Cardiovascular & Haematological Disorders - Drug Targets - Volume 18, Issue 1, 2018

Background: Smooth muscle contraction is triggered primarily by activation of Ca2+/calmodulin-dependent myosin light chain kinase leading to phosphorylation of the regulatory light chains of myosin II. Numerous contractile stimuli also induce inhibition of myosin light chain phosphatase thereby prolonging the contractile response. The phosphatase is a trimeric enzyme containing a catalytic subunit, a regulatory, myosin-binding subunit (MYPT1) and a third subunit of uncertain function. MYPT1 is phosphorylated at multiple sites by several kinases, which regulate phosphatase activity, protein-protein interactions and subcellular localization. The best-characterized phosphorylation events involve phosphorylation by Rho-associated coiled-coil kinase (ROCK) at T697 and T855, which inhibits phosphatase activity, and phosphorylation by cAMP- or cGMPdependent protein kinases (PKA and PKG, respectively) at S696, T697, S854 and T855, which has no effect on phosphatase activity. Furthermore, phosphorylation by ROCK at T697 and T855 prevents phosphorylation by PKA or PKG at the neighboring serine residues. Some 30 phosphorylation sites have been identified in MYPT1 with many more suggested by large-scale phosphoproteomic studies. It is important to gain as complete understanding as possible of the complex phosphorylation-mediated mechanisms of regulation of MYPT1 functions in part because of their involvement in pathological processes. For example, dysfunctional MYPT1 phosphorylation has been implicated in the pathogenesis of several vascular disorders, including type 2 diabetes. Conclusion: Much effort is now being devoted to the development of novel therapeutics targeting MYPT1 and specific kinases involved in the phosphorylation of MYPT1.

Background: Recently, the treatment and prevention of ischemic cardiomyopathy is one of the emerging research topics in the cardiovascular field. Gap junction is the basic structure of cardiac electrophysiology. Connexin is the basic unit of gap junctions. Connexin43(CX43) is the most abundant member of Cx family in the heart, the normal expression of Cx43 is important for heart development, electrically coupled cardiomyocytes activities and coordination of myocardial function. The connection between Cx43 and myocardial ischemia/reperfusion or reperfusion injury has become the focus of current research. Methods: We undertook a structured search of bibliographic database for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyze the interventions and findings of included studies using a conceptual framework. Results: Twenty-one papers were included in the review, eight papers outlined the relationship of Cx43 and reperfusion arrhythmias. Eight papers pointed out the effect on the infarct size of Cx43. Conclusion: The findings of this review confirm that Cx43 is the most abundant member of Cx family in the heart and is vital for myocardial protection during ischemia/reperfusion process and for ischemia/reperfusion injury. Many of its mechanism are still not very clear and require future research in the future.

Atherosclerosis affects the majority of adult individuals in industrialized nations and it is beginning to affect even traditionally spared populations. The classic view has been that the precipitating events are intraluminal. However, good evidence supports the possibility that at least part of the atherosclerosis burden may be the consequence of extra-luminal noxious stimuli. Additionally, the epidemic of obesity, insulin resistance and diabetes mellitus has generated a strong interest in the potential role of visceral adipose tissue as an extra-luminal promoter of atherosclerosis. The epicardial space is filled with adipose tissue with an embryological origin similar to that of abdominal visceral fat. Both fats are highly inflamed in obese patients, patients with the metabolic syndrome and in those with established coronary artery disease. Additionally they are capable of secreting large quantities of pro-inflammatory cytokines and free fatty acids but also anti-inflammatory adipokines like adiponectin. In this manuscript we review the current evidence supporting the role of epicardial adipose tissue in the development of atherosclerosis and its complications.

Cholesterol is an important lipid for maintaining cell membrane fluidity and generation of various hormones and bile acids. Thus, it is critical to maintain cholesterol homeostasis including absorption, trafficking, biosynthesis, and efflux; dysregulation of cholesterol homeostasis may lead to human disorders such as atherosclerosis. As a cholesterol sensor, nuclear receptor liver X receptor (LXR) is an important factor regulating cholesterol homeostasis. Extensive research has been carried out to examine the roles of LXR in atherosclerosis. In this review, we summarize our current understanding of the mechanisms how LXR regulates cholesterol synthesis, efflux, absorption, and conversion of cholesterol esters to cholesterol in the context of atherosclerosis. In addition, we also discuss the possibility of targeting LXR and cholesterol homeostasis as a potential interventional strategy for treating atherosclerosis.

Decades of research has provided evidence for the role of the endocannabinoid system in human health and disease. This versatile system, consisting of two receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and metabolic enzymes has been implicated in a wide variety of disease states, ranging from neurological disorders to cancer. CB2 has gained much interest for its beneficial immunomodulatory role that can be obtained without eliciting psychotropic effects through CB1. Recent studies have shed light on a protective role of CB2 in cardiovascular disease, an ailment which currently takes more lives each year in Western countries than any other disease or injury. By use of CB2 knockout mice and CB2-selective ligands, knowledge of how CB2 signaling affects atherosclerosis and ischemia has been acquired, providing a major stepping stone between basic science and translational clinical research. Here, we summarize the current understanding of the endocannabinoid system in human pathologies and provide a review of the results from preclinical studies examining its function in cardiovascular disease, with a particular emphasis on possible CB2-targeted therapeutic interventions to alleviate atherosclerosis.

Background: The immunomodulatory properties of Nigella sativa seed, as a basis of its clinical applications by many cultures have been reviewed. Thymoquinone (TQ) is one of the major bioactive components of the volatile oil of N. sativa seeds. Methods: The review on immunomodulatory and anti- inflammatory effects of TQ was focused on published literature in the English language. The literature search was conducted in the following databases: PubMed (2004-2017), Scopus (2004-2017) and Google Scholar (2004-2017). The keywords used were the following terms: thymoquinone, immunomodulation, inflammation, autoimmune and asthma. Results: The present investigations provide a comprehensive review of the ability of TQ to modulate inflammation and immune-related disorders in the various important disease states. This finding showed that TQ has anti-inflammatory properties that prevent the biosynthesis of important mediators in inflammatory processes and asthma such as 5-LO, COX, PGD2 and LTs. TQ also reduced LPS-induced proinflammatory cytokines such as interleukins (ILs) and TNF-α. In addition, TQ showed immunomodulatory role in the cellular and humoral immunity. This study also found that TQ improves imidacloprid toxicity through reducing oxidative stress and increasing chemokinesis, chemotaxis, phagocytic activity, antibody levels and the hemagglutination of immunoglobulins as well as by reducing serum MDA levels and hepatic enzymes. Conclusion: The study indicated the beneficial effects of TQ in immune-related diseases, however, well designed clinical trials in humans are required to confirm these effects.

Background: The developments of new parenteral approaches to target PCSK-9 for the treatment of LDL-Cholesterol has yielded impressive results; and have shown significant decreases in the risk of mortality associated with hypercholesterolemia. However improved and convenient alternate approaches that exploit the beneficial drug target properties of PCSK-9 also need to be explored and developed. One such approach is the oral administration of Berberine using nanotechnology. Methods: Nanoprecipitation encapsulation and physiochemical characterization of Berberine Chloride in PLGA-PEG-PLGA block copolymer has been developed and characterized in Hep-G2 cells using Berberine Chloride encapsulated nanoparticle (Bc-NP). Evaluation of PCSK-9, SREBP- 1, LDL-r, HNF-1alpha mRNAs and PCSK-9 protein expression was performed using quantitative real-time PCR (qPCR) and median fluorescence intensity (MFI) of flow cytometric studies respectively. Pearson's correlation analysis of PCSK-9 mRNA and protein levels in Berberine chloride delivery was performed. Results: The PCSK-9 mRNA and protein expression shows a relationship to the release of Berberine from the encapsulating PLGA-PEG-PLGA polymer in a time dependent manner. Conclusion: PCSK-9 modulation by oral administration of Berberine using nanotechnology approach can improve its pharmacokinetic profile. Further studies are needed to maximize its delivery efficiency.

Introduction: Anvillea radiata Coss. & Durieu (Asteraceae) is an endemic plant from North Africa (Morocco and Algeria). This plant has many traditional uses including treatment of obesity and diabetes. Aim of the Study: The study aims to evaluate the antidiabetic effect of aqueous extract of Anvillea radiata (A. radiata) leaves on both normal and streptozotocin (STZ)-induced diabetic rats treated at a dose of 10 mg/kg body weight for fifteen days. In addition, a preliminary pytochemical screening for various components was realized. Results: The blood glucose levels were lowered in diabetic rats treated with A. radiata, but no effect was observed in normal rats. Single oral administration of A. radiata reduced blood glucose levels from 22.15±0.98 mmol/L to 14.00±1.89 mmol/L (p<0.0001) six hours after administration in STZ diabetic rats. Furthermore, blood glucose levels were decreased from 22.15±0.98 mmol/L to 4.39±1.29 mmol/L (p< 0.0001) in STZ diabetic rats after fifteen days of treatment. According to the oral glucose tolerance test, the A. radiata (10 mg/kg) was shown to significantly prevent the increase in blood glucose levels in normal treated rats 30 min, 60 min and 120 min after glucose administration when compared to the control group. Concerning the preliminary phytochemical screening of A. radiata, several compounds of chemicals have been found such as polyphenols, flavonoids, tannins, mucilage, sesquiterpenes, terpenoids and carbohydrates. Conclusion: The results show that aqueous extract of A. radiata leaves possesses a significant antihyperglycemic activity.