Here, a group of specific lipids, comprising phosphatidylethanolamine (PE)- or phosphatidylcholine (PC)-esterified 12S-hydroxyeicosatetraenoic acid (12S-HETE), generated by 12-lipoxygenase was identified and characterized. 12S-HETE-PE/PCs were formed within 5 min of activation by thrombin, ionophore, or collagen. Esterified HETE levels generated in response to thrombin were 5.85 ± 1.42 (PE) or 18.35 ± 4.61 (PC), whereas free was 65.5 ± 17.6 ng/4 × 107 cells (n = 5 separate donors, mean ± S.E.). Their generation was stimulated by triggering protease-activated receptors-1 and -4 and signaling via Ca2+ mobilization secretory phospholipase A2, platelet-activating factor-acetylhydrolase, src tyrosine kinases, and protein kinase C. Stable isotope labeling showed that they form predominantly by esterification that occurs on the same time scale as free acid generation. Unlike free 12S-HETE that is secreted, esterified HETEs remain cell-associated, with HETE-PEs migrating to the outside of the plasma membrane. 12-Lipoxygenase inhibition attenuated externalization of native PE and phosphatidylserine and HETE-PEs. Platelets from a patient with the bleeding disorder, Scott syndrome, did not externalize HETE-PEs, and liposomes supplemented with HETE-PC dose-dependently enhanced tissue factor-dependent thrombin generation in vitro. This suggests a role for these novel lipids in promoting coagulation. Thus, oxidized phospholipids form by receptor/agonist mechanisms, not merely as an undesirable consequence of vascular and inflammatory disease.

Apoptosis in megakaryocytes results in the formation of platelets. The role of apoptotic pathways in platelet turnover and in the apoptotic-like changes seen after platelet activation is poorly understood. ABT-263 (Navitoclax), a specific inhibitor of antiapoptotic BCL2 proteins, which is currently being evaluated in clinical trials for the treatment of leukemia and other malignancies, induces a doselimiting thrombocytopenia. In this study, the relationship between BCL2/BCL-X L inhibition, apoptosis, and platelet activa- IntroductionAll nucleated cells in multicellular organisms are genetically programmed to undergo apoptosis to remove unnecessary or damaged cells from the whole organism. This program has been recognized as the central mechanism of platelet production from megakaryocytes. 1 However, the role of apoptosis in anuclear, mature platelets is less well characterized, with apoptotic-like changes seen in both aging platelets and in the formation of procoagulant microparticles after agonist stimulation.Two main pathways lead to the execution of apoptosis: the extrinsic and the intrinsic (or mitochondrial) pathways. Both converge into the activation of caspases, which are proteases that cleave Ͼ 500 cellular targets and induce typical morphologic changes associated with apoptosis in nucleated cells. A critical step in the intrinsic pathway is the loss of mitochondrial membrane potential (MMP) and the release of cytochrome c into cytosol, where it triggers the activation of caspase-9. Therefore, the release of cytochrome c from mitochondria needs to be tightly regulated: a function that is fulfilled by the BCL2 protein family, which consists of proapoptotic and antiapoptotic members that promote or block the release of cytochrome c, respectively. 2,3 The proapoptotic family members BAX and BAK play an essential role in directly mediating the release of cytochrome c by forming a pore in the outer mitochondrial membrane. Antiapoptotic BCL2 proteins, including BCL2, BCL-X L , BCL-w, MCL1, and BCL2A1, prevent the activation of BAX and BAK. Besides their function in regulating mitochondrial cytochrome c release, BCL2 proteins have also been implicated in the regulation of intracellular calcium homeostasis at the endoplasmic reticulum (ER), possibly by interacting with inositol triphosphate receptors. 4,5 Because of their key role, the antiapoptotic BCL2 proteins are attractive targets for anticancer therapy, with several small molecule inhibitors currently in preclinical testing or early clinical trials. 6,7 Among these, the most promising and specific inhibitors are ABT-263 (Navitoclax) and 9 ABT-737 shows promising antitumor activity in animal models of leukemia and lymphoma. A related compound, ABT-263, is metabolically more stable and currently in phase 1 and 2 clinical trials for leukemia and other malignancies. 10 Both compounds have often been regarded as interchangeable because they bind with high affinity to BCL2, BCL-X L , and BCL-w but do not inhibit MCL1 or BCL2A1. 11 Early results from the clinica...

Cardiovascular (CV) death remains the largest cause of mortality in dialysis patients, unexplained by traditional risk factors. Endothelial microvesicles (EMVs) are elevated in patients with traditional CV risk factors and acute coronary syndromes while platelet MVs (PMVs) are associated with atherosclerotic disease states. This study compared relative concentrations of circulating MVs from endothelial cells and platelets in two groups of dialysis patients and matched controls and investigated their relative thromboembolic risk. MVs were isolated from the blood of 20 haemodialysis (HD), 17 peritoneal dialysis (PD) patients and 20 matched controls. Relative concentrations of EMVs (CD144+ ve) and PMVs (CD42b+ ve) were measured by Western blotting and total MV concentrations were measured using nanoparticle-tracking analysis. The ability to support thrombin generation was measured by reconstituting the MVs in normal plasma, using the Continuous Automated Thrombogram assay triggered with 1µM tissue factor. The total concentration of MVs as well as the measured sub-types was higher in both patient groups compared to controls (p<0.05). MVs from HD and PD patients were able to generate more thrombin than the controls, with higher peak thrombin, and endogenous thrombin potential levels (p<0.02). However there were no differences in either the relative quantity or activity of MVs between the two patient groups (p>0.3). Dialysis patients have higher levels of circulating procoagulant MVs than healthy controls. This may represent a novel and potentially modifiable mediator or predictor of occlusive cardiovascular events in these patients.

Purpose: Anemia is one of the most common disorders affecting the population in both low-income and developing countries. This study aimed to determine the prevalence of anemia and iron deficiency in apparently normal male and female students of

Advanced glycation end products (AGEs) are implicated in several central nervous system (CNS) pathologies including Alzheimer and Parkinson's diseases. In the face-off of AGE menace, we have attempted to investigate the zinc oxide nanoparticle (ZnONP) role in inhibition of AGE formation. Synthesized ZnONPs were used to investigate the inhibitory effects on AGE formation. The inhibitory effects of ZnONPs on AGE formation were determined by biophysical immunological and biochemical techniques. The results showed that ZnONP is a potential anti-glycating agent inhibiting AGE formation as well as protecting the protein structure from change. Therefore, our findings suggest ZnONPs may be used as a therapeutic in resolving the AGE role in CNS-related complications.

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Pulmonary embolism (PE) is a life-threatening complication arising from venous thromboembolism with a difficult diagnosis and treatment and is often associated with increased mortality and morbidity. PE had a significantly low incidence prior to the COVID-19 epidemic. This condition saw a sharp surge during the COVID-19 pandemic, indicating an evident viral influence on PE’s pathophysiology in COVID-19 patients. The hypercoagulable state induced by the viral load seems to be the major contributor, and the classical causative factors seem to play a lesser role. PE in COVID-19 infection has become a mammoth challenge since the diagnosis is quite challenging due to overlapping symptoms, lack of prior-known predisposing risk factors, limited resources, and viral transmittance risk. Numerous factors arising out of the viral load or treatment lead to an increased risk for PE in COVID-19 patients, besides the fact that certain unknown risk factors may also contribute to the incidence of PE in COVID-19 patients. The management of PE in COVID-19 infection mainly comprises thromboprophylaxis and anticoagulant therapy with mechanical ventilation, depending on the risk stratification of the patient, with a post-COVID-19 management that prevents recurrent PE and complications. This review aims to discuss various aspects of COVID-19-infection-associated PE and major differential aspects from non-COVID-19 PE.

Objectives:To evaluate the prevalence of undiagnosed hemoglobinopathies among individuals visiting the premarital screening Centre.Methods:This study was conducted at Premarital Screening Centre, King Fahad Central Hospital and Research Centre, Jazan, between January 2018 and October 2018. A total of 3,970 (male n =1,859 and female n = 2,111) individuals were included in the study. Data of complete blood count, hemoglobin electrophoresis and sickling tests of all individuals recruited in the study were obtained and statistically analyzed.Results:One thousand three hundred and twelve individuals had abnormal complete blood counts or hemoglobin electrophoresis results, that include sickle cell trait (13.5%), sickle cell disease (0.7%), β thalassemia with sickle cell trait (2.46%), β thalassemia trait (1.51%), β thalassemia major (0.075%), suspected α thalassemia or other hemoglobinopathies (4.43%), hemoglobin H (0.3%), hemoglobin E (0.075%), undiagnosed cases (0.91%) and iron deficient (7.23%).Conclusion:A high percentage of individuals are suspected for α thalassemia or other hemoglobinopathies that needs to be diagnosed. Further investigations shall be included in the premarital screening program to diagnose these inconclusive cases. Coexistence iron deficiency with thalassemia shall also be ruled out during premarital screening program.