Influence of CYP450 Enzymes and ABCB1 Polymorphisms on Clopidogrel Response in Moroccan Patients with Acute Coronary Syndromes.

Introduction: Clopidogrel is an antiplatelet prodrug primarily prescribed to prevent or treat acute coronary syndrome (ACS) or acute ischemic stroke (IS), polymorphisms of genes encoding cytochrome P-450 (CYP) and P-glycoprotein transporter, could affect the efficiency of clopidogrel absorption and biotransformation, especially during the first critical hours following its administration. Methods: The present study was designed to investigate the potential association of clopidogrel responsiveness and 14 polymorphisms in the genes encoding the CYPs (CYP2C9, 2C19, 3A4, 3A5, 1A2, and 2B6), the ATP binding cassette subfamily B member 1 (ABCB1). Platelet aggregation activity was measured after 8h of 300mg clopidogrel administration for fifty-five ACS patients. Results: There was no significant association between polymorphism of the studied CYPs and clopidogrel responsiveness (P>0.05). The frequency of the ABCB1 3435 T allele in clopidogrel non-responders was higher (78.9%) compared to responders (52.8%), but this difference was not significant (P=0.057). Demographic characteristics, comorbidities, concomitant treatments were not associated with clopidogrel response. Discussion: There was no effect of the studied genetic variations and demographic factors on the platelet activity of clopidogrel in Moroccan ACS patients.

FLT3 Mutations in Acute Myeloid Leukemia: Unraveling the Molecular Mechanisms and Implications for Targeted Therapies.

Acute myeloid leukemia (AML) is a heterogeneous and aggressive form of blood cancer characterized by the uncontrolled proliferation of myeloid precursor cells in the bone marrow. It affects individuals of all ages, with incidence increasing notably in those over 65 years old. Despite advancements in treatment, overall survival rates remain unsatisfactory, underscoring the need for a deeper understanding of the disease. Among the various genetic alterations implicated in AML pathogenesis, mutations in the FLT3 (Fms-like tyrosine kinase 3) gene have emerged as significant contributors to leukemogenesis. The FLT3 ​​​​​gene encodes a type III receptor tyrosine kinase crucial in regulating normal hematopoiesis. Approximately one-third of AML patients carry FLT3 mutations, making it one of the most frequently mutated genes in the disease. FLT3 mutations can be classified into internal tandem duplications (ITDs) and point mutations in the tyrosine kinase domain (TKD). FLT3 mutations are associated with adverse clinical features and are independent prognostic factors for poor overall survival and decreased remission rates in AML patients. Understanding the molecular mechanisms underlying FLT3 mutations in AML is critical for improving risk stratification, prognosis assessment, and the development of targeted therapies. By reviewing the current literature, this study aims to elucidate the functional consequences of FLT3 mutations in AML pathogenesis, explore the interaction of FLT3 signaling with other oncogenic pathways, and assess the prognostic significance of FLT3 mutations in clinical practice, providing information that can guide future research directions and facilitate the development of more effective therapeutic strategies.

Review of prostate cancer genomic studies in Africa.

Prostate cancer (PCa) is the second most commonly diagnosed in men worldwide and one of the most frequent cancers in men in Africa. The heterogeneity of this cancer fosters the need to identify potential genetic risk factors/biomarkers. Omics variations may significantly contribute to early diagnosis and personalized treatment. However, there are few genomic studies of this disease in African populations. This review sheds light on the status of genomics research on PCa in Africa and outlines the common variants identified thus far. The allele frequencies of the most significant SNPs in Afro-native, Afro-descendants, and European populations were compared. We advocate how these few but promising data will aid in understanding, better diagnosing, and precisely treating this cancer and the need for further collaborative research on the genomics of PCa in the African continent.

In Vitro Alpha-Amylase and Alpha-Glucosidase Inhibitory Activity and In Vivo Antidiabetic Activity of Withania frutescens L. Foliar Extract.

Withania frutescens L. is a wild perennial woody plant used by the local population for diverse therapeutic purposes. This work aims to study for the first time the potential inhibitory effect of this plant hydroethanolic extract on α-amylase and α-glucosidase activities using in vitro methods and its antidiabetic and antihyperglycemic activities using alloxan-induced diabetic mice as a model for experimental diabetes. Two doses were selected for the in vivo study (200 and 400 mg/kg) and glibenclamide, a well-known antidiabetic drug (positive control) in a subacute study (28 days) where the antihyperglycemic activity was also assessed over a period of 12 h on diabetic mice. The continuous treatment of diabetic mice with the extract of Withania frutescens for 4 weeks succeeded to slowly manage their high fasting blood glucose levels (after two weeks), while the antihyperglycemic test result revealed that the extract of this plant did not control hyperglycemia in the short term. No toxicity signs or death were noted for the groups treated with the plant extract, and it shows a protective effect on the liver and kidney. The in vitro assays demonstrated that the inhibition of alpha-amylase and alpha-glucosidase might be one of the mechanisms of action exhibited by the extract of this plant to control and prevent postprandial hyperglycemia. This work indicates that W. frutescens have an important long term antidiabetic effect that can be well established to treat diabetes.

Antioxidant, Anti-Inflammatory and Antidiabetic Proprieties of LC-MS/MS Identified Polyphenols from Coriander Seeds.

Coriandrum sativum L. seeds are traditionally used to treat diabetes and its complications (inflammation and formation of reactive oxygen species) around the world. The present study investigates the antidiabetic, anti-inflammatory, and antioxidant effects of the polyphenol fraction of Coriandrum sativum seeds (PCS). Diabetic mice were orally administered with PCS (25 and 50 mg/kg b.w.) for 28 days. Oral glucose tolerance (OGTT) was also evaluated along with the anti-inflammatory effect, assessed by measuring paw edema development induced with carrageenan in Wistar rat and the antioxidant activity assessed using two tests (ß-carotene discoloration and DPPH). Treatment of diabetic mice with PCS for four weeks managed their high fasting blood glucose levels, improved their overall health, also revealed an excellent antihyperlipidemic activity. The OGTT result showed a potent antihyperglycemic activity, and following the anti-inflammatory and antioxidant effects, the PCS exhibited a perfect activity. LC-MS/MS result revealed the presence of 9 polyphenols. This modest work indicates that the PCS have an important antidiabetic, antihyperglycemic, antihyperlipidemic, anti-inflammatory, and antioxidant effect that can be well established treatment of diabetes and its complications.

Combination of Catechin, Epicatechin, and Rutin: Optimization of a novel complete antidiabetic formulation using a mixture design approach.

Nowadays, synthetic chemical antidiabetic drugs, besides their therapeutic effects, present adverse effects that could be hard to handle over time. In the last decade, studies reported new alternative molecules with more health benefits and less adverse effects. The goal of this study is to optimize a new antidiabetic formulation using plant flavonoids: Catechin, Epicatechin, and Rutin. They are also a powerful antioxidant and anti-inflammatory molecules. A mixture design experiment will optimize their combination to obtain a new, safe multi-targets antidiabetic formulation making it a powerful combination for the management of diabetes and its complications. To study the variation of blood glucose level in response to the treatment over the time we performed an Oral Glucose Tolerance Test. The blood glucose level variations recorded as responses for the mixture design experiment. We used the molecules at a dose of 10 mg/kg. According to the software analysis, the prediction profiler showed us the optimum combination, and the result was a binary combination between Rutin and Epicatechin (25% and 75%, respectively). This combination prevented hyperglycemia and hypoglycemia, along with the best area under the curve, and after that, we validated it through a repeated oral administration on alloxan-induced diabetic mice for 28 d. Rutin, Catechin, and Epicatechin exhibit a potent antihyperglycemic activity, their synergistic combination validates a new formulation that could be a real candidate to conventional drugs.

In-Vivo Antidiabetic Activity and In-Silico Mode of Action of LC/MS-MS Identified Flavonoids in Oleaster Leaves.

BACKGROUND: Olea europea L. subsp. europaea var. sylvestris (Mill) Lehr (Oleaster) is a wild endemic olive tree indigenous to the Mediterranean region. Olea europea leaves represent a natural reservoir of bioactive molecules that can be used for therapeutic purposes. AIM OF THE STUDY: This work was conducted to study antidiabetic and antihyperglycemic activities of flavonoids from oleaster leaves using alloxan-induced diabetic mice. The mode of action of flavonoids against eight receptors that have a high impact on diabetes management and complication was also investigated using molecular docking. RESULTS: During 28 days of mice treatment with doses 25 and 50 mg/kg b.w, the studied flavonoids managed a severe diabetic state (<450 mg/dL), exhibiting a spectacular antidiabetic and antihyperglycemic activity, and improved mice health status compared to diabetic control. The in-silico mode of action of oleaster flavonoids revealed the inhibition of protein tyrosine phosphatase 1B (PTP1B), Dipeptidyl-peptidase 4 (DPP4), α-Amylase (AAM), α-Glucosidase inhibition, Aldose reductase (AldR), Glycogen phosphorylase (GP), and the activation of free fatty acid receptor 1 (FFAR1). CONCLUSION: The findings obtained in the present work indicate that the flavonoids from the oleaster may constitute a safe multi-target remedy to treat diabetes.

Thermostable Cellulases from the Yeast Trichosporon sp.

OBJECTIVES: Identification of cellulolytic microorganisms is of great interest to the hydrolysis of cellulosic biomass. This study focuses on the identification of cellulolytic yeasts and the optimization of cellulase activities produced by the best performing isolate. RESULTS: 30 cellulolytic yeast isolates were selected. Enzymes produced by an isolate from the Trichosporon genus showed the property to hydrolyze different substrates: carboxymethyl cellulose (CMC), cellulose fiber, and filter paper (FP). The optimum measured temperature was 55°C for CMCase and 60°C for FPase. The optimal pH was 5 for CMCase and 4 to 6 for FPase. The effect of the substrates concentration showed that the best activities were obtained at 100 mg/mL CMC or FP. The highest activities were 0.52 for the CMCase and 0.56 for the cellulase fiber at 10 min incubation, 0.44 IU/mL at 15 min incubation, and 24 h FPase preincubation. CONCLUSION: Cellulases produced by the studied yeast are capable of hydrolyzing soluble and insoluble substrates at elevated temperatures and at a wide pH range. They are considerable interest in the production of fermentable sugars from lignocellulosic substrates.