decompensated HCV cirrhosis is determined compared to healthy matched controls. Furthermore, Cytoscape has used network analysis. The proteome comparison between two groups identified proteins with significant expression changes (p<0.05 and fold change ≥ 1.5). RESULTS: We found upregulation of IGHA1, C3, A1BG, IGKC and one isoform of HP. Also, lower expression of APOA4 and the other spot of HP in advanced cirrhosis patients were revealed based on HCV compared to matched controls. According to network analysis, ALB has been introduced as a key protein, which may play an important role in pathogenesis. CONCLUSION: Integration of the proteomics with protein interaction data led to the identification of several novel key proteins related to the immune system that may reflect the long-term effects of hepatitis C virus on the liver, and can introduce as therapeutic targets for advanced HCV- cirrhosis.

Introducing Potential Key Proteins and Pathways in Human Laryngeal Cancer: A System Biology Approach.

The most common malignant neoplasm of the head and neck region is laryngeal cancer which presents a significant international health problem. The present study aims to screen potential proteins related to laryngeal cancer by network analysis to further understanding disease pathogenesis and biomarker discovery. Differentially expressed proteins were extracted from literatures of laryngeal cancer that compare proteome profiling of patient>s tissue with healthy controls. The PPI network analyzed for up and down regulated proteins with Cytoscape Version 3.4. After PPI construction, topological properties of the two networks have been analyzed. Besides, by using MCODE. the Gene Ontology (GO) analysis, the related modules and pathways were examined. Our study screened 275 differentially changed proteins, including 136 up- and 139 down-regulated proteins. For each network, it has been considered 20 key proteins as hub and 20 as bottleneck. A number of 26 hub-bottleneck nodes is introduced for the two networks. A total of 11 modules including 6 downregulated and 5 upregulated network modules were obtained. The most significant GO function in the significant upregulated module was the RNA processing, and the most significant one in the downregulated module with highest score was the respiratory electron transport chain. Among 275 investigated proteins, 12 crucial proteins are determined that 4 of them can be introduce as a possible biomarker panel including YWHAZ, PPP2R1A, HSP90AA1, and CALM3 for human laryngeal cancer.

Serum Proteomic Profiling of Obsessive-Compulsive Disorder, Washing Subtype: A Preliminary Study.

INTRODUCTION: Obsessive-Compulsive Disorder (OCD) is a disabling mental condition that its proteomic profiling is not yet investigated. Proteomics is a valuable tool to discover biomarker approaches. It can be helpful to detect protein expression changes in complex disorders such as OCD. METHODS: Here, by the application of 2D gel electrophoresis (2DE), a pilot study of serum proteome profile of females with washing subtype of OCD was performed. Serum samples were obtained from females with washing subtype of OCD. Following the protein extraction from the serum with acetone perception, the samples were subjected to 2DE for separation based on pI and molecular weight (MW) with triple replications. Finally, the protein spots were visualized using Coomassie blue staining method and analyzed by Progenesis SameSpots software. Furthermore, protein-protein interaction (PPI) network analysis was handled by the application of Cytoscape software. RESULTS: The results suggested that 41 matched spots demonstrated significant expression alterations among which 5 proteins including immunoglobulin heavy constant alpha-1 (IGHA1), apolipoprotein A-4 (APOA4), haptoglobin (HP), protein α-1-antitrypsin (SERPINA1), and component 3 (C3) were identified by database query. Additionally, PPI network analysis indicated the central role of SERPINA1 and C3 in the network integrity. However, albumin (ALB), amyloid precursor protein (APP), and protein α-1-antitrypsin (APOA1) proteins were important in OCD PPI network as well. The identified proteins were related to 3 processes: acute-phase response, hydrogen peroxide catabolic process, and regulation of triglyceride metabolic process. CONCLUSION: It was concluded that these proteins may have a fundamental role in OCD pathogenesis. Moreover, the dysregulation of inflammatory and antioxidant systems in OCD risk was suggested by the current study. However, evaluation of bigger sample sizes and application of mass spectrometry are essential requirements to confirm this preliminary evaluation.

Er:YAG Laser and Cyclosporin A Effect on Cell Cycle Regulation of Human Gingival Fibroblast Cells.

Introduction: Periodontitis is a set of inflammatory disorders characterized by periodontal attachment loss and alveolar bone resorption. Because of deficiency in periodontitis mechanical therapy, this study was aimed to explore the molecular influence of the erbiumdoped: yttrium aluminum garnet (Er:YAG) laser and cyclosporin A (CsA) on human gingival fibroblasts (HGFs) for improvement in periodontal diseases therapy. Methods: We focused on articles that studied the proteome profiles of HGFs after treatment with laser irradiation and application of CsA. The topological features of differentially expressed proteins were analyzed using Cytoscape Version 3.4.0 followed by module selection from the protein-protein interaction (PPI) network using Cluster ONE plugin. In addition, we performed gene ontology (GO) enrichment analysis for the densely connected region and key proteins in both PPI networks. Results: Analysis of PPI network of Er:YAG laser irradiation on HGFs lead to introducing YWHAZ, VCP, HNRNPU, YWHAE, UBA52, CLTC, FUS and IGHG1 as key proteins while similar analysis revealed that ACAT1, CTSD, ALDOA, ANXA2, PRDX1, LGALS3, ARHGDI and EEF1A1 are the crucial proteins related to the effect of drug. GO enrichment analysis of hubbottleneck proteins of the 2 networks showed the different significant biological processes and cellular components. The functional enrichments of module of Er:YAG laser network are included as fatty acid transmembrane transport, cytokinesis, regulation of RNA splicing and asymmetric protein localization. There are not any significant clusters in network of HGF treated by CsA. Conclusion: The results indicate that there are 2 separate biomarker panels for the 2 treatment methods.

Diabetic Retinopathy and Laser Therapy in Rats: A Protein-Protein Interaction Network Analysis.

Introduction: Diabetic retinopathy (DR) is a serious microvascular complication of diabetes which can cause vision loss or blindness ultimately. Non enzymatic glycation of proteins leads to advanced glycation end products (AGEs) in DR. Since laser therapy is a well-established method, in this study, protein-protein interaction (PPI) network is applied for protein targets in DR disease in rats treated by laser. Methods: In this study, we focused on articles that investigated and compared the proteome profiles of DR rats with healthy control and also DR rats before and after laser therapy. The networks of related differentially expressed proteins were explored using Cytoscape version 3.3.0, the PPI analysis methods and ClueGO. Results: Analysis of PPI network of 37 related proteins to DR rats including 108 nodes, introduced 10 hub-bottleneck proteins and 5 concerned biochemical pathways. On the other hand, PPI analysis of related proteins to DR rats before and after laser therapy corresponded to 33 proteins and 2 biological pathways. Discussion: Centrality and cluster screening identified hub-bottelneck genes, including Aldoa, HSPD1, Pgam2, Mapk3, SLC2A4, Ctnnb1, Ywhab, HSPA8, GAPDH and Actb for DR rats versus healthy control and ENO1, Aldoa, GAPDH for DR samples after laser therapy. CONCLUSION: Gene expression analysis of the DR samples treated via laser therapy provides a molecular evidence in support of the therapeutic effect of laser.

Protein-protein interaction network of celiac disease.

AIM: The aim of this study is to investigate the Protein-Protein Interaction Network of Celiac Disease. BACKGROUND: Celiac disease (CD) is an autoimmune disease with susceptibility of individuals to gluten of wheat, rye and barley. Understanding the molecular mechanisms and involved pathway may lead to the development of drug target discovery. The protein interaction network is one of the supportive fields to discover the pathogenesis biomarkers for celiac disease. MATERIAL AND METHODS: In the present study, we collected the articles that focused on the proteomic data in celiac disease. According to the gene expression investigations of these articles, 31 candidate proteins were selected for this study. The networks of related differentially expressed protein were explored using Cytoscape 3.3 and the PPI analysis methods such as MCODE and ClueGO. RESULTS: According to the network analysis Ubiquitin C, Heat shock protein 90kDa alpha (cytosolic and Grp94); class A, B and 1 member, Heat shock 70kDa protein, and protein 5 (glucose-regulated protein, 78kDa), T-complex, Chaperon in containing TCP1; subunit 7 (beta) and subunit 4 (delta) and subunit 2 (beta), have been introduced as hub-bottlnecks proteins. HSP90AA1, MKKS, EZR, HSPA14, APOB and CAD have been determined as seed proteins. CONCLUSION: Chaperons have a bold presentation in curtail area in network therefore these key proteins beside the other hub-bottlneck proteins may be a suitable candidates biomarker panel for diagnosis, prognosis and treatment processes in celiac disease.

Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases.

Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies.

Protein-protein interaction network analysis of cirrhosis liver disease.

AIM: Evaluation of biological characteristics of 13 identified proteins of patients with cirrhotic liver disease is the main aim of this research. BACKGROUND: In clinical usage, liver biopsy remains the gold standard for diagnosis of hepatic fibrosis. Evaluation and confirmation of liver fibrosis stages and severity of chronic diseases require a precise and noninvasive biomarkers. Since the early detection of cirrhosis is a clinical problem, achieving a sensitive, specific and predictive novel method based on biomarkers is an important task. METHODS: Essential analysis, such as gene ontology (GO) enrichment and protein-protein interactions (PPI) was undergone EXPASy, STRING Database and DAVID Bioinformatics Resources query. RESULTS: Based on GO analysis, most of proteins are located in the endoplasmic reticulum lumen, intracellular organelle lumen, membrane-enclosed lumen, and extracellular region. The relevant molecular functions are actin binding, metal ion binding, cation binding and ion binding. Cell adhesion, biological adhesion, cellular amino acid derivative, metabolic process and homeostatic process are the related processes. Protein-protein interaction network analysis introduced five proteins (fibroblast growth factor receptor 4, tropomyosin 4, tropomyosin 2 (beta), lectin, Lectin galactoside-binding soluble 3 binding protein and apolipoprotein A-I) as hub and bottleneck proteins. CONCLUSION: Our result indicates that regulation of lipid metabolism and cell survival are important biological processes involved in cirrhosis disease. More investigation of above mentioned proteins will provide a better understanding of cirrhosis disease.

Evaluation of liver cirrhosis and hepatocellular carcinoma using Protein-Protein Interaction Networks.

AIM: In the current study, we analysised only the articles that investigate serum proteome profile of cirrhosis patients or HCC patients versus healthy controls. BACKGROUND: Increased understanding of cancer biology has enabled identification of molecular events that lead to the discovery of numerous potential biomarkers in diseases. Protein-protein interaction networks is one of aspect that could elevate the understanding level of molecular events and protein connections that lead to the identification of genes and proteins associated with diseases. METHODS: Gene expression data, including 63 gene or protein names for hepatocellular carcinoma and 29 gene or protein names for cirrhosis, were extracted from a number of previous investigations. The networks of related differentially expressed genes were explored using Cytoscape and the PPI analysis methods such as MCODE and ClueGO. Centrality and cluster screening identified hub genes, including APOE, TTR, CLU, and APOA1 in cirrhosis. RESULTS: CLU and APOE belong to the regulation of positive regulation of neurofibrillary tangle assembly. HP and APOE involved in cellular oxidant detoxification. C4B and C4BP belong to the complement activation, classical pathway and acute inflammation response pathway. Also, it was reported TTR, TFRC, VWF, CLU, A2M, APOA1, CKAP5, ZNF648, CASP8, and HSP27 as hubs in HCC. In HCC, these include A2M that are corresponding to platelet degranulation, humoral immune response, and negative regulation of immune effector process. CLU belong to the reverse cholesterol transport, platelet degranulation and human immune response. APOA1 corresponds to the reverse cholesterol transport, platelet degranulation and humoral immune response, as well as negative regulation of immune effector process pathway. CONCLUSION: In conclusion, this study suggests that there is a common molecular relationship between cirrhosis and hepatocellular cancer that may help with identification of target molecules for early treatment that is essential in cancer therapy.

The Association between Polymorphismsin Insulin and Obesity Related Genesand Risk of Colorectal Cancer.

Colon cancer is the cancer of the large intestine (colon), which is located in the lower part of digestive system. Colon cancer is the third most common cancer in men and the second in women worldwide.Genetic background is thought to play a role in modulating individual risks of this cancer.Many studies support an association between insulin pathway gene polymorphisms and regulation of tumor cell biology in colorectal cancer. This review examines the role of polymorphisms of insulin and obesity pathway genes (IGFs, INS, INSR, ADIPOQ, ADIPOQR, LEP and LEPR) in development of colorectal cancer.

The -4817 G>A (rs2238136) variant of the vitamin D receptor gene: a probable risk factor for colorectal cancer.

Vitamin D appears to have anti-tumor activities in the large bowel. Our aim was to investigate whether -4817 G>A (rs2238136) polymorphism located at 5'-untranslated region (5'-UTR) of the human vitamin D receptor (VDR) gene was associated with colorectal cancer (CRC) risk. We conducted a case-control study and VDR genotypes, determined by Bpu10I restriction endonuclease digestion of PCR-amplified DNA, were performed on 327 cases with CRC and 327 controls. The distribution of VDR -4817 G>A genotypes and alleles differed significantly between cases with CRC and controls even after adjustment for confounding factors such as age, BMI, sex, and smoking status. Individuals carrying the "AA" genotype had a 2.09-fold increased risk compared with those with "GG" genotype (P = 0.016, OR = 2.09, 95% CI = 1.15-3.78) and a 1.87-fold increased risk compared with those with "GG and GA" genotypes (P = 0.033, OR = 1.87, 95% CI = 1.05-3.33) for CRC. Furthermore, the VDR "A" allele was significantly overrepresented in cases with CRC than controls (P = 0.044; OR = 1.28, 95% CI = 1.01-1.63). Interestingly, the analysis of the SNP revealed that all these associations were stronger for women subjects than for all subjects combined. These data indicated for the first time a direct association between "AA" genotype of VDR gene -4817 G>A polymorphism and CRC, with a stronger association for female subjects. However, our findings remain to be confirmed in other populations.

Association of leptin receptor gene Gln223Arg polymorphism with susceptibility to colorectal cancer.

AIM: Leptin is a 16 kDa polypeptide hormone which secreted by adipose tissue and has an important role in energy balance, insulin pathway and inflammation, because of that it may play an important role in colorectal cancer (CRC). Leptin exerts its effect through the leptin receptor (LEPR) a member of the class I cytokine receptor family. BACKGROUND: We have investigated whether glutamine to arginine substitution (Gln223Arg) in exon 6 of the leptin receptor gene, has implications for susceptibility to CRC. PATIENTS AND METHODS: Polymerase chain reaction (PCR) and restriction enzyme digestion (RFLP) was performed to evaluate the association between the Gln223Arg polymorphism of the LEPR and CRC risk in a case-control study in 346 subjects involving 173 cases with CRC and 173 controls. RESULTS: There was no statistically evidence of significant difference in genotype and allele frequencies between the cases with CRC and controls for the Gln223Arg polymorphism of LEPR, before or after adjusting for confounders (age, BMI, sex, and smoking status). Furthermore, no significant difference was observed between the CRC cases and controls by BMI, sex and smoking status. CONCLUSION: Our findings suggest that the LEPR Gln223Arg polymorphism is not associated with the risk of CRC in Iranian population.