@article {515, title = {Biochemical and pharmacological characterization of a toxic fraction and its cytotoxin-like component isolated from Russell{\textquoteright}s viper (Daboia russelii russelii) venom. (Mass Spectrometry)}, journal = {Comp Biochem Physiol C Toxicol Pharmacol}, volume = {168}, year = {2015}, month = {2015 Feb}, pages = {55-65}, abstract = {

The pathophysiological significance of a toxic fraction (GF-VI DEAE-II) isolated from Russell{\textquoteright}s viper venom (RVV) is characterized. GF-VI DEAE-II represents 1.6\% of the total RVV protein and it comprises of a 27.6kDa minor component (RP-I) (0.04\%, w/w) and a major 6.6kDa non-enzymatic peptide (1.11\%, w/w), named Rusvitoxin. The LC-MS/MS analysis of RP-I showed its identity to snake venom serine proteases, whereas Rusvitoxin demonstrated its close identity with snake venom three finger toxins, cytotoxins and cardiotoxins particularly from Naja sp. GF-VI DEAE-II was found to be non-cytotoxic to the tested mammalian cancer cells and non-hemolytic; nevertheless, it demonstrated α-fibrin(ogen)ase activity and in vivo toxicity in BALB/c mice with an LD50 (i.p.) of 2.3mg/kg. GF-VI DEAE-II induced lethargy and hind-leg paralysis in mice within 10min of i.p. injection. GF-VI DEAE-II induced hyperfibrinogenomia, and significantly altered (p\<0.05) the plasma levels of factor X, pro- and anti-inflammatory cytokines viz. TNF-α, IL-6 and IL-10 in treated mice. Histological observations of tissues and biochemical properties of serum from GF-VI DEAE-II-treated mice suggested multiple organ dysfunctions. Conversely, Rusvitoxin at a dose of 5mg/kg did not induce toxicity in BALB/c mice. At 1:15 (antigen: antivenom, w/w) ratio, commercially polyvalent and monovalent antivenoms neutralized more than 80\% of the fibrinolytic and anticoagulant activities of GF-VI DEAE-II. The present study suggests the significant role of GF-VI DEAE-II in RVV-induced pathogenesis in victim/prey.

}, keywords = {Animals, Anticoagulants, Antivenins, Cytotoxins, Fibrinolytic Agents, Interleukin-10, Interleukin-6, Mice, Mice, Inbred BALB C, Mollusk Venoms, Russell{\textquoteright}s Viper, Tumor Necrosis Factor-alpha, Viper Venoms}, issn = {1532-0456}, doi = {10.1016/j.cbpc.2014.12.001}, author = {Thakur, Rupamoni and Chattopadhyay, Pronobesh and Mukherjee, Ashis K} } @article {514, title = {Elucidation of procoagulant mechanism and pathophysiological significance of a new prothrombin activating metalloprotease purified from Daboia russelii russelii venom. (Mass Spectrometry)}, journal = {Toxicon}, volume = {100}, year = {2015}, month = {2015 Jun 15}, pages = {1-12}, abstract = {

The procoagulant proteases present in Russell{\textquoteright}s Viper venom (RVV) are responsible for promoting consumption coagulopathy in victims. In this study, a procoagulant metalloprotease (Rusviprotease) possessing prothrombin activating and α-fibrinogenase properties has been purified and characterized from RVV. Rusviprotease is a 26.8\ kDa glycoprotein which also exists in other multimeric forms. The peptide mass fingerprinting and secondary structure analyses of Rusviprotease revealed its similarity with snake venom prothrombin activators and metalloproteases. Similar to group A prothrombin activators, Rusviprotease cleaved prothrombin independent of any co-factor requirement generating meizothrombin which is further cleaved to form thrombin. The Km and Vmax values of Rusviprotease towards prothrombin were determined to be 1.73\ μM, and 153.5\ nM thrombin generated/min/μmoles of Rusviprotease, respectively. The Km and Vmax values of Rusviprotease towards fibrinogen were calculated to be 3.14\ μM and 78.7\ nmol/min, respectively. Spectrofluorometric study provided the evidence of interaction between Rusviprotease and factor Xa with a Kd value of\ 6.64\ nM. This interaction augmented the prothrombin activating property of the factor Xa-prothrombinase-Rusviprotease complex by 2.5 fold. Intravenous injection of Rusviprotease to BALB/c mice (0.1\ mg/kg) resulted in in\ vivo defibrinogenation rendering the blood incoagulable. In conclusion, Rusviprotease is the first example of a prothrombin activator with fibrinogenolytic property purified from Daboia russelii russelii venom.

}, keywords = {Animals, Blood Coagulation, Blood Platelets, Chemical Fractionation, Coagulants, Erythrocytes, Goats, Metalloproteases, Mice, Inbred BALB C, Plasma, Russell{\textquoteright}s Viper, Toxicity Tests, Acute, Viper Venoms}, issn = {1879-3150}, doi = {10.1016/j.toxicon.2015.03.019}, author = {Thakur, Rupamoni and Chattopadhyay, Pronobesh and Ghosh, Siddharth S and Mukherjee, Ashis K} } @article {712, title = {An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression.}, journal = {Cell}, volume = {151}, year = {2012}, month = {2012 Dec 21}, pages = {1474-87}, abstract = {

DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells,\ and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.

}, keywords = {Amino Acid Sequence, Animals, Cell Line, Tumor, Disease Models, Animal, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Ligase ATP, DNA Ligases, Drug Design, Drug Resistance, Neoplasm, Humans, Lymphocytes, Lymphoma, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Molecular Sequence Data, Neoplasms, Protein Structure, Tertiary, Pyrimidines, Radiation Tolerance, Rats, Schiff Bases, Sequence Alignment}, issn = {1097-4172}, doi = {10.1016/j.cell.2012.11.054}, author = {Srivastava, Mrinal and Nambiar, Mridula and Sharma, Sheetal and Karki, Subhas S and Goldsmith, G and Hegde, Mahesh and Kumar, Sujeet and Pandey, Monica and Singh, Ram K and Ray, Pritha and Natarajan, Renuka and Kelkar, Madhura and De, Abhijit and Choudhary, Bibha and Raghavan, Sathees C} }