Coagulin

The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and procofactors) in the next step of the cascade via limited proteolysis. The ultimate outcome is the polymerization of fibrin and the activation of platelets, leading to a blood clot. This process is protective, as it prevents excessive blood loss following injury (normal hemostasis). Unfortunately, the blood clotting system can also lead to unwanted blood clots inside blood vessels (pathologic thrombosis), which is a leading cause of disability and death in the developed world. There are two main mechanisms for triggering the blood clotting, termed the tissue factor pathway and the contact pathway. Only one of these pathways (the tissue factor pathway) functions in normal hemostasis. Both pathways, however, are thought to contribute to thrombosis. An emerging concept is that the contact pathway functions in host pathogen defenses. This review focuses on how the initiation phase of the blood clotting cascade is regulated in both pathways, with a discussion of the contributions of these pathways to hemostasis versus thrombosis.

There is a strong relationship between tissue factor (TF) and cancer. Many cancer cells express high levels of both full-length TF and alternatively spliced (as) TF. TF expression in cancer is associated with poor prognosis. In this review, the authors summarize the regulation of TF expression in cancer cells and the roles of TF and asTF in tumor growth and metastasis. A variety of different signaling pathways, transcription factors and micro ribonucleic acids regulate TF gene expression in cancer cells. The TF/factor VIIa complex enhances tumor growth by activating protease-activated receptor 2 signaling and by increasing the expression of angiogenic factors, such as vascular endothelial growth factor. AsTF increases tumor growth by enhancing integrin β1 signaling. TF and asTF also contribute to metastasis via multiple thrombin-dependent and independent mechanisms that include protecting tumor cells from natural killer cells. Finally, a novel anticancer therapy is using tumor TF as a target to deliver cytotoxic drugs to the tumor. TF may be useful in diagnosis, prognosis, and treatment of cancer.

Plant derived product can be used as other alternatives to currently used drugs for controlling chronic diseases like Diabetes mellitus. The potential of Coagulin L (a constituent of Withania coagulans) as dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated by molecular modelling study. It was observed that amino acid residues such as Glu205, Glu206, Tyr 547, His 740, and Try662 interacts with Coagulin L and Saxagliptin (a known DPP-4 inhibitor). Other nonbonded interactions of Coagulin L and Saxagliptin with DPP-4 binding residues were also found similar. The docking energy of Coagulin L was found to be -7.69 Kcal/mol whereas -8.44 kcal/mol was recorded for Saxagliptin. MD simulation study revealed stable binding throughout 100 ns simulation. RMSD plot of the complex was stabilized in 43 ns and remained stable during entire simulation(100 ns). RMSF plot of DPP-4 Coagulin L interaction showed major fluctuations at residue 246 and 766, however, Arg 125, Glu 205, Ser 209 and His 740 showed no major perturbations. Principal Component Analysis showed that important dynamics of the protein remain unchanged during entire simulation since the non-polar, van der waals, ionic interaction and solvation energy, altogether play important role in the complex stability. The molecular modelling study of DPP-4 with Coagulin L was an effort to establish correlation with traditional practices of Withania coagulans as antidiabetic agent in Indian subcontinent.Communicated by Ramaswamy H. Sarma.