Direct Host Plasminogen Binding to Bacterial Surface M-protein in Pattern D Strains of Streptococcus pyogenes Is Required for Activation by Its Natural Coinherited SK2b Protein

Hossain

BMC Complement Altern Med

et al. 2016

Background Hopea Odorata, locally known as Telsur (Bangladesh), has some traditional uses as folk medicine. This study aims to investigate the antioxidant, antidiarrheal, hypoglycemic and thrombolytic activities of H. odorata leaf extracts as new therapeutic prospects predicting the activity of some of the isolated compounds of this plant.MethodsLeaves of Hopea odorata was extracted with pure methanol (MEHO), ethanol (EEHO) and water (AEHO). The extract was tested for antioxidant activity by using reducing power and H2O2 scavenging assay. Antidiarrheal effects were assayed by three standard methods of bioassay: Castor oil-induced diarrhea, Castor oil induced enteropooling and gastrointestinal transit test. Hypoglycemic effect was determined by normoglycemic model of mice. Thrombolytic activity was evaluated by clot lyses test for human and mice blood. In silico PASS prediction was applied for phytoconstituents namely Balanocarpol, Hopeaphenol and Ampelopsin H isolated from this plant. ResultAmong the all extracts, MEHO exhibited strong antioxidant activity in both reducing power and H2O2 scavenging assay. Phenol content of MEHO was 297.22 ± 0.78 mg/g and flavonol content was 91.53 ± 1.82 mg/g. All the experiment of extracts at dose of 200 and 400 mg/kg and the standard drug loperamide (5 mg/kg) showed significant (p < 0.001) inhibition against castor oil induced diarrhea and castor oil induced enteropooling in mice. There were also significant (p < 0.01) reduction in gastrointestinal motility in the charcoal meal test. Leaf extract showed no significant (P < 0.01) decrease of blood glucose compared to Glibenclamide in normoglycemic mice. Using an in vitro thrombolytic model, MEHO showed the highest and significant clot lysis of human and mice blood compared to Streptokinase. PASS predicted the wide range of antioxidant, free radical scavenger, Nitric oxide scavenger, cardioprotectant, hepatoprotectant, thrombolytic, fibrinolytic, antibacterial, antifungal, anticarcinogenic, anthelmintic and anti-inflammatory activity of examined phytoconstituents.ConclusionThese findings suggest that the plant may be a potential source of new antidiarrheal, thrombolytic and antioxidative agents but it is found to have no antidiabetic capability. PASS prediction matched with present study for the extracts. Further study needs to identify the PASS predicted biological actions of the phytoconstituents.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1461-x) contains supplementary material, which is available to authorized users.

Section: Discussionmentioning

confidence: 99%

Antioxidant, antidiarrheal, hypoglycemic and thrombolytic activities of organic and aqueous extracts of Hopea odorata leaves and in silico PASS prediction of its isolated compounds

Hossain

BMC Complement Altern Med

et al. 2016

“…Upon activation of free host plasminogen to plasmin by the plasminogen•SK complex [183], the tighter binding plasmin•SK complex is formed, and degrades the host extracellular matrix to facilitate pathogen invasion and dissemination. Numerous streptococcal strains also increase their invasiveness by recruiting host plasminogen and plasmin to bacterial cell wall M-proteins [184]. Von Willebrand factor-binding protein (VWbp) is another conformational prothrombin activator secreted by S. aureus , and belongs to the family of staphylococcal and streptococcal homologs named zymogen activator and adhesion proteins (ZAAPs), based on the SC structure [185].…”

Section: Proteases and Diseasementioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

Journal of Biological Chemistry

“…Cells were resuspended in hPg activation buffer (10 mM HEPES, 150 mM NaCl, pH 7.4). Aliquots of 100 l of the cell suspension were distributed to individual wells of a protein-nonbinding 96-well plate along with 100 l of activation buffer that also contained the chromogenic substrate for hPm, S2251 (0.5 mM), and 10 nM SK (24). Substrate cleavage was detected by p-nitroanaline release as the change in A 405 nm over time.…”

Section: Effects Of Human Fibrinogen (Hfg) On the Activation Of Hpg Omentioning

confidence: 99%

“…Isogenic mutants of strain AP53/CovS Ϫ , with targeted deletions of streptokinase (SK) (AP53/CovS Ϫ /⌬SK), PAM (AP53/CovS Ϫ /⌬PAM), and fibronectin-binding protein (Fbp) (AP53/CovS Ϫ /⌬Fbp), were constructed as described earlier (16,22,24). GAS strains were grown in Todd-Hewitt-1% yeast (THY) medium at 37°C to an A 600 nm of ϳ0.6 (mid-log phase).…”

Section: Gas Strains and Culture Conditions-the Isogenic Gas Strains mentioning

confidence: 99%

Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria

Agrahari

Zhong

Glinton

et al. 2016

Self Cite

Evasion of complement-mediated opsonophagocytosis enables group A Streptococcus pyogenes (GAS) to establish infection. Different strain-dependent mechanisms are employed by the host to accomplish this goal. In general, GAS inhibits the amplification of the complement cascade on its cell surface by facilitating the degradation of C3b, an opsonin, to an inactive product, inactivated C3b (iC3b), in a step catalyzed by factor I (FI) and its cofactor, factor H (FH), with or without the participation of human host plasmin (hPm). GAS recruits FH to its cell surface via FH receptors, which are transcriptionally controlled by the two-component cluster of virulence responder-sensor system. The manner in which FI-FH and hPm function together on GAS cells is unknown. Using GAS strain AP53, which strongly binds host human plasminogen/plasmin (hPg/hPm) directly via an hPg/hPm surface receptor (PAM), we show that both FI-FH and hPm sequentially cleave C3b. Whereas FI-FH proteolytically cleaves C3b into iC3b, PAM-bound hPm catalyzes cleavage of iC3b into multiple smaller peptides. Unlike AP53, GAS strain M23ND weakly binds FH and recruits hPg/ hPm to its cell surface indirectly via fibrinogen bound to M-protein, M23. In this case, FH-FI cleaves C3b into iC3b, with negligible degradation of iC3b by hPm that is bound to fibrinogen on the cells. AP53 and M23ND display similar resistance to human neutrophil-mediated phagocytosis, which results in a corresponding high lethality in mice after injection of these cells. These results suggest that GAS utilizes diverse mechanisms to degrade C3b and thus to protect bacterial cells from the complement response of the host.