Sepsis is one of the major causes of human morbidity and results in a considerable number of deaths each year. Lipopolysaccharide-induced sepsis has been associated with TLR4 signalling pathway which in collaboration with the JAK/STAT signalling regulate endotoxemia and inflammation. However, during sepsis our immune system cannot maintain a balance of cytokine levels and results in multiple organ damage and eventual death. Different opinions have been made in previous studies about the expression patterns and the role of proinflammatory cytokines in sepsis that attracted our attention towards qualitative properties of TLR4 and JAK/STAT signalling pathways using computer-aided studies. René Thomas’ formalism was used to model septic and non-septic dynamics of TLR4 and JAK/STAT signalling. Comparisons among dynamics were made by intervening or removing the specific interactions among entities. Among our predictions, recurrent induction of proinflammatory cytokines with subsequent downregulation was found as the basic characteristic of septic model. This characteristic was found in agreement with previous experimental studies, which implicate that inflammation is followed by immunomodulation in septic patients. Moreover, intervention in downregulation of proinflammatory cytokines by SOCS-1 was found desirable to boost the immune responses. On the other hand, interventions either in TLR4 or transcriptional elements such as NFκB and STAT were found effective in the downregulation of immune responses. Whereas, IFN-β and SOCS-1 mediated downregulation at different levels of signalling were found to be associated with variations in the levels of proinflammatory cytokines. However, these predictions need to be further validated using wet laboratory experimental studies to further explore the roles of inhibitors such as SOCS-1 and IFN-β, which may alter the levels of proinflammatory cytokines at different stages of sepsis.
Viral infections are the cause of serious infirmities in humans and kill millions of people every year. Management of viral diseases is one of the challenges faced by the whole world which needs improvement in prevention and treatment options. Complete understanding of the consequences of viral proteins interaction network on host physiology is essential. Towards this goal, deciphering viral protein-protein interactions is one of the perspective which can help in our understanding about the basis of viral pathogenesis and the development of new antivirals. Indeed, viral infection network based on viral-viral proteins will provide an elusive and investigative framework to articulate rationalize drug discovery based on proteomics scale of viruses. In this study, proteomics a collection of viral-viral protein interactions reporting different studies of Hepatitis C virus, Influenza A virus, Dengue virus and SARS Coronavirus. Our effort of protein-interactions was focused on different studies reporting interactions between viral proteins encoded by the viruses under study. The study is integrated with a broad and original literature-curated data of viral-viral protein (197 non-redundant) interactions.
Cytochrome P450 enzyme family plays significant roles in carcinogenesis and xenobiotic detoxification. CYP1A1 is the P450 family 1 enzyme preferably expressed extrahepatically and participates extensively in monooxygenase activity which can either change the substrate to normal or carcinogenic metabolites, having the ability to initiate oncogenesis in lung and breast. Variegated structural properties evident in the prosites of available Cytochrome P450 (CYP) structures show versatility among CYP catalyzed reactions. In order to understand the CYP1A1 functions, hypothesized homology model has been constructed and characterization of the active site was performed by identifying important residues using docking studies and pharmacophore analysis. Model of CYP-1A1- Human has been constructed using the available crystal structure of CYP-1A2- Human. Active site and entry site of CYP-1A1 was found to be more compact than CYP1A2. Difference of wildtype CYP1A1 against its polymorphisms shows the role of mutations in active site architecture, which explains that the M2 and M4 mutations in CYP1A1 have no possible significant roles in the substrate binding and orientation for detoxification or carcinogenic activation. Different ligands including A- naphthoflavone (ANF), Ethoxyresorufin, Theophylline, Tamoxifen, Ethanol, Phenacetin and Hesperetin were docked and reconfirm the ligand specific wet lab studies.
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