Novel antiplatelet targets in the treatment of acute coronary syndromes

Acute coronary syndromes (ACS) are a global cause of mortality and morbidity that affect millions of lives worldwide. Following atherosclerotic plaque rupture, platelet activation and aggregation are the two major elements that initiate thrombus formation inside a coronary artery, which can obstruct blood flow and cause myocardial ischemia; ergo, antiplatelet therapy forms a major part of the treatment strategy for ACS. Patients with ACS routinely receive dual antiplatelet therapy (DAPT), which consists of aspirin and a platelet P2Y12 inhibitor to both treat and prevent atherothrombosis. Use of platelet glycoprotein (GP) IIb/IIIa inhibitors is now limited due to the risk of severe bleeding and thrombocytopenia. Thus, administration of GPIIb/IIIa inhibitors is generally restricted to bail out thrombotic events associated with PCI. Furthermore, current antiplatelet medications mainly rely on thromboxane A2 and P2Y12 inhibition, which have broad-acting effects on platelets and are known to cause bleeding, which especially limits the long-term use of these agents. In addition, not all ACS patients treated with current antiplatelet treatments are protected from recurrence of arterial thrombosis, since many platelet mechanisms and activation pathways remain uninhibited by current antiplatelet therapy. Pharmacological antagonism of novel targets involved in platelet function could shape future antiplatelet therapies that could ultimately lead to more effective or safer therapeutic approaches. In this article, we focus on inhibitors of promising targets that have not yet been introduced into clinical practice, including inhibitors of GPVI, protease-activated receptor (PAR)-4, GPIb, 5-hydroxytryptamine receptor subtype 2A (5-HT2A), protein disulfide isomerase, P-selectin and phosphoinositide 3-kinase β

GC-MS-based profiling and ameliorative potential of Carissa opaca Stapf ex Haines fruit against cardiac and testicular toxicity: An In vivo study

Fruit of Carissa opaca Stapf ex Haines (C. opaca) is a feed additive and is commonly used against cardiac dysfunction, fever, asthma, diarrhea, gastrointestinal ailments, and skin diseases. In this study, we aimed to evaluate the metabolic profile and antioxidant potential of C. opaca fruit against carbon tetrachloride (CCl4)-induced cardiotoxicity and testicular toxicity in rats. Gas Chromatoghraphy-Mass Spectrometry (GC-MS) analysis of C. opaca fruit for the identification of potential metabolic profile, followed by methanolic extract of C. opaca and its derived fractions including n-hexane, ethyl acetate, chloroform, butanol, and aqueous were used to assess the antioxidant potential of fruits. Ten groups of rats received different treatments and got evaluated for cardiac and testicular antioxidant enzymes, histological architecture, and serum hormonal levels. GC-MS analysis of methanolic extract of C. opaca fruit showed the presence of some bioactive metabolites like cyclodecane, diethyl 2,6-pyridine dicarboxylate, tetrahydro-geraniol, S-[2-[N, N-Dimethylamino]ethyl]morpoline, 2,3-Methylenedioxyphenol, alpha-d-Glucopyranoside, 5,10-Diethoxy-2,3,7,8-tetrahydro-1H, 6H-dipyrrolo [1,2-a; 1′,2′-d] pyrazine and 1,3-Benzothiazol-2(3H)-one,3-(3,3-dimethyl-1-oxobutyl) that corresponds the medicinal properties of C. opaca fruit. Prepared fractions of C. opaca fruits mitigated the toxicity induced by CCl4 in the heart and testicular tissues of rats. Oxidative stress was caused by the inhibition of activities of glutathione and other antioxidant enzymes of the body, while on the other hand elevating the levels of nitrite and hydrogen peroxide. Treatment with C. opaca fruit extract normalized the levels of enzymes, reproductive hormones, and free radicals thus restoring the histopathological and enzymatic biomarkers towards the normal group. The study supports the indigenous use of fruits as an alternative medicine against cardiac dysfunction by providing scientific evidence of protection against CCl4-induced injuries, and it also concludes the antioxidant defensive role in testicular tissues

Impact of Methionine Synthase Reductase Polymorphisms in Chronic Myeloid Leukemia Patients

Introduction： Metabolism methionine and of folate play a vital function in cellular methylation reactions, DNA synthesis and epigenetic process.However, polymorphisms of methionine have received much attention in recent medical genetics research. Objectives: To ascertain whether the common polymorphisms of the MTRR (Methionine Synthase Reductase) A66G gene could play a role in affecting susceptibility to Chronic Myeloid Leukemia (CML) in Sudanese individuals. Methods: In a case-controlled study, we extracted and analyzed DNA from 200 CML patients and 100 healthy control subjects by the PCR-RFLP method. Results: We found no significant difference in age orgender between the patient group and controls. The MTRR A66G genotypes were distributed based on the Hardy-Weinberg equilibrium (p > 0.05). The variation of MTRR A66G was less significantly frequent in cases with CML (68.35%) than in controls (87%) (OR = 0.146, 95% CI = 0.162–0.662, p < 0.002). Additionally, AG and GG genotypes and G allele were reducing the CML risk (Odds ratio [OR] = 0.365; 95% CI [0.179–0.746]; p = 0.006; OR = 0.292; 95% CI [0.145–0.590]; p = 0.001 and OR = 0.146; 95% CI [0.162–0.662]; p = 0.002 and OR = 2.0; 95% CI [1.3853–2.817]; respectively, (p = 0.000)). Conclusions: Our data demonstrated that heterozygous and homozygous mutant genotypes of MTRR polymorphisms were associated with decreased risk of developing CML in the Sudanese population

Effects of Thymoquinone Alone or in Combination with Losartan on the Cardiotoxicity Caused by Oxidative Stress and Inflammation in Hypercholesterolemia

Dietary cholesterol accelerates oxidative and pro-inflammatory processes, causing hypercholesterolemia and cardiovascular diseases. Thus, the purpose of the current study is to compare the protective effects of thymoquinone (TQ) alone or in combination with losartan (LT) against the heart damage caused by a high-cholesterol diet (HCD). HCD-fed rat groups revealed an elevated activity of indicators of cardiac enzymes in the serum. Serum and cardiac lipids were also found to be significantly higher in HCD-fed rat groups. Cardiac pro-inflammatory and oxidative markers were also increased in HCD-fed rat groups, whereas antioxidant indicators were decreased. However, all of these biochemical, inflammatory, antioxidant, and oxidative change indicators returned to levels similar to those of normal rats after treatment with TQ alone or in combination with LT administered to HCD-fed rat groups. Hypercholesterolemia considerably induced the lipid peroxidation product, thiobarbituric acid reaction substances (TBARs), and oxidative radicals in cardiac cells, which were attenuated by QT and LT treatments, particularly when combined. Finally, QT, LT, and their combination were able to reduce the histological changes changes brought on by cholesterol excess in cardiac tissues. In conclusion, administration of TQ in a combination with LT which has a better protective effect, significantly reduced the hypercholesterolemic-induced oxidative and inflammatory changes that occurred in cardiac tissue

Insight into Oncogenic Viral Pathways as Drivers of Viral Cancers: Implication for Effective Therapy

As per a recent study conducted by the WHO, 15.4% of all cancers are caused by infectious agents of various categories, and more than 10% of them are attributed to viruses. The emergence of COVID-19 has once again diverted the scientific community’s attention toward viral diseases. Some researchers have postulated that SARS-CoV-2 will add its name to the growing list of oncogenic viruses in the long run. However, owing to the complexities in carcinogenesis of viral origin, researchers across the world are struggling to identify the common thread that runs across different oncogenic viruses. Classical pathways of viral oncogenesis have identified oncogenic mediators in oncogenic viruses, but these mediators have been reported to act on diverse cellular and multiple omics pathways. In addition to viral mediators of carcinogenesis, researchers have identified various host factors responsible for viral carcinogenesis. Henceforth owing to viral and host complexities in viral carcinogenesis, a singular mechanistic pathway remains yet to be established; hence there is an urgent need to integrate concepts from system biology, cancer microenvironment, evolutionary perspective, and thermodynamics to understand the role of viruses as drivers of cancer. In the present manuscript, we provide a holistic view of the pathogenic pathways involved in viral oncogenesis with special emphasis on alteration in the tumor microenvironment, genomic alteration, biological entropy, evolutionary selection, and host determinants involved in the pathogenesis of viral tumor genesis. These concepts can provide important insight into viral cancers, which can have an important implication for developing novel, effective, and personalized therapeutic options for treating viral cancers

Enhanced apoptotic activity of Pluronic F127 polymer-encapsulated chlorogenic acid nanoparticles through the PI3K/Akt/mTOR signaling pathway in liver cancer cells and in vivo toxicity studies in zebrafish

In this study, chlorogenic acid nanoparticles encapsulated in Pluronic F127 polymer were synthesized and characterized to determine if they could treat human liver cancer. The nanoparticles were synthesized using standard procedures and characterized using physical and biological techniques such as X-ray diffraction, Fourier transform infrared spectroscopy, UV-Vis, dynamic light scattering, Photoluminescence, scanning electron microscopy, and transmission electron microscopy. The anticancer effects were assessed using MTT analysis, acridine orange/ethidium bromide, reactive oxygen species (ROS), COMET assay, annexin-V/FITC, cell cycle analysis, and expression of marker genes against HepG2 cell lines. The results showed significant cytotoxicity, apoptosis induction, and increased ROS production in treated cells compared to control cells. The nanoparticles also activated the apoptotic cascade and regulated the PI3K/AKT/mTOR pathways. The nanocomposites exhibited unique characteristics such as anticancer efficacy in vitro. Further research was conducted using zebrafish to model hematological parameters, liver enzymes, and histopathology to study effectiveness. Green-synthesized Pluronic F127–chlorogenic acid nanoparticles can be considered potential cancer therapy agents