scholarly journals Beneficial effects of combining a type II ATP competitive inhibitor with an allosteric competitive inhibitor of BCR-ABL for the treatment of imatinib-sensitive and imatinib-resistant CML

Leukemia ◽  
2010 ◽  
Vol 24 (7) ◽  
pp. 1375-1378 ◽  
Author(s):  
E Weisberg ◽  
X Deng ◽  
H G Choi ◽  
R Barrett ◽  
S Adamia ◽  
...  
Keyword(s):  
Competitive Inhibitor ◽  
Type Ii ◽  
Beneficial Effects ◽  
Imatinib Resistant

scholarly journals A mechanistic and kinetic analysis of the interactions of the diastereoisomers of adenosine 3′,5′-(cyclic)phosphorothioate with purified cyclic AMP-dependent protein kinase

1988 ◽  
Vol 251 (3) ◽  
pp. 757-762 ◽  
Author(s):  
J D Rothermel ◽  
L H Parker Botelho
Keyword(s):  
Protein Kinase ◽  
Linear Regression ◽  
Cyclic Amp ◽  
Competitive Inhibitor ◽  
Type Ii ◽  
Sulphur Atom ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
Activation Data ◽  
Dependent Protein

The binding affinities of the diastereoisomers of adenosine 3′,5′-(cyclic)phosphorothioate, Sp-cAMP[S] and Rp-cAMP[S], for the cyclic AMP- (cAMP-)binding sites on purified and reconstituted pig heart type II cAMP-dependent protein kinase holoenzyme were determined by measuring the ability of these compounds to displace [3H]cAMP from this enzyme. Sp-cAMP[S], a cAMP agonist, displaced 50% of the [3H]cAMP bound to the holoenzyme at a concentration 10-fold higher than that of cAMP; Rp-cAMP[S], a cAMP antagonist, required a 100-fold higher concentration relative to cAMP. Activation of the isolated holoenzyme, determined as phosphotransferase activity, was measured in the presence of the agonist and in the absence and in the presence of increasing concentrations of the antagonist. The results of fitting the activation data to sigmoid curves with a non-linear-regression program and to Hill plots by using a linear-regression program showed that Rp-cAMP[S] had no effect on Vmax, increased the EC50 values for agonist activation and had no effect on the co-operativity of activation (h). A Ki value of 11 microM was determined for Rp-cAMP[S] inhibition of cAMP-induced activation of purified type II cAMP-dependent protein kinase. Electrophoresis of the holoenzyme on polyacrylamide gels under non-denaturing conditions in the presence of saturating concentrations of the diastereoisomers resulted in 100% dissociation of the subunits with Sp-cAMP[S] and 0% dissociation with Rp-cAMP[S]. Sp-cAMP[S], the isomer with an axial exocyclic sulphur atom, binds to the holoenzyme, releases the catalytic subunit and activates the phosphotransferase activity. Rp-cAMP[S], the isomer with an equatorial exocyclic sulphur atom, binds to the holoenzyme but does not result in dissociation, and thus acts as a competitive inhibitor of phosphotransferase activity.

scholarly journals Sulfatide Attenuates Experimental Staphylococcus aureus Sepsis through a CD1d-Dependent Pathway

2013 ◽  
Vol 81 (4) ◽  
pp. 1114-1120 ◽  
Author(s):  
Jakub Kwiecinski ◽  
Sara Rhost ◽  
Linda Löfbom ◽  
Maria Blomqvist ◽  
Jan Eric Månsson ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Subset ◽  
Early Response ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Microbial Infection ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Beneficial Effects

ABSTRACTNatural killer T (NKT) lymphocytes are implicated in the early response to microbial infection. Further, sulfatide, a myelin self-glycosphingolipid, activates a type II NKT cell subset and can modulate disease in murine models. We examined the role of NKT cells and the effect of sulfatide treatment in a murine model ofStaphylococcus aureussepsis. The lack of CD1d-restricted NKT cells did not alter survival after a lethal inoculum ofS. aureus. In contrast, sulfatide treatment significantly improved the survival rate of mice withS. aureussepsis, accompanied by decreased levels of tumor necrosis factor alpha and interleukin-6 in the blood. The protective effect of sulfatide treatment depended on CD1d but not on type I NKT cells, suggesting that activation of type II NKT cells by sulfatide has beneficial effects on the outcome ofS. aureussepsis in this model.

scholarly journals Mechanism of Binding of Prothioconazole toMycosphaerella graminicolaCYP51 Differs from That of Other Azole Antifungals

2010 ◽  
Vol 77 (4) ◽  
pp. 1460-1465 ◽  
Author(s):  
Josie E. Parker ◽  
Andrew G. S. Warrilow ◽  
Hans J. Cools ◽  
Claire M. Martel ◽  
W. David Nes ◽  
...  
Keyword(s):  
Scientific Literature ◽  
Competitive Inhibitor ◽  
Sterol Composition ◽  
Specific Information ◽  
Type Ii ◽  
Wild Type ◽  
Binding Studies ◽  
Difference Spectra ◽  
Mechanism Of Inhibition ◽  
Noncompetitive Inhibitors

ABSTRACTProthioconazole is one of the most important commercially available demethylase inhibitors (DMIs) used to treatMycosphaerella graminicolainfection of wheat, but specific information regarding its mode of action is not available in the scientific literature. Treatment of wild-typeM. graminicola(strain IPO323) with 5 μg of epoxiconazole, tebuconazole, triadimenol, or prothioconazole ml−1resulted in inhibition ofM. graminicolaCYP51 (MgCYP51), as evidenced by the accumulation of 14α-methylated sterol substrates (lanosterol and eburicol) and the depletion of ergosterol in azole-treated cells. Successful expression of MgCYP51 inEscherichia colienabled us to conduct spectrophotometric assays using purified 62-kDa MgCYP51 protein. Antifungal-binding studies revealed that epoxiconazole, tebuconazole, and triadimenol all bound tightly to MgCYP51, producing strong type II difference spectra (peak at 423 to 429 nm and trough at 406 to 409 nm) indicative of the formation of classical low-spin sixth-ligand complexes. Interaction of prothioconazole with MgCYP51 exhibited a novel spectrum with a peak and trough observed at 410 nm and 428 nm, respectively, indicating a different mechanism of inhibition. Prothioconazole bound to MgCYP51 with 840-fold less affinity than epoxiconazole and, unlike epoxiconazole, tebuconazole, and triadimenol, which are noncompetitive inhibitors, prothioconazole was found to be a competitive inhibitor of substrate binding. This represents the first study to validate the effect of prothioconazole on the sterol composition ofM. graminicolaand the first on the successful heterologous expression of active MgCYP51 protein. The binding affinity studies documented here provide novel insights into the interaction of MgCYP51 with DMIs, especially for the new triazolinethione derivative prothioconazole.

scholarly journals Management of Patients with Hereditary Angioedema During the COVID-19 Pandemic

2021 ◽  
Vol 19 (3) ◽  
pp. 166-173
Author(s):  
Eray YILDIZ ◽  
Şevket ARSLAN ◽  
Fatih ÇÖLKESEN ◽  
Filiz Sadi AYKAN ◽  
Recep EVCEN ◽  
...  
Keyword(s):  
Hereditary Angioedema ◽  
Clinical Symptoms ◽  
Type I ◽  
Type Ii ◽  
Kinin System ◽  
Beneficial Effects ◽  
Phone Calls ◽  
History Of ◽  
Kallikrein Kinin System

Objective: The aim of this study was to determine the clinical course and treatment outcomes of patients with hereditary angioedema (HAE) after infection with coronavirus disease 2019 (COVID-19). Materials and Methods: Thirty-nine patients with HAE were included in this study. These patients were regularly followed up over phone calls since the first COVID-19 case was seen in our country. Patients were asked to visit the hospital if there was a history of contact with a confirmed COVID-19 patient or if the patient developed clinical symptoms of COVID-19.Results: There were 21 (54%) patients with type I HAE, and 18 (46%) with type II HAE. All patients received treatment for angioedema attacks (C1-inhibitor [C1-INH], icatibant), and seven (20%) received long-term prophylaxis (danazol). Treatment for attacks was continued for all patients during the pandemic. Patients taking danazol were switched to long-term prophylaxis using the C1-INH concentrate. Eleven (28%) patients with HAE developed COVID-19 during this study. Only one patient had severe COVID-19. Six patients (54.5%) were diagnosed with type II HAE, and five (45.5%) were diagnosed with type I HAE. The most common COVID-19 symptoms were fever (7/11; 64%) and myalgia (6/11; 55%). Mild angioedema attacks were experienced by 36% (4/11) of the HAE patients diagnosed with COVID-19. Icatibant was used in all patients.Conclusion: Agents used for HAE block the kallikrein-kinin system and may be useful in the treatment of COVID-19. Considering their beneficial effects on COVID-19, it is recommended that HAE patients should continue the use of agents blocking the kallikrein-kinin system. Keywords: COVID-19, hereditary angioedema, kallikrein-kinin system, bradykinin, C1-INH

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