ABSTRACT
Imatinib Mesylate is the drug used for targeted tyrosine kinase inhibition in the beginning of management of all Chronic Myeloid Leukemia (CML) newly diagnosed cases. However, resistance presents a considerable limit to its efficacy. Currently, it is impossible to anticipate IM resistance which makes the recognition of early flags an important treatment goal in CML. In this work we studied the connection between microRNA 30a (miR-30a) and Beclin 1 mediated autophagy and IM resistance in Egyptian CML patients. The study included newly diagnosed (group I, n = 20), imatinib responder (group II, n = 30), imatinib resistant (group III, n = 30) CML patients and a healthy demographically matched control group (group IV, n = 20). miR-30a expression was assayed by quantitative reverse transcription polymerase chain reaction. The variation in expression of miR-30a between CML cases and healthy controls was calculated using relative quantification method (2-ΔΔCT). Beclin 1 was assayed in Peripheral blood mononuclear cells by western blotting. miR-30a was over expressed and Beclin 1 was under expressed in imatinib responders compared to resistant cases median 1.21(0.55-3.02) versus median 0.65 (0.03-1.0) (p = 0.001) and median 950.0 (400.0-2410.0) versus, median 1570.0 (920.0-5430.0) (p < 0.001) respectively. Beclin 1 correlated significantly positively with miR-30a in new cases (p = 0.001) and negatively in imatinib responders (p = 0.021). Receiver Operating Curves demonstrated the performances of miR-30a and Beclin 1 to detect imatinib resistance. They showed sensitivities of 97.14% and 94.29% and specificities of 53.33% and 42.22% at the cut-off values of 1 and 940 respectively. Both miR-30a and Beclin 1 levels showed a relation with imatinib response and can therefore be put forward as valuable markers for detection of resistance and may also have promising future therapeutic implications.
ABSTRACT
INTRODUCTION: Hyperlipidemia is a risk factor for cardiovascular diseases such as acute infarction. Inflammation and platelet activation are critical phenomena in acute myocardial infarction (AMI). AIM: The aim of the study was to assess potential protective effects of aspirin and/or clopidogrel on AMI in hypercholesterolemic rats. METHODS: Forty adult male Wistar rats were divided into five groups (eight rats in each). Group I included normal healthy rats. The other 32 rats were subjected to induction of hypercholesterolemia by high-fat diet for 3 weeks, followed by induction of AMI by subcutaneous injections of isoproterenol (85 mg/kg/day, for 2 days). Rats were divided into the following groups: group II, rats with induced hypercholesterolemia and AMI; group III, hypercholesterolemic rats that received aspirin 30 mg/kg/day orally for 7 days before induction of AMI; group IV, hypercholesterolemic rats that received clopidogrel 10 mg/kg/day orally for 7 days before induction of AMI; and group V, hypercholesterolemic rats treated with both aspirin and clopidogrel in the same doses for 7 days before induction of AMI. Serum levels of pentraxin 3 (PTX3), transforming growth factor-ß1 (TGF-ß1), creatine kinase (CK), lactate dehydrogenase (LDH), total cholesterol and triglycerides were estimated in all rats. RESULTS: Isoproterenol-induced AMI in hypercholesterolemic rats was associated with an increase in serum levels of PTX3, TGF-ß1, CK and LDH. Aspirin and/or clopidogrel pretreatment for 1 week led to a reduction of their levels as compared with non-treated rats. However, the reduction caused by combination of aspirin and clopidogrel was more than that caused by each drug separately. CONCLUSION: Combination of aspirin and clopidogrel could be a therapeutic option for hypercholesterolemic patients to attenuate the complex vascular inflammatory process which is a key step in the setting of AMI.
