Current Pharmaceutical Design - Volume 23, Issue 8, 2017

Reducing sugars can react non-enzymatically with amino groups of proteins and lipids to form irreversibly cross-linked macroprotein derivatives called as advanced glycation end products (AGEs). Cross-linking modification of extracellular matrix proteins by AGEs deteriorate their tertiary structural integrity and function, contributing to aging-related organ damage and diabetes-associated complications, such as cardiovascular disease (CVD). Moreover, engagement of receptor for AGEs, RAGE with the ligands evoke oxidative stress generation and inflammatory, thrombotic and fibrotic reactions in various kinds of tissues, further exacerbating the deleterious effects of AGEs on multiple organ systems. So the AGE-RAGE axis is a novel therapeutic target for numerous devastating disorders. Several observational studies have shown the association of dietary consumption of fruits and vegetables with the reduced risk of CVD in a general population. Although beneficial effects of fruits and vegetables against CVD could mainly be ascribed to its anti-oxidative properties, blockade of the AGERAGE axis by phytochemicals may also contribute to cardiovascular event protection. Therefore, in this review, we focus on 4 phytochemicals (quercetin, sulforaphane, iridoids, and curcumin) and summarize their effects on AGE formation as well as RAGE-mediated signaling pathway in various cell types and organs, including endothelial cells, vessels, and heart.

Cardiovascular disease still remains the primary cause of death worldwide and obesity is becoming recognized as one of the most critical contributing risk factors. The increased prevalence of obesity casts a cloud over the global health and the whole societies and will still be burdened in the future. Therefore, prevention and therapy of obesity is a beneficial strategy for the prevention of chronic cardiovascular disease. Numerous studies have demonstrated that gut microbiota takes part in human health and disease including obesity. Traditional herbs hold great potential to improve people’s health and wellness, particularly in the area of chronic inflammatory diseases although the mechanisms of action remain poorly understood. Emerging explorations of gut microbiotaherb interactions provide a potential to revolutionize the way we view herbal therapeutics. This review summarizes the experimental studies performed on animals and humans regarding the gut microbiota-herb interactions targeting obesity. This review also discusses the opportunity of herbs with potent activities but low oral bioavailability conundrum for prevention and therapy for obesity and related cardiovascular disease.

A wide variety of agents have been traditionally used in cardiovascular medicine worldwide and their precise mechanisms of action have been demonstrated to be largely related to the cardiomyocyte mitochondria and apoptosis. Abnormalities in the structure and function of the mitochondria and mutations in mitochondrial DNA can decrease energy production, alter the redox system, impair calcium homeostasis, and induce the mitochondrial permeability transition pore (MPTP), causing cell death. All of these data provide evidence of mitochondrial signaling pathways as targets to downregulate cardiac cell apoptosis and thus to prevent and treat cardiovascular diseases. This review focuses on the protective roles of various agents, mostly natural compounds, which express beneficial effects on mitochondrial function and suspend the apoptotic signaling mechanisms by modulating the activity of mitogen-activated protein kinases (MAPKs). Examining cellular and molecular targets of these agents offers essential experimental information for future pharmacological studies, drug discovery, clinical trials and applications.

Epigenetic mechanisms, which are involved in the regulation of gene expression, are tightly controlled. Loss of a proper epigenetic control can lead to global epigenetic alterations frequently observed in various diseases including cancer. Aberrant epigenetic changes induced in malignant cells lead to emergence of neoplastic properties, which inhibit cell differentiation and strict cell cycle control but greatly enhance stemness-related features. However, abnormal epigenetic patterns can be reversed by action of epigenetically active agents. Epigenetic machinery comprises a variety DNA/histone modifiers and chromatin remodelers. Chemical substances able to influence on the activity of epigenetic factors such as inhibitors of DNA methyltransferases or histone deacetylase inhibitors can be used as therapeutic agents for improving aberrant epigenetic signatures in cancer cells. Preclinical studies showed efficiency of such epigenetic drugs for the treatment of variety of cancers. So far, several epigenetically active compounds were approved for therapy of hematological malignancies. However, many challenges should be resolved for efficient use of epidrugs in the treatment of non-hematological solid tumors and advanced cancers associated with chemoresistance and higher risk of relapse.

The burden of cardio-vascular and other age-related non-communicable diseases are rapidly increasing worldwide. Majority of these chronic ailments are curable, if diagnosed at early stages. Candidate biomarkers of early detection are therefore essential for identification of high-risk individuals, prompt and accurate disease diagnosis, and to monitor therapeutic response. The functional significance of circulating nucleic acids that recapitulate specific disease profiles is now well established. But subtle changes in DNA sequence may not solely reflect the differentiation of gene expression patterns observed in diverse set of diseases as epigenetic phenomena play a larger role in aetiology and patho-physiology. Unlike genetic markers, knowledge about the diagnostic utility of circulating epigenetic signatures: methylated DNA; micro RNA and modified histones are deficient. Characterization of these novel entities through omics-based molecular technologies might prompt development of a range of laboratory-based strategies, thereby accelerating their broader translational purpose for early disease diagnosis, monitoring therapeutic response and drug resistance. However, largest opportunity for innovation lies in developing point-of-care tests with accurate diagnostic and higher prognostic score that is applicable for screening of high-risk populations.

Systemic hypertension and aortic valve stenosis (AVS) are both age-related diseases. Severe aortic stenosis affects ≈2% to 5% of adults age > 65 years. Systemic hypertension is a frequent comorbidity in patients with AVS and is coexistent for a longer period of time before AVS is treated. Essential systemic hypertension, per se, plays an important role in the creation of lesions on the aortic side of the valve, the region of higher exposure to tension stress. The subsequent endothelial defect represents the principal site of inflammatory process and oxidative stress, leading to aortic sclerosis and calcification. In this review, we want to describe the pharmacological features of the common antihypertensive drugs, analysing the recent literature, in order to achieve useful and updated information about the best treatment of systemic hypertension in patients with concomitant severe aortic stenosis.

Atherosclerosis is one of the main problems in modern medical practice. This multifactorial disease can remain asymptomatic for a long time before manifesting itself in cardiovascular disorders, causing ischemic heart disease, myocardial infarction and even sudden death. Many synthetic drugs have been developed to reduce the symptoms of atherosclerosis, however, their efficacy in terms of reduction of atherosclerotic lesions progression is a matter of debate. Adverse effects of the exiting therapy should also be taken into account. The development of cellular models and improved understanding of the mechanisms of atherogenesis at the vascular wall level helped establishing the “direct anti-atherosclerosis therapy” approach. In this approach, the decrease of intracellular lipid deposition and atherogenicity of human blood serum are considered primary (direct) antiatherosclerotic effects. Screening of synthetic and natural substances for anti-atherosclerotic activity revealed a number of botanicals that could be used for direct anti-atherosclerotic therapy to treat early-stage atherosclerosis. As a result, 3 novel non-pharmaceutical products were developed (Allicor, Inflaminat and Karinat). Studies on in vitro and ex vivo models of atherogenesis confirmed their anti-atherosclerotic and anti-atherogenic activities and safety in patients. Clinical studies of Allicor, Inflminat and Karinat were carried out in subjects with diagnosed early stage atherosclerosis, demonstrating a clinically significant anti-atherosclerotic effect of the drugs. In this overview, we will present the complete process of the development of novel non-pharmaceutical products and report the results obtained in the conducted pre-clinical and clinical studies of these medications.

Large-scale epidemiological studies firmly established the association between low plasma levels of high-density lipoprotein-cholesterol (HDL-C) and elevated risk of cardiovascular disease. This relationship is thought to reflect the key biological function of HDL, which involves reverse cholesterol transport from the arterial wall to the liver for further excretion from the body. Other aspects of the cardioprotective HDL functionality include antioxidative, anti-inflammatory, anti-apoptotic, anti-thrombotic, vasodilatory, anti-infectious and antidiabetic activities. Over the last decades, wide interest in HDL as an athero- and cardioprotective particle has resulted in the development of HDL-C raising as a therapeutic approach to reduce cardiovascular risk. Several strategies to increase circulating HDL-C concentrations were developed that primarily included use of niacin and fibrates as potent HDL-C raising agents. In the statin era, inhibition of cholesteryl ester transfer protein, infusion of artificially reconstituted HDL and administration of apolipoprotein A-I mimetics were established as novel approaches to raise HDL-C. More recently, other strategies targeting HDL metabolism, such as upregulation of apolipoprotein A-I production by the liver, were added to the list of HDL therapeutics. This review summarises current knowledge of novel HDL-targeting therapies and discusses perspectives of their use.

Over the past two decades, the viewpoint of atherosclerosis has been replaced gradually by a lipiddriven, chronic, low-grade inflammatory disease of the arterial wall. Current treatment of atherosclerosis is focused on limiting its risk factors, such as hyperlipidemia or hypertension. However, treatment targeting the inflammatory nature of atherosclerosis is still very limited and deserves further attention to fight atherosclerosis successfully. Here, we review the current development of inflammation and atherosclerosis to discuss novel insights and potential targets in atherosclerosis, and to address drug discovery based on anti-inflammatory strategy in atherosclerotic disease.

Background: Complex hemostatic mechanisms are involved in the pathophysiology of various diseases, including cardiovascular diseases. Among them, dysregulation of platelet activity is linked to the progression of atherosclerosis and mainly involves platelet aggregation and a decrease in blood flow in the vascular endothelium. The major platelet activation pathways mediated by agonists involve the arachidonic acid pathway, adenosine diphosphate pathway, serotonin pathway, nitric oxide pathway, and action of free radicals on molecules involved in platelet aggregation. These mechanisms have been widely studied and discussed because they are inhibited by the use of medicinal plants in complementary and alternative medicine, thus reducing platelet aggregation. Results: Of the main plants discussed in this review, which have antiplatelet activity, some include saffron, garlic, green tea, St. John's wort, ginger, ginkgo biloba, ginseng, and guavirova. These herbal medicines have phytochemical components, which are directly related to the antiplatelet activity of the plant, such as flavonoids, curcumins, catechins, terpenoids, polyphenols, and saponins. While the majority of the medicinal plants mentioned here were native to the Asian continents, some are distributed worldwide, and found to a smaller extent throughout the American continent, European continent, Mediterranean, African continent, and the Middle East. Conclusion: This review showed that several plants and/or compounds exhibit anti-platelet activity, and are therefore potential research targets for developing drugs to treat diseases related to aggregation disorders.

Heart failure, hypertension, cirrhosis and nephritic syndrome are among conditions that alter volume and composition of body fluids and are modulated by diuretics. Natural products are important source of diuretics and have been considered remarkable alternative with greater effectiveness and fewer side effects. However, many of these plants used in traditional medicine must be scientifically assessed about their efficacy and toxicity. Despite the large number of published articles claiming that plants or plant-derived components may act as diuretic agents, few studies have addressed the mechanism of action of medicinal plants. Thus, the aim of this review was to provide an overview of the current knowledge about the major cellular and molecular mechanisms of diuretic plants and/or their main compounds. Many well-established mechanisms (water channels, renal carriers, nitric oxide-cGMP and prostaglandin-cAMP pathways, renin-angiotensin and kinin-kallikrein systems, carbonic anhydrase, and osmotic effects), along with other newly identified targets, are connected to the diuretic activity of many natural products. However, the central path responsible for the activity of these agents remains unclear. Further studies may help clarifying the central role of each of these pathways in the pleiotropic response of these agents.

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. Herbal medicine and exercise interventions have individually been shown to be effective in the prevention and management of CVD. However, the complementary roles of herbal medicine and exercise interventions for CVD prevention and management have not been adequately reported. Objective: 1. Identify studies analysing complementary roles of herbal medicine and exercise intervention in CVD prevention and management, 2. Identify herbs and exercise strategies that have been reported to exhibit complementary roles in CVD prevention and management, and 3. Summarize evidence of complementary roles of herbal medicine and exercise interventions for CVD prevention and management. Method: PubMed, CINAHL and Web of Science were searched with a customised search strategy in May 2015. Two reviewers screened the search results for inclusion using pre-specified criteria. Data were extracted from full text of selected abstracts in a predetermined template by two reviewers and verified by the third reviewer when needed. Results: A total of 35 titles were identified for full texts review after screening 827 abstracts. Data were extracted from 23 titles, representing 12 human studies and six animal studies. This review identified effects of 14 different herbs and 10 exercise strategies on over 18 CVD risk factors and markers. Complementary roles of herbal medicine and exercise were reported from five studies. Conclusion: Evidence of complementary role of herbal medicine and exercise is emerging from animal studies. More robust clinical studies on proven risk factors are needed before they can be recommended for clinical practice.

Background: Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood. It represents a major public health issue, with a prevalence of over 23 million worldwide. The lifetime risk of developing HF is one in five and the most important risk factors identified are ischemic heart disease, hypertension, smoking, obesity and diabetes. Preventive approaches are based on improvements of lifestyle, associated with pharmacological therapy. Several nutraceuticals have shown interesting clinical results in prevention of HF as well as in the treatment of the early stages of the disease, alone or in association with pharmacological therapy. Aim: The aim of this review is to resume the available clinical evidence on phytochemicals effect on HF prevention and/or treatment. Methods: A systematic search strategy was developed to identify trials in PubMed (January 1980 to April 2016). The terms ‘nutraceuticals’, ‘dietary supplements’, ‘herbal drug’ and ‘heart failure’ were incorporated into an electronic search strategy. Results: Clinical trials reported that the intake of some nutraceuticals (hawthorn, coenzyme Q10, L-carnitine, Dribose, Carnosine, Vitamin D, Some probiotics, Omega-3 PUFAs, Beet nitrates) is associated with improvements in functional parameters such as ejection fraction, stroke volume and cardiac output in HF patients, with minimal side effects. These findings were sometimes reinforced by subsequent meta-analyses, which further concluded that benefits tended to be greater in earlier stage HF. The main mechanisms involved are antioxidant, antinflammatory, anti-ischemic and antiaggregant effects. Conclusions: Evidence suggests that the supplementation with nutraceuticals may be a useful option for effective management of HF, with the advantage of excellent clinical tolerance.