Cardioprotective Natural Products

The following sections are included:

• Dedication
• Contents
• Foreword
• Preface
• Editor Biography
• List of Contributors

This chapter is aimed to offer an overview of the present book, and summarizes the contents and subject matter of each chapter with an intention to highlight on certain glimpses of the coverage to the readers before they go in-depth.

For thousands of years, nature has supplied us food and an unlimited source of compounds for treating various diseases. It is now well-established that the type of food-intake directly affects human health. Most of the chronic diseases have direct correlation with a long-term poor diet. Therefore, researchers, physicians, and pharmaceutical industries are discovering and popularizing the most effective nutrients to prevent or treat various diseases. Based on the worldwide heart disease mortalities, and the abundant research on the natural cardioprotective compounds, we have reviewed the potential natural remedies for heart diseases. Among various mechanisms, we have elaborated herein on the inhibitory effects of the most studied natural compounds (e.g. fatty acids and flavonoids) on matrix metalloproteinases (MMPs) which are overexpressed in cardiovascular diseases.

Cardiovascular disease is the name for the cluster of disorders of the heart and blood vessels, including hypertension, coronary heart disease (heart attack), cerebrovascular disease (stroke), heart failure and peripheral vascular disease. A steady increase of cardiac disorders has been observed recently throughout the world. A search for herbal and natural cardioprotective agents with minimum or no side effects is therefore gaining interest. From ancient times natural products have been considered as an extremely productive source for new medicines and continue to deliver a great variety of structural templates for drug discovery and development. In this chapter, we would like to discuss the prophylactic role of some natural antioxidant cardioprotective agents in drug- and toxin-induced pathophysiological conditions along with their underlying mechanisms of action.

In the recent past, a number of medicinal plants have been scientifically evaluated and found effective in the treatment of cardiovascular diseases. Extracts of several plants have been found to ameliorate cardiotoxicity induced by a variety of agents like arsenic, cadmium, aflatoxin, and so forth. Extracts of other plants like Urtica parviflora, Curcumis trigonus, Premna serratifolia, Mangifera indica, Olea europaea and so forth were found to have cardioprotective effect against isoproterenolinduced myocardial infarction. Other drugs like doxorubicin and cyclophosphamide induced oxidative stress and cardiotoxicity was found to be suppressed by extracts of plants like Terminalia arjuna, Stachys schimperi Vatke and so forth. Many phytochemicals with cardioprotective activity have also been isolated from different parts of various plants. Echinocystic acid, a pentacyclic triterpene isolated from the fruits of Gleditsia sinensis; rutin obtained from the plant Sophora japonica; salvianolic acids isolated from dried root of Salvia miltiorrhiza; gallic acid, an endogenous plant phenol; mangiferin from Mangifera indica; epigallocatechin gallate from leaves of Camellia sinensis; oleuropein from Olea europaea; resveratrol, a phytoalexin extracted from Polygonum cuspidatum and grapes are some of the well-studied plant-derived cardioprotective agents. Apart from the plant-derived natural cardioprotective molecules, some other natural agents were also found with promising cardioprotective activity. Polysaccharides (chitin and fucoidan) derived from marine algae are also found to play a vital role in cardioprotective activity.

Therefore, from the above discussion it is clear that these molecules serve as important cardioprotective agents in different drugs- and toxininduced pathophysiological conditions. It can, thus, be anticipated that these natural products may also augment the conventional treatment and offer better management of the cardiovascular diseases with minimum or no side effects.

Cardiovascular diseases remain the major cause of death throughout the world. Apart from various natural risk factors, certain drugs, especially anthracyclines, are involved in the incidence of cardiotoxicity. Although anthracyclines revolutionised the cancer treatment, the complications associated with the treatment are limiting their use as effective chemotherapeutic agents. Cardiomyopathy, congestive heart failure and alterations in the electrocardiogram (ECG) are the major shortcomings reported with the use of these drugs. Cardiac tissue is highly prone to damage from oxidative stress and anthracyclines were known to cause cardiac damage by increasing the production of ROS. They are also known to cause mitochondrial and inflammatory damage which further progresses to apoptosis and necrosis.

Use of plants and plant-based products in the treatment of ailments is known to mankind from ancient times and major research is focused on harnessing the potential of various phytochemicals for the treatment of diseases. Numerous preclinical studies revealed the beneficial effects of natural compounds against cardiotoxicity. Apart from being rich sources of antioxidants, phytochemicals are also known to impede the progression of cardiac tissue damage. The present chapter offers an account of some phytochemicals and natural compounds found effective against cardiotoxicity along with elucidating their underlying mechanisms of action.

Doxorubicin (DOX) is a potent and widely used anthracycline antibiotic as anti-cancer drug; however, it also causes dose-dependent organ toxicity, mainly cardiotoxicity. The occurrence of fatal cardiotoxicity characterized by an irreversible cardiomyopathy often compromised the clinical usage of DOX. The appearance of association between significant burden of cancer and chemotherapy-induced cardiotoxicity brings enthusiasm among researchers for search of targeted strategies that can simultaneously provide long-term cardio-protection from DOX-associated cardiotoxicity without compromising the efficacy of DOX. Numerous preclinical and human studies reveal that oxidative stress, inflammation and subsequent cardiomyocytes apoptosis are the primary pathogenic mechanisms leading to cardiomyopathy. The clinical application of traditional cytotoxic drugs remains to continue a favored mode for the treatment of cancer due to inadequacies of presently available adjuvants in terms of pharma-economics, short-term efficacy and innate adverse effects. Recently, various dietary plants of natural origin gained attention as anticancer, chemopreventive and cardioprotective agent. Apart from synthetic agent, the naturally occurring plants may prove to be better as adjuvants in chemotherapy. The ideal cardioprotective agents should not interfere with cytotoxicity of DOX and will be devoid of cumulative or irreversible toxicity along with capacity to reverse chemoresistance or chemosensitize the tumor cells to DOX. In the past few years, plant derivedphytochemicals as novel small molecules of natural origin found to either prevent or reverse the cardiotoxicity caused by DOX pursuing disease modifying approach. The present review renders an overview of cardioprotective effects of some promising plants against DOXinduced cardiotoxicity in experimental models. The review employing the synoptic tables documents the cardioprotective potential of plant extracts, the experimental models used and the major mechanism of cardioprotection. The review also discusses the challenges, limitations and future prospects in pharmaceutical development of plants extracts and their potential utilization for further drug development characterizing the potential phytoconstituents attributed to the cardioprotective efficacy. These compounds may provide an alternative and valuable source of ideal, cost-effective, safe adjuvant to chemotherapy utilized for drug discovery and development. These could be utilized as effective cardioprotective agents in management of DOX-associated cardiotoxicity.

Cardiovascular diseases (CVDs), whether congenital or acquired, are considered as a leading cause of death worldwide. Acquired CVDs are greatly correlated to dietary and other life style factors including inadequate nutrition style, exposure to oxidative stress and lack of exercise. In fact, CVDs can be easily prevented and/or controlled, as advised by physicians, through quit of smoking, consumption of diet rich in polyunsaturated fatty acids, control of blood pressure, increase in physical activity, and maintenance of weight within normal limits.

In addition, certain functional foods and dietary supplements are reported to contain diverse physiologically active components with established potential in the management and/or prevention of CVDs, especially those acquired. The present chapter is intended to survey the beneficial role of these products and their individual ingredients with special emphasis on their chemical composition and mode/mechanism of action.

The role of dietary plant metabolites, viz. polyphenols, phytosterols and phytostanols, terpenoids and saponins as cardioprotective, are separately overviewed in this chapter. Besides, examples of commonly used herbs and herbal products, claimed to reduce CVD-risk incidence and suggested for incorporation in daily diets, are also mentioned.

Cardiovascular disease is the major cause of morbidity and mortality worldwide due to its complex pathogenesis. A different type of cardiovascular disease includes hypertension, coronary heart disease (heart attack), cerebrovascular disease (stroke), heart failure and peripheral vascular disease. Recent years have witnessed a steady increase in the incidence of cardiovascular disorders throughout the world. Naturally occurring new promising molecules are being extracted, examined and considered to be potential therapeutic targets recently as those are considered relatively safe and non-toxic, and usually derived from commonly consumed foodstuff. So, search for herbal and natural cardioprotective agents with minimum or no side effect is therefore gaining increasing interest. Such chemical substances derived from natural sources have been investigated and proved to be beneficial for the treatment of human diseases for a long time. Some recent reviews and reports described the importance of natural products and the therapeutic properties of extracts from plants in various types of cardiac disease. These compounds could also serve as one of the valuable sources in industrial pharmaceutical research and can be treated as complementary and alternative medicine. Oxidative stress plays an important role in various types of cardiac pathophysiology. In this chapter, we would like to highlight the beneficial role of some bioactive molecules in cardiac pathophysiology and also plan to discuss the underlying mechanism of their protective action. The multifunctional therapeutic applications of small bioactive molecules are also well established. Arjunolic acid, a naturally occurring long chiral triterpenoid saponin isolated from the bark of Terminalia arjuna, is well reputed for a multitude of biological activities, including antioxidant, antidiabetic, antifungal, antibacterial, anticholinesterase, antitumor, antiasthmatic, wound healing and insect growth inhibitor activity. However, this compound is particularly well known for its beneficial role in cardiac disease. Taurine, a conditionally essential amino acid, also has clinical implications for the prevention of toxin and druginduced cardiac dysfunction. Ginkgo biloba is also familiar to have intrinsic antibiotic and anti-fungal properties for a long time. The extract from this plant has been well reported to prevent cardiac damage in drug-induced pathophysiology. Morin also considered as major bioactive molecule which is beneficial for the prevention of hepatotoxicity and also the protective effects of this molecule against oxidative stress and inflammation. In addition many signaling molecules like p38 and ERK1/2 MAPKs, etc. play important roles in regulating oxidative stress and cardiac damage. The role of all these compounds and signaling molecules has been discussed in this book chapter. These discussions untie the multifunctional therapeutic application of small bioactive molecules and represent a therapeutic promise of alternative medicine in cardiac diseases. It can thus, be anticipated that these natural products may also augment the conventional treatment and offer better management of the cardiovascular diseases with minimum or no side effects.

Since the discovery in 2003 of Proprotein Convertase Subtilisin Kexin9 (PCSK9), the 9^th and final member of this family of enzymes, it has become the most widely studied PCSK because of its crucial role in cholesterol metabolism. This secreted soluble protein is expressed predominantly in the liver and can also be produced in the cerebellum, small intestine, and kidney. Extensive research during the past decade has confirmed that PCSK9 plays a key role in maintaining a correct balance of Low Density Lipoprotein (LDL)-cholesterol via its action in degrading the LDL-Receptor (LDL-R). Thus higher levels of circulating PCSK9 coincide with lower levels of the LDL-R leading to reduced clearance of LDL-cholesterol from the blood — a condition known as “Hypercholesterolemia” which is considered a risk factor for cardiovascular diseases such as hypertension and stroke. Years of research has identified a number of mutations in the human PCSK9 gene. Mutations causing “gain of function” in PCSK9 are of great concern because they lead to an accumulation of plasma LDLcholesterol due to reduced LDL-R levels. Hence, PCSK9 represents a novel target for treating dyslipidemia, most notably in patients with increased cardiovascular disease (CVD) risk. Thus serious attention has been devoted towards the development of PCSK9 inhibitors as potential therapeutic agents as an alternative to statins for lowering LDL-cholesterol. Already two PCSK9 inhibitors namely Alirocumab (Praluent®) and Evolocumab (Repatha™) have been developed by Sanofi-Regeneron Pharmaceutical Companies, and Amgen Pharmaceutical Company respectively. These protein-based monoclonal antibody drugs were approved by the Food & Drug Agency (FDA), USA and European Drug/ Medicine Agency in late 2015 as a new class of lipid lowering agents. A third drug, Bococizumab developed by Pfizer Company is currently in phase 3 of clinical trial but recently Pfizer dropped this program. Although effective, the above two drugs are highly expensive and require administration via sub-cutaneous injection. Owing to these reasons, efforts are ongoing to develop small molecule, less expensive and orally active PCSK9 inhibitors. To date, only a few peptides and natural products have generated some interests in this regard. But none of these are used as drugs due to lack of potency, specificity or other reasons including toxicity. Thus alternate strategies are required for the development of such compounds. Because of this, we turn our attention to medicinal plants as possible sources. Specifically we focus on four key plants which have been shown by scientific and/or traditional in vitro studies to lower plasma cholesterol and lipid. Additionally some of these plant extracts also showed cardioprotective activities in animal and cellular models. These plants are (i) Allium sativum (garlic), (ii) Mimosa pudica, (iii) Enicostemma littorale Blume (or Swertia japonica) and (iv) Coleus forskohlii. We became particularly interested in the major chemical constituent of these plants namely Allicin, Mimosine, Swertiamarin and Forskolin. These commercially available natural compounds were investigated in vitro using liver cell lines for their potential hPCSK9 inhibitory and hLDL-R promoting activity. The results were compared with that of berberine, a natural alkaloid from the plant Berberis vulgaris that has been shown to exhibit cholesterol-reducing activity. Herein we report the comparative bio-activities of these compounds in model hepatic cells and discuss their therapeutic potential as non-statin based small molecule agents for lowering cholesterol. Based on our studies conducted in two human hepatic cell lines, namely Huh7 and HepG2, we conclude that forskolin, mimosine and swertiamarin promote hLDL- R level without significantly changing hPCSK9 levels. Among these forskolin appears to be most effective and thus deserves further investigation for its anti-lipidemic and anti-cholesterol activities. The possible biological impact of this study and the proposed underlying mechanism of action of these phytocompounds are also discussed in this report.

This review deals with the isolation, purification, spectral properties, chiral resolution into individual enantiomers, total syntheses and evaluation of anti-hypertensive activity of 7,8-dihydroxy-3-methylisochroman- 4-one, an isocromanone constituent of banana (Musa sapientum L.) peel. This molecule possesses high possibility to be an excellent lead molecule in cardiovascular drug discovery programs.

The following section is included:

• Index