Bioactive Compounds and Nanodelivery Perspectives for Treatment of Cardiovascular Diseases

Abstract

Bioactive compounds are comprised of small quantities of extra nutritional constituents providing both health benefits and enhanced nutritional value, based on their ability to modulate one or more metabolic processes. Plant-based diets are being thoroughly researched for their cardiovascular properties and effectiveness against cancer. Flavonoids, phytoestrogens, phenolic compounds, and carotenoids are some of the bioactive compounds that aim to work in prevention and treating the cardiovascular disease in a systemic manner, including hypertension, atherosclerosis, and heart failure. Their antioxidant and anti-inflammatory properties are the most important characteristics that make them favorable candidates for CVDs treatment. However, their low water solubility and stability results in low bioavailability, limited accessibility, and poor absorption. The oral delivery of bioactive compounds is constrained due to physiological barriers such as the pH, mucus layer, gastrointestinal enzymes, epithelium, etc. The present review aims to revise the main bioactive compounds with a significant role in CVDs in terms of preventive, diagnostic, and treatment measures. The advantages of nanoformulations and novel multifunctional nanomaterials development are described in order to overcome multiple obstacles, including the physiological ones, by summarizing the most recent preclinical data and clinical trials reported in the literature. Nanotechnologies will open a new window in the area of CVDs with the opportunity to achieve effective treatment, better prognosis, and less adverse effects on non-target tissues.

1. Introduction

Cardiovascular disease (CVD) is one of the major disorders leading to death. It is mostly seen in both technologically advanced countries as well as in the evolving world, and it is accountable for high economic healthcare expenses [1]. Smoking, hypertension, hyperlipidemia, malnutrition, inadequate physical exercise, and obesity can all increase the risk of CVD. Coronary artery disease (CAD) is a condition caused by atherosclerosis as a result of the narrowing or blockage of coronary arteries. Atherosclerosis is a result of cholesterol and fatty deposits (plaques) inside the arteries.

Congestive heart failure, heart rhythm complications, congenital heart disease (heart disease that develops at birth), and endocarditis are just a few CV disorders [2,3]. The worldwide CVD deaths escalated by 21% from 2007 to 2017 because of population growth and aging; most deaths occur in low- and middle-income countries [4]. The World Health Organization (WHO) expresses that by 2030, CVD would be the major reason for around 23.3 million deaths [5]. The progress of CVD is accelerated by certain threat elements (smoking, dyslipidemia, hypertension, diabetes, and overweight). Fortunately, by adding prevention strategies, these can be avoided [6,7]. A transition to a healthier diet is a major key factor in preventing CVD and thus a shift to an ailment-free time [8].

An unhealthy diet is indeed one of the primary causes of CVD death, with about 72% of all CVD deaths [9]. Recent epidemiological data show that plant-based intakes are proficient and effective against CVD and cancer [10]. The term “plant-based diet” refers to a broad range of eating habits that include fewer animal products (such as meat and dairy products) and much more plant-source foods [11]. According to the recent literature [12], there is no consensus to describe “bioactive compound”. However, it is broadly acknowledged that these “complexes have the proficiency and aptitude with one or more parts of active tissue by predicting most of the effects” [13]. They provide a beneficial health-boosting impact and are being investigated for deferent pathologies prevention: cancer, heart disease, diabetes mellitus, etc. Lycopene, resveratrol, lignan, tannins, and indoles are only a few examples of bioactive compounds [14]. Bioactive compounds are grouped according to their biochemical configuration and functions. These compounds have been shown to have a protective nature against certain pathologies correlated with the immune system, oxidative stress, and inflammation, and they also can lower LDL cholesterol oxidation and control endothelial nitric oxide amalgamation; some of them have poor estrogenic properties [15]. These compounds might contribute significantly to minimizing the onset of age-related chronic illnesses and to control the glucose metabolic rate [16].

Abundant epidemiologic studies show that enhancing vegetable and fruit intake is linked to a reduction in the rate of CVD [17]. Considerable data indicate the protective mechanism of fruits and vegetables, nuts and seeds, whole grains, and seafood in the prevention and treatment of various cancer and heart diseases [18,19]. The ocean’s ecosystem accounts for half including all diversity in the world, rendering aquatic microbes a potential long-term reservoir of unique bioactive metabolites [20,21]. These dietary oral nutrients, when combined along with a regular meal, will help people get more of the components that are thought to have therapeutic outcomes [22]. It is well known that tea and coffee, the most consumed drinks worldwide, have certain beneficial properties. The caffeine present in the coffee seed is a purine alkaloid, i.e., 1,3,7-trimethylxanthine, with its latent properties, which are of some debated topics [23]. Meanwhile, components obtained from Allium sativum, also identified as garlic, is an herb belonging to the Alliaceae family that is frequently used as a seasoning in Southeast Asia and Europe. It comprises a high concentration of organosulfur complexes and flavonoids along with some other combinations that work together to impart a range of health benefits [24]. In the field of dietary supplements and universal healthcare, the bioactive constituents derived using environmental extraction techniques are gaining preference. The extraction acquiesces and pharmacological activities during the extraction method are also pressing issues that must be addressed. Scholarly research is being conducted on an ever-growing inventory of bioactive compounds [25].

However, in everyday life, it is difficult to ingest all the necessary nutrients to assure the proper function of the body or to complementary assist a drug-based treatment in CVDs. This is the reason why encapsulation techniques of nutraceuticals emerged as an effective approach designed to protect the bioactive compounds during the fabrication and storage, avoiding deterioration under environmental factors such as temperature, light, and UV exposure. Moreover, the development of encapsulated nutraceuticals into different carriers, overcomes the main drawback regarding their low bioavailability (such is the case of polyphenols), which greatly depends on several parameters, including solubility, digestibility, absorption, and metabolism. In addition, most bioactive compounds are unstable in alkaline conditions of biological fluids. By encapsulation in an adequate matrix, the incorporated compounds can be released with a specific concentration and time profile at a desirable site of action. At the nano-scale, the advanced nano-delivery systems have been demonstrated to boost the bioavailability and efficacy of bioactive compounds for therapeutic purpose [26]. On the other hand, effective nano-delivery systems have optimal characteristics for medicative agent-controlled release, long storage life, and enhanced therapeutic efficacy with no or minimal side effects.

In this context, the aim of this narrative review is to revise the main bioactive compounds with a significant role in CVDs in terms of preventive, diagnostic, and treatment measures. A discussion of the current evidence showing the advantages of nanoformulations and novel multifunctional nanomaterials able to overcome multiple obstacles, including the physiological ones, is made by summarizing the most recent preclinical data and clinical trials reported in the literature, describing the newer methodology and nanoformulation technologies that influence adequate drug or nutraceutical delivery.

2. Plant Bioactive Compounds

The phytoactive biocompounds can be isolated from plants using different extraction techniques. Based on specific functional group positions, bioactive compounds are categorized into primary and secondary metabolites [27]. Several metabolites are derived from fungi and vegetation based on their functional phase, tissue arrangement, ecological circumstances, and some other emphasis. Metabolites play a vital role in regulating cell maturation by functioning as plant development compounds. The most commonly found bioactive compounds are ethylene, auxin, gibberellins, plant development-abscisic acid, phytohormones–cytokinins, polyhydroxy steroids, and polyamines [28]. Glycosylated or covalently linked forms of bioactive compounds are engaged in the protection process that enables the plant to produce and store them in a harmless state [29]. Secondary metabolites used in traditional medicine can be extracted using a variety of methods, including Soxhlet extraction, maceration, and hydrodistillation. To minimize the use of solvents and introduce smoother extraction yields, ultrasonography, radiation, electromagnetic waves, high atmospheric pressure, and the use of supercritical fluids have already been examined [30,31,32]. Concentrated remains are acquired as the water drops are eradicated, and hence, the acquired part is known as an essential oil. Bioactive compounds are organized into three major classes based on their metabolic derivation: (a) phenolics; (b) terpenes; and (c) compounds containing nitrogen.

Fruit and vegetables consist of a wide range of bioactive compounds such as anthocyanins, betalains, carotenoids, flavonoids, glucosinolates, plant sterols, and tannins [33,34,35,36]. The occurrence and therapeutic properties of phytochemicals (phenolics, flavonoids, and carotenoids) have been collected in

Table 1. Bioactive compounds in fruits and vegetables along with their therapeutic properties.

No.	Source	Bioactive Compounds	Therapeutic Potential	Ref.
1.	Abelmoschus esculentus	Quercetin	Anti-inflammatory, antioxidant, hypolipidemic.	[36]
2.	Ajuga iva	Naringein, apigenin-7-O-neohesperidoside.	Antioxidant, anti-inflammatory, antihypercholesterolemia.	[37]
3.	Anchusa italica Retz.	Rutin, hesperidin, quercetin, kaempferol, naringenin.	Anti-inflammatory, antioxidant, anticoagulant.	[38]
4.	Apples	Lutein, carotenoids, antioxidant: phlorizin, quercetin, catechin, procyanidin, epicatechin.	Antioxidant, antifungal, anti-proliferative.	[39]
5.	Barley leaves	2β-O-Glucosylisovitexin.	Antioxidant, membrane stabilizer, antitumor.	[40]
6.	Broccoli	Lutein, zeaxanthin, β-carotene, flavonoids.	Antioxidant, anti-inflammatory, anticarcinogenic.	[41]
7.	Carrots	Lignin, carotene.	Treat leukemia.	[42]
8.	Cereal crops	Orizanol, isovitexin, cyanidine-3- O-β-D-glycopyranoside, pinoresinol.	Prevent cardiovascular diseases and cancer diseases.	[43]
9.	Cocoa	Phytochemicals: methylxanthine, proantho-cyanidin, theobromin.	Antioxidant, anti-inflammatory, hypoglycemic, antiplatelet, antihypertensive.	[44]
10.	Corchorus olitorius Leaf and Corchorus capsularis	Luteolin	Antioxidant, hypotensive, diuretic.	[45,46]
11.	Cotton seed oil	Quercetin, rutin, kaempferol, gossypeti, heracetin, dihydroquercetin, quercetrin, isoquercetrin.	Total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) lowered.	[47]
12.	Cymbopogon citratus (DC) Sapf.	Tannins, luteolin, apigenin.	Vasorelaxation, antioxidant, anti-inflammatory.	[48]
13.	Danshen (Salvia miltiorrhiza)	Tanshinones, salvianolic acids.	Angina, ischemic stroke, hyperlipidemia, antithrombotic.	[49]
14.	Dracocephalum moldavica L.	Tallianine, luteolin, apigenin, diosmetin.	Anticancer, anti-inflammatory, antioxidant.	[50]
15.	Edible wild fruit	Polyphenols: procyanidin, quercetin, phenolic acid, anthocyanin, carotenoids.	Anti-inflammatory, anti-obesity, antidiabetic.	[51]
16.	Ephedra herb	Epiafzelechin (flavanol), quercetin, gallocatechin, apigenin, luteolin.	Diuretic, anti-inflammatory, hypotensive, antioxidant.	[52]
17.	Equisetum arvense L. (Horsetail)	Resveratrol, apigenin, quercetin.	Antioxidant, anti-inflammatory.	[53]
18.	Flaxseed oil	Phytoestrogens lignans, coumestran, enterolactone, enterodial, coumestrol.	Reduce the growth rate of mammary cancer, lowered plasma LDL cholesterol.	[54]
19.	Foxglove (Digitalis species)	Glycoside digoxi.	Treat heart failure, atrial fibrillation.	[55]
20.	Garlic (Allium sativum)	Allicin.	Treat hypertension, hyperlipidemia, antithrombotic.	[56]
21.	Ginkgo (Ginkgo biloba)	Flavonol glycosides–quercetin and catechin and terpenoids–ginkgolides and bilobalides.	Cerebral insufficiency, peripheral vascular disease, antithrombotic.	[57]
22.	Ginseng (Panax species)	Triterpene saponins– ginsenosides.	Angina, hypertension, antidiabetic.	[58]
23.	Grapes	Polyphenols: resveratrol, carotenoids, flavonoids.	Antioxidant, anti-inflammatory, antihypertensive, antidiabetic.	[59]
24.	Hawthorn (Crataegus species)	Phenolic acids, quercetin, pyrocatechin, phlorodizin, terpenoids, lignans, steroids, organic acids, and sugars.	Heart failure, angina, hyperlipidemia.	[60]
25.	Heliotropium taltalense (Phil.)	Naringenin, pinocembrin, quercetin.	Anti-inflammatory, antioxidant, vasorelaxation.	[61]
26.	Lentil (Lens culinaris Medik.)	Quercetin, kaempferol.	Anticoagulant, antiplatelet.	[62]
27.	Lingzhi (Ganoderma lucidum)	Polysaccharides, triterpenes, polyphenols, proteins, amino acids, and organic germanium.	Hyperlipidemia, hypertension, antidiabetic.	[63,64]
28.	Moringa oleifera Lam.	Catechin, epicatechin, kaempferol, quercetin.	Antioxidant, anti-inflammatory.	[65]
29.	Mustard seed	Glucosinolates, sinigrin, phenolic acids, sinapic acid, methyl ester.	Anti-inflammatory, Anticancer, antioxidant, antihyperglycemia.	[66]
30.	Oats	β-Glucan, pectin, psyllium, esters of caffeic and ferulic acids.	Reduce both total cholesterol and LDL cholesterol.	[67]
31.	Olives	Phenolic compounds, hydroxy-tyrosol, oleuropein, polyphenols, flavonoids, theanine, quercetin.	Antioxidant, anti-inflammatory, antihypertensive, anti-obesity.	[68]
32.	Onions	Quercetin, myricetin.	Treat obesity, coagulation, inflammation, atherosclerosis, hyperlipidemia.	[69]
33.	Peanuts	Taxifolin, resveratrol.	Triacylglycerol (TAG) reduced.	[70]
34.	Polygonum minus (Persicaria minor)	Myricetin, quercetin, methyl-flavonol.	Antioxidant, anti-inflammatory.	[71]
35.	Psyllium seed	β-glucan, pectin, psyllium, soluble dietary fibers.	Antioxidant, laxative.	[72]
36.	Red wine	Resveratrol.	Anticancer activity.	[73]
37.	Rice bran oil	Plant sterols, sitostanol, stigmasterol, campesterol.	Hypocholesterolemic effect, total cholesterol and LDL cholesterol reduced.	[74]
38.	Soybeans	Genistein, daidzein, isoflavones.	Reduced LDL-cholesterol level.	[75]
39.	Thai Perilla frutescens	Cyanidins, luteolin, phenolic acids.	Anti-inflammatory, antioxidant.	[76]
40.	Tomato	Phenols: phenolic acid, flavonoids, carotenoids.	Antioxidant, anti-inflammatory, antiplatelet, antihypertensive.	[77]
41.	Trichosanthes kirilowii	Luteolin.	Hypolipidemic, antioxidant, antiatherosclerotic.	[78]
42.	Wild rice	Phytic acid, luteolin glycoside, p- hydroxy acetophenone glycoside, 3,4,5-trimethoxycinnamin acid.	Health-promoting.	[79]

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3. Types of Bioactive Compounds

To summarize, we will present the recent advances on bioactive compounds that are widely recognized as promising strategies in the prevention, adjuvant therapy, or even cure of different chronic diseases of the 21st century, with a focus on CVs. Their multi-facet features in terms of dietary lifestyles shows positive effects on treating and preventing CVDs being emphasized in the next sections.

3.1. Flavonoids

Flavonoids are a copious and distinct cluster of bioactive compounds that occur as the core elements of polyphenols. They are divided into flavonols, flavones, flavanonols, flavanones, flavans (catechins, anthocyanins, and proanthocyanidins) and isoflavones and flavanonols [80]. Each flavonoid subclass and category have its own arrangement of herbal sources, roles, and therapeutic effects. As for their recognized antioxidant and anti-inflammatory effects, this arrangement of herbal bioactive compounds was revealed to have wellness benefits for individuals [81]. The main properties, source, and structure of flavonoids are briefly presented in

Table 2. The main properties, source, and health benefits of flavonoids.

Flavonoids with Main Features	Natural Sources	Bountiful Health Benefits
- Flavonoids are hydrophilic. It has a C6–C3–C6 backbone. It consists a 15-carbon skeleton (two benzene rings linked with three-carbon chain i.e., oxygenated ring). - It is produced in response to microbial infection by plants. - The antioxidant activity is dependent on arrangement of functional groups. - Flavonoid basic structure [82,83]. - Isoflavonoids basic structure.	Berries, spices, leeks, ginger, herbs, grapefruit, carrot, grapes, apple, onion, broccoli, cabbage, kale, tomato, lemon, parsley, buckwheat, legumes, coffee, tea.	- Rich in phytonutrients, antioxidant. - Neutralize free radicals. - Limit cells damage. - Anti-inflammatory, anti-aging properties. - Improve the quality of blood vessels [84].

, while a list containing the types of flavonoids, their functional unit, source, and therapeutic properties are presented in

Table 3. Types of flavonoids, their functional unit, plant source, and therapeutic properties.

No.	Type of Flavonoid	Major Food Flavonoids	Functional Unit of B-Ring	Unsaturation in B-Ring	Common Plant Source	Therapeutic Effect	Ref.
1.	Anthocyanins	Cyanidin, delphinidin, malvidin, peonidin.	3-Hydroxy.	1-2, 3-4 Double bond.	Strawberries, red wine, and blueberries.	- Endothelial-dependent vasodilation. - Reduce risk of acute myocardial infarction.	[85]
2.	Flavan-3-ols [flavanols]	Cathechin, gallocatechin, epicatechin, epiallocatechin-3-gallate.	3-Hydroxy, 3-O-gallate.	None.	Red wine, blueberries, apples, chocolate, pears, cocoa, tea, and grape.	- Reduce systolic blood pressure. - Anti-inflammatory. - Antioxidant. - Antiatherogenic action.	[86]
3.	Flavanones	Eriodictyol, naringenin, hesperetin.	4-Oxo.	None.	Herbal tea, juice, fruit peels, and citrus fruit.	- Antioxidant. - Reduce blood pressure. - Modulate nitric oxide. - Antihypertensive effect.	[87]
4.	Flavones	Apigenin, luteolin, tangeretin, baicalein.	4-Oxo.	2-3 Double bond.	Herbal tea, garlic, celery, chamomile tea, and green peppers.	- Lower blood pressure. - Improve vasodilation. - Increase accumulation of camp. - Induces vascular relaxation by NO, regulated by Ca and K channels.	[88]
5.	Flavonols	Myricetin, quercetin, isorhamnetin, kaempferol.	3-Hydroxy, 4-Oxo.	2-3 Double bond.	Red wine, kale, broccoli, cherry, tomato, garlic, onions, tea, strawberries, beans, Spinach.	- Modulate the renin–angiotensin–aldosterone system. - Produces vasodilation. - Lowers blood pressure. - Decreases oxidative stress.	[89]
6.	Isoflavones	Daidzein, genistein, glycitein, biochaninA, glycitein.	4-Oxo.	2-3 Double bond.	Peanuts, legumes, and soy products.	- Act as estrogen receptor agonist. - Diminish oxidative stress. - Antihypertensive effects.	[90]

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3.2. Anthocyanins

Anthocyanin is one of the subclasses of phenolic phytochemicals; they are produced in cell sap and are hydrophilic in nature. They occur in higher plants tissue, such as fruits, flowers, leaves, and roots. Anthocyanins are the major cause for their specific coloration. In a brief manner,

Table 4. The main source, benefits, and chemical structure of anthocyanins.

Chemical Structure and Main Features	Sources	Bountiful Health Benefits
- Phenolic entity of 15 C-atoms, which is made up of two benzene rings connected by a three-carbon chain. - Two benzyl rings A and B. it usually has a single glucoside unit, and many have two, three, or more sugar attached at multiple positions. - Sugar moiety at C-3 as 3-monoglycosides in the C-ring. - Sugar moiety at C-5, 7-position as diglycosides in the A-ring. - R3′, R4′, and R5′ on B-ring–glycosylation - R3′ and R5′ positions of B-ring have different components attached and form different compounds. - 6 Anthocyanins ubiquitously distributed are cyanidin (Cy), delphinidin (Dp), petunidin (Pt), peonidin (Pn), pelargonidin (Pg), and malvidin (Mv).	Acai, blackcurrant, blueberry, bilberry cherry, red grape, and purple corn.	- Low stability and poor absorption—this is not beneficial! - Anticancer activity, reduce cancer cell proliferation, and inhibit tumor formation. - Anti-inflammatory properties. - Interact with other phytochemicals to potentiate biological effects. - Free-radical scavenging and antioxidant capacities.

presents the structure, biological source, and main therapeutic effects of anthocyanins [91].

3.3. Tannins

Tannins are water-soluble polyphenols that are astringent and form bonds with proteins, as well as other organic compounds and macromolecules. Secondary metabolites easily get sequestered in plant cell vacuoles and protect different cell constituents.

Table 5. The chemical structure, therapeutic benefits, and biological source of tannins.

Chemical Structure and Main Features	Natural Sources	Bountiful Health Benefits
- Gallic acid is the base unit in the complex mixtures of polymeric polyphenols. - It is classified into condensed (C-C linkage) and hydrolyzable (ester-like compounds) tannins. - Colorless to yellow or brown. - Causes astringency of food. - Gallic acid. - Phloroglucinol	Teas, coffee, pomegranates, persimmons, cranberries, strawberries, blueberries, grapes, red wine, cinnamon, vanilla, cloves, thyme, and oak gallnuts (tannin content of 50–70%).	- Acceleration of blood clotting. - Reduction of blood pressure. - Decrease serum lipid levels. - Modulation of immune response.

contains the brief information related to chemical structure, biological source, and therapeutic benefits of tannins [92,93].

3.4. Betalains

Betalains are nitrogen (N)-containing vacuole pigments, similar to anthocyanins and flavonoids in appearance, yet pigments are red and yellow; they are capable of dissolving in water, as they contain nitrogen, and they can be found almost exclusively in families of the Caryophyllales. They are commonly used as color additives in food, being toxicologically safe. In

Table 6. Structure, biological source, and therapeutic benefits of betalains.

Chemical Structure and Main Features	Sources	Bountiful Health Benefits
- Indole derivatives, classified into red-violet betacyanins and yellow-orange betaxanthins. - The colors determine resonating double bonds in the betalain structures. - They are hydrophilic and therefore can be incorporated into aqueous food systems.	- Families of caryophyllales order and some higher-order fungi. - Beetroot (red and yellow), leafy amaranth, pear, swiss chard, red pitahaya, and cacti.	- Antioxidant. - Anticancer. - Antilipidemic. - Antimicrobial. - Nontoxic. - Promising agent for supplement therapies in oxidative stress, inflammation, and dyslipidemia-related. - Diseases such as stenosis of the arteries, atherosclerosis, hypertension, and some types of cancer.

, a brief presentation of the chemical structure, biological source, and therapeutic effects of betalains are presented [94,95].

3.5. Carotenoids

Carotenoids are usually found in chloroplast in the form of red, yellow, and orange pigments. Carotenoids are in the category of lipid-soluble hydrocarbons. Xanthophylls are oxygenated derivatives of carotenoids. The red color of carrots denotes their name, but they are also present in green leaves, yellow fruits and red fruits, several fungi, and rhizomes. They are responsible for the color of egg yolk and some fish.

Table 7. The structure, biological source, and therapeutic benefits of carotenoids.

Chemical Structure and Main Features	Sources	Bountiful Health Benefits
- Class of hydrocarbons and their oxygenated derivatives, composed of eight isoprenoid units linked in composition of isoprene entity, overturned in middle of the complexes. - Absorbs wavelength 400–550 nm and produces deeply yellow, orange, or red-colored complex. - It is broadly classified into two groups i.e., carotenes (orange color) and xanthophylls (yellow color). The main difference between the two group is that xanthophylls contain an oxygen group and carotenes are hydrocarbons without any oxygen group. - β-carotene (carotene) - β-Cryptoxanthin (Xanthophyll)	Apricots, carrots, cilantro, collard, cantaloupes, mango, plum, thyme, turnip, squash, kale.	- Precursor of vitamin A. - Anticancer, antioxidant. - Robust immune system. - Promote healthy skin. - Eye health and vision.

presents the main features related to carotenoids in a brief manner [96,97,98,99].

Carotenoids are further classified into following categories according to

Table 8. Classification of carotenoids.

No	Types of Carotenoids	Composition	Source	Properties	Health Benefits	Ref.
1	α-Carotene	C40H56, carotene with β-ionone ring and α-ionone ring.	Carrots, pumpkin, broccoli, spinach, avocado, sweet potato, squash.	This is second most common carotenoid.	- Antioxidant properties. - Reduce risk of cancer. - Lower risk of CVD.	[100]
2	β-Carotene	C40H56, group consisting of isoprene units.	Carrots, apricots, mango, red pepper, greens (kale, spinach, broccoli).	This is the major and natural carotenoid present.	- Maintains eye health, helps in embryonic development and improves the immune system performance.	[101,102]
3	β-Cryptoxanthin	C40H56O, isoprene unit with a hydroxyl unit.	Orange, peaches, tangerines, papaya, egg yolk, butter, apples.	Natural carotenoid pigments.	- Improves respiratory function. - Pro-vitamin A activity.	[103]
4	Lutein and Zeaxanthin	C40H56O2, they have similar isomers but differ in double bond location. Lutein shows the presence of three chiral canters, while zeaxanthin has two.	Kale, spinach, broccoli, sprouts, lettuce, egg yolk, yellow corns, and parsley.	These are dietary oxygenated carotenoids.	- Lowers risks of CHD and stroke. - Improves eye health. - Beneficial for skin health. - Prevents lipid peroxidation.	[104,105]
5	Lycopene	C40H56, in this a tetraterpene, is arranged with eight isoprene units of carbon and hydrogen.	Tomato, watermelon, grape, papaya, guava, rose.	These are hydrophilic, acyclic carotenoids with eleven conjugated double bonds.	- Effective antioxidant. - Reduce risk of CVD. - Prevents aging.	[106]

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3.6. Plant Sterols

Plant sterols, also called phytosterols, are plant-derived fatty compounds. They are found in non-esterified and esterified forms of cinnamic/fatty acids. Plant sterol esters reduce coronary heart disease.

Table 9. The structure, biological source, and therapeutic benefits of plant sterols.

Chemical Structure and Main Features	Sources	Bountiful Health Benefits
- Cholesterol-like compounds influence cholesterol absorption and metabolism in both animals and humans. - It is a fused polycyclic structure. There is variation in the presence of the double bond and carbon side chain. - Nomenclature of plant sterol steroid skeleton - Stigmasterol—by removing a hydrogen from C-22 and 23.	Vegetable oils, nuts, legumes, grains, cereals, wood pulp, margarine, milk, yogurt, soybean oil, and leaves.	Reduce the level of the LDL cholesterol in blood.

presents the data related to plant sterols in a brief manner [106,107].

3.7. Glucosinolates

Glucosinolates are natural, anionic plant secondary metabolites. These are sulfur rich and belong to the order Brassicaceae.

Table 10. Structure, biological source, and therapeutic benefits of glucosinolates.

Chemical Structure and Main Features	Sources	Bountiful Health Benefits
- Glucose and amino acid release substances such as sulfur and nitrogen that make up the glucosinolates. - They have a central carbon atom that links to the thioglucose group by a sulfur atom and to the sulfate group by a nitrogen atom.	Cruciferous vegetables: wasabia japonica, cabbage, garden cress, kale, broccoli, and watercress.	- Protective role against cancer - Protective role in dementia risk.

presents the structure, biological source, and therapeutic benefits of glucosinolates [108,109,110,111].

4. Therapeutic Effect of Bioactive Compounds on Cardiovascular System

The advancement of disorders such as atherosclerosis and CVD is facilitated by oxidative stress. Diverse bioactive compounds’ anti-oxidative, anti-inflammatory, and metabolic effects are linked to their defense against atherosclerosis and CVD [112].

4.1. Carotenoids

Carotenoids are found in high amount in fruits and vegetables. Their sub-categorization is as per the chemical structure they have; i.e., as carotenes and xanthophylls. Carotenoids have antioxidant properties that are beneficial for health. Human organs and tissues have carotenoids. In tissues, the level of carotenoids is high as they have high levels of low-density lipoprotein receptors. Carotenoids help in the prevention of chronic cardiovascular diseases such as stroke and coronary heart disease. They have a multifaceted metabolism and react to systemic forces. As an antioxidant, they improve superoxide dismutase, glutamate dehydrogenase, catalase, and glucan particles. Carotenoids also inhibit IGF-1 activity and have been proved to be effective as an anticancer agent [113,114,115,116].

4.2. Polyphenols (Anthocyanins)

Berries are high in polyphenols, especially anthocyanins, as well as micronutrients and fiber. The consumption of berries results in an improvement in heart health. Chokeberries, cranberries, blueberries, and strawberries contain distilled anthocyanin derivatives. They showed substantial progress in LDL oxidation, lipid peroxidation, total plasma antioxidant potential, dyslipidemia, and glucose metabolism. It causes the activation of endothelial nitric oxide synthase, the lowered activity of carbohydrate digestive enzymes, and reduced oxidative stress by increasing the endothelial functions and the plasma lipid profiles. This led to a reduction of abnormal platelet aggregation. The research recommends berries (anthocyanins) as an important fruit group in a heart-healthy diet [117].

Pomegranate juice contains anthocyanins, catechins, quercetin, rutin, and ellagitannins, and it results in reducing high blood pressure, which is a result of the ACE activity antioxidant activity due to the radical scavenging effect of anthocyanins and hydrolyzable tannins [118,119,120,121].

4.3. Lycopene

Lycopene is a hydrocarbon carotenoid that is oxygenated and has quite a similar structure to β-carotene. Lycopene has an antioxidant property due to the presence of conjugated double bonds. This fat-soluble pigment imparts red color to a good variety of food items such as tomato, guava, watermelon, and others. Smoking is a major CVD risk factor. Smoke introduces free radicals into the human body, causing LDL oxidation, foam formation, and leading to atherogenesis. The severity of atherosclerosis is linked with an increase in LDL oxidation inclination. Lycopene prevents the oxidation of LDL and protects humans from coronary heart disease (CHD) [122].

Lycopene and plasma levels in cardiovascular disease have been investigated by researchers. The findings were analyzed. The higher intake of lycopene was compared with reduced levels of estone. Here, a 17% of reduction of CVD was linked with lycopene. It works by several mechanism such as the reduction of oxidation of biomolecules, the antiangiogenic effects, the reduction of cholesterol levels, the stimulation of apoptosis, and the reduction of inflammation [123].

4.4. Flavonoids

Randomized trials and many cohort studies have shown that flavonoids reduce CVD risk. Flavonoids produce a suitable response to LDL cholesterol, sensitiveness to insulin, and endothelial function [123]. A comprehensive evaluation of many investigations has indicated that the nutritional consumption of different groups of flavonoids, specifically as flavonols, anthocyanidins, proanthocyanidins, flavones, flavanones, and flavan-3-ols, minimize any chances of CVD drastically [124]. The quality of flavonoid subcategories in foods will be more essential than total flavonoids. Furthermore, the inverse correlation between flavonoid consumption and CVD risk is more pronounced in females than males. Even so, owing to the complementary nature of randomized clinical trials, there is indeed a lot of variance in the evidence [125].

Flavonoid research has exploded in popularity since its inception [126]. Understanding the availability of flavonoids, both natural and synthetic, and finding ways to improve their bioavailability were two of the most difficult tasks [127]. The scarcity of flavonoids is well known, but recently, these problems have been addressed. According to new research, the gut and its microbiome play a significant function in the development of prebiotic and microbiota enhancers as phenolic metabolites [128].

Flavonoids have been shown to reduce gastric and intestinal inflammation, as the metabolites act as enhancers of gut immune function [129]. As a result, attempts to increase flavonoids’ bioavailability aiming primarily on increasing their intestinal absorption. Borneol and methanol combination are traditional drug absorption enhancers [130]. Both borneol and methanol are toxic, and methanol causes blindness [131,132].

Effect on CV System

Regarding antiatherosclerotic effects, the pathogenesis of atherosclerosis begins with the oxidative alteration of low-density lipoproteins (LDL) by free radicals. Foam cells develop when oxidatively modified LDL is rapidly absorbed through a scavenger receptor. They act as antioxidant-chain breaking, in which flavonoids are radical species [133]. The capacity of quercetin and quercetin glycosides to shield LDL from oxidative activation has been shown to be successful [134]. A Japanese study found an inverted relationship between the flavonoid consumption and total plasma cholesterol levels [135].

Regarding antithrombogenic effects, platelet aggregation is critical in the composition of thrombotic disorders. Activated platelets bind to the vascular endothelium and develop lipid peroxides and oxygen free radicals, which prevent the formation of prostacyclin and nitrous oxide (NO) in the endothelium. Tea pigment shows the prevention of platelet adhesion or aggregation, and it reduces blood coagulation as well as increases fibrinolysis [136]. Flavonoids such as quercetin, kaempferol, and myricetin have been shown to inhibit platelet aggregation in animals [137]. Flavonols are particularly antithrombotic because they scavenge free radicals, keeping endothelial prostacyclin and nitric oxide concentrations constant [138].

Regarding cardioprotective effects, from both advanced and emerging economies, CVD is now the major cause of death. Atherosclerosis, coronary heart disease, arterial hypertension, and heart failure are all cardiovascular system (CVS) disorders. Oxidative stress is the primary cause of CVS disorders. Endogenous oxidants and reactive oxygen/nitrogen species (RONS) are in equilibrium in oxidative stress, with free radicals predominating. A prolonged dispensing of flavonoids has been shown to diminish or threaten to degrade the rate of CVD and its effects. They have an elevated inclination to transfer electrons, chelate ferrous ions, and sift reactive oxygen species [139]. Flavonoids are potential protectors against the persistent cardiotoxicity triggered by cytostatic medication such as doxorubicin [140,141].

As a vasorelaxant agent, flavonoids help to reduce endothelial dysfunction (ED) by improving the vasorelaxation mechanism, which lowers arterial blood pressure [142,143]. ED is a crucial occurrence in the progression of CVD as well as a significant consequence involving arteriosclerosis as well as the occurrence of arterial thrombosis [144]. Flavonoids help to avoid a variety of CVD, such as high blood pressure and atherosclerosis [145,146]. Current laboratory studies show that these polyphenols can lower arterial pressure and improve the vasodilating system. Flavonoids have long been known to cause an endothelium-reliant response. Moreover, researchers discovered that anthocyanin delphinidin has a major endothelium-dependent vaso-relaxing effect [147,148]. Some of the cardiovascular risk factors, with a description of the pathophysiological effects they cause, and some bioactive compounds that may reduce the severity of the risk factors and also the positive changes they induce are described in Figure 1.

5. Nano-Delivery Systems of Bioactive Compounds

The nano-delivery method allows for the regulation of food bio-active components’ stability, solubility, and bioavailability, and it also maintains their targeted and controlled release. Food safety is a major issue because the usage of nano-delivery for food and drug delivery has grown in popularity [149,150,151,152]. Nano-delivery is carried out in two different ways: liquid and solid. Nano-emulsions, nano-liposomes, and nano-polymerases are the three different forms of liquid nano-delivery systems. Nano-liposomes are divided into SLVs (single lamellar vesicles) and MLVs (multilamellar large vesicles). Nanoparticles, polymeric nanoparticles, and nanocrystals are the three forms of solid nano-delivery systems. Solid lipid nanoparticles (SLNS) and nano-structured lipid carriers (NLCS) are two types of lipid particles. Polymeric nano-particles are of two different types, i.e., nano-spheres and nano-capsules. The types of nano-delivery system are presented in Figure 2.

Due to chemical and enzymatic barriers and the poor solubility of compounds in the GI tract, a significant decrease in the quality of orally delivered drugs was noticed. It is well known that the action of bioactive compounds depends upon the extent of the bioaccessibility and bioavailability to the organism. There are several conventional drug carrier systems currently used for the effective delivery of cardioprotective drugs, either as oral tablets, parenteral/intravenous administration, or transdermal patches. However, some CVD treatments such as medications against angina pectoris (nitrates, calcium channel blockers, β blockers) produce significant adverse effects such as rash, constipation, nausea, drowsiness, edema, low blood pressure, or headache [153].

In this context, nanotechnology plays a determinant role by manipulating bioactive compounds encapsulated into nano-carriers with dimensions of 1–100 nm, providing a longer half-life, longer circulation time, longer mean residence time, and better pharmacokinetic clearance from the body [154]. These systems particularly depend on physicochemical factors that will influence their absorption, distribution, metabolism, and excretion, which are critical for administering bio-active compounds with improved in vivo results [155]. As the high surface to volume ratio of nanoparticles allows the conjugation, absorption, or encapsulation of bioactive molecules for delivery to the target site, drug delivery vehicles are successfully employed owing to their ability to deliver poorly soluble or highly toxic drugs to the target areas. Nanoparticles bind to the gut mucosa and epithelial cells, enter the bloodstream, and then are distributed to tissues and organs such as the liver, kidneys, spleen, heart, lungs, and brain. Nanoparticles and their metabolites are mainly excreted into the liver, kidneys, and colon [156,157].

Nowadays, conventional synthetic drugs are less present in practice owing to their costs and associated complications and side effects, while natural products have received much attention, as they are affordable for the majority of the population and possess multi-targeted effects with fewer side effects than synthetic drugs.

It is well known that polyphenols exhibit high antioxidant and anti-inflammatory properties, which are important for certain pathological conditions, including cardiovascular disease. Polyphenol consumption has been shown to improve endothelial function, blood pressure, and platelet function as well as the regulation of cellular processes such as inflammation and NO synthesis in vitro and in vivo [158]. The antioxidant mechanism is attributed to their ability to scavenge free oxygen and nitrogen species and to stimulate the expression of antioxidant enzymes (catalase, superoxide dismutase). When assessing the beneficial effects of polyphenols, it must be considered that only a small proportion of the ingested polyphenols are absorbed in the intestine, and therefore, a high quantity of polyphenols is required to achieve the expected improvement in terms of blood pressure lowering. The poor bioavailability is due not only to the low water solubility of polyphenols but also to the instability in alkaline conditions of biological fluids [159]. In order to overcome these drawbacks, nanoencapsulation technologies have emerged as a novel trend in drug carrier development, being nontoxic in nature, with the ability to escape from the host immune system, along with other advantages such as biodegradability, biocompatibility, and drug-targeting properties.

The encapsulation of active ingredients is nowadays a routine fabrication process and can be realized through different techniques: spray or freeze drying, coacervation, ionic gelation, extrusion, emulsion, electrospinning, electro-spraying, and liposomes formulation [160]. Encapsulation is also designed to protect the bioactive compounds during processing, storage, and transport from different undesirable factors such as temperature, light, and environmental oxidation. In this respect, biological materials such as polysaccharides, proteins, lipids, or low molecular surfactants are used [161], being highly biocompatible and nontoxic for human consumption. The release mechanisms might be related to diffusion, swelling, erosion, fragmentation, dissolution, or stimuli-controlled release. β-carotene, curcumin, quercetin, resveratrol, and epigallocatechin-3-gallate are only a few examples of nano-encapsulated bioactive compounds with improved bioavailability and metabolism when compared to non-encapsulated ones [26]. Based on literature research,

Table 11. Nanocarrier formulations of different bioactive compounds.

Bioactive Compound	Nanoformulation	In Vitro/In Vivo Experimental Model	Main Results	Ref.
Curcumin	Chitosan NPs	In vitro/Ehrlich ascites carcinoma and in vivo animal model (albino mice)	Protection against myocardial injury and cardiac function, ameliorates EAC-induced cardiotoxicity.	[162]
	PEG-PDLLA (polyethylene glycol methyl ether-block-poly (D, L lactide) NPs	In vitro/cardiomyocytes exposed to palmitate	Inhibition of cell apoptosis and NADPH-mediated oxidative stress; protective effect possibly mediated by endoplasmic reticulum stress-related signaling pathway.	[163]
	Nano emulsion/glyceryl monooleate oil phase	In vitro/HMG-CoA reductase assay	Increased not only the HMGR inhibition (showing antihypercholesterolemic effect) but also angiotensin-converting enzyme (antihypertensive effect).	[164]
Curcumin + resveratrol	Pluronic® F127 micelles	In vitro/embryonic rat cardiomyocytes	Cardioprotection, reduction in apoptosis and ROS of cardiomyocytes treated with doxorubicin.	[165]
Resveratrol NPs	Solid–lipid NPs/glycerol monostearate oil phase	In vivo pharmacodynamic study/male mice	Protecting the myocardium, improving the cardiomyocyte calcium cycling, inhibiting of doxorubicin cardiotoxicity, inhibiting the production of reactive oxygen species.	[166]
	Albumin NPs	In vivo/male Sprague–Dawley rats	Improved neurological score and decreased infarct volume at 24 h after administration in a dose-dependent manner; significantly attenuated oxidative stress due to prolonged circulation in blood and sustained release pattern.	[167]
Quercetin	PLGA NPs	In vitro/H9c2 cells, a surrogate model of cardiac cells	Improves cardioprotection during hypoxia–reoxygenation injury through the preservation of mitochondrial function; superior protection capability of PLGA–quercetin NP with respect to free quercetin.	[168]
	Mesoporous silica nanoparticles	In vivo rat model of myocardial ischemia reperfusion	Improves the apoptosis degree and oxidative stress level of myocardial cells by regulating the JAK2/STAT3 signaling pathway, promoting the recovery of cardiac blood flow.	[169]
Coenzyme Q10	Nano emulsion/soybean oil and egg lecithin surfactant	In vitro/cardiomyocytes and Fibroblasts model	Providing multiple molecular mechanisms of cardioprotection during doxorubicin and trastuzumab treatments; anti-inflammatory activities modulating the heart microenvironment.	[170]

summarizes the most recent nanocarrier formulations developed for bioactive compounds with therapeutical indications in CVDs, along with experimental models (in vitro or in vivo) and the main outputs.

5.1. Clinical Trials

Curcumin is probably the most studied polyphenol in treatment of CVD, being an inhibitor of p300 histone acetyltransferase activity, which is associated with heart failure. Highly bioavailable curcumin has been developed as a nanoformulation commercially known as Theracurmin^® [171]. This revolutionary formulation is a submicron crystal solid dispersion of curcumin, consisting of 10 w/w% curcumin, 2% other curcuminoids (such as dimethoxy-curcumin and bisdemethoxycurcumin), 4% of gum ghatti, and 84% of water. In a clinical study performed with healthy participants, low (150 mg) and high (210 mg) doses of Theracurmin^® were administrated in order to evaluate plasma curcumin levels in a dose-dependent manner [172]. The study evidenced that nanoformulation increases plasma curcumin levels in a dose-dependent manner without saturating the absorption system. Another clinical study revealed that the treatment of hypertensive patients using 60 mg/day of Theracurmin for 24 weeks significantly improved the parameters of diastolic function assessed by doppler echocardiography, which suggests that the nanoformulation improves left ventricular diastolic function without interfering with blood pressure in hypertensive patients [171].

However, it is difficult to interpret whether the observed effect is due to the nanoparticle formulation or to curcumin itself, as the authors did not include a non-encapsulated formulation of curcumin as a control group. A comparison between curcumin nanoformulation and powder curcumin was performed by Sasaki et al. [173] upon administration in a healthy participant, revealing that the bioavailability of Theracurmin^® orally administrated was 27-fold higher than that of curcumin powder, even at a low dosage (30 mg). It was concluded that Theracurmin^® shows higher bioavailability than currently available preparations (curcumin powder).

Despite the large number of reported preclinical studies related to polyphenol nanoformulations, their transition to the clinical sector been proven to have several limitations, as it is well known that the concentrations of polyphenols proved to be effective in vitro or in small animal models are much higher than the required levels in human subjects. Moreover, the effectiveness of nano-nutraceutical products strongly depends on preserving the bioavailability of the bioactive compounds.

5.2. Nanoparticles for Theranostic

The concept of a theranostic is derived from combined therapy and diagnostic tools assembled into a single platform [174], while the nano-theranostic embodies the most advanced technological approach with multifunctional attributes such as multimodal imaging, controlled, and localized drug targeting, allowing the development of personalized medicine. In this respect, engineered nanomaterials consisting of magnetic nanoparticles, liposomes, carbon-based nanomaterials, metal and/or polymeric based nanoparticles are good candidates for dual applications in terms of both diagnostics and therapeutic approaches [175,176,177]. For example, magnetic nanoparticles coated with natural compounds have proved their efficiency in the imaging of CVDs. Suzuki et al. [178] reported ultra-small superparamagnetic iron oxide nanoparticles coated with a specific polysaccharide (fucoidan) which have been successfully employed in MRI as contrast agents for arterial thrombus and elastase-induced vascular injury in a rat model. Another example is the case of gold nanoparticles used as contrasting agents, for the efficient detection and diagnosis of myocardial infarction. The method is based on engineered gold NPs conjugated with collagen, which demonstrated high-resolution detection of myocardial and ischemic injuries, along with adequate therapeutic tools [179]. Liposomal platforms have also proved to be a successful tool for diagnostic and therapeutic methods for platelet targeting in CVDs. The surface of liposomes with natural peptides was demonstrated to facilitate the drug delivery of active compounds and at the same time to target the cardiovascular tissues or damaged areas [180]. Many evidences for nano-based theranostics in terms of prognosis of atherosclerosis, myocardial infarction, aneurysms, angiogenesis, and other CVDs [175] have been reported, highlighting the benefit of sensitive detection of pathophysiological conditions combined with concomitant therapeutic measures. Although there has been reported success of preclinical studies related to theranostic nanoplatforms, the translational approach to clinical sectors remains unexplored, and moreover, the innate toxicity and stability of the nanoformulations are less studied. Most of the in vivo models were considered with small animals, and hence, huge differences might be detected by comparison with human anatomical features. On the other hand, the costs/benefits ratio must be considered, as there is a lack of studies reporting these aspects.

Developing innovative multifunctional nanomaterials with qualities that allow them to deliver specialized therapies through various physiological obstacles and to target specific cell types, tissues, and organs in the body is a major challenge for this project. Effective nano-delivery systems have ideal characteristics for controlled release of medicament, long storage life, and enhanced therapeutic efficacy with no or minimal side effects [181,182].

6. Conclusions

Several bioactive compounds are being diagnosed and tested to see if they have the potential to improve human health. They have antioxidant, anti-inflammatory, and anticarcinogenic factors, in addition to physiological and cellular benefits that protect against infectious diseases and metabolic illnesses such as diabetes, cardiovascular disorder, and cancer. They are derived from plants, and their consumption in diets has been related to tremendous fitness outcomes, making them ideal assets for the manufacturing of new nutritional dietary supplements with extensive shielding and preservative abilities.

Considering the high prevalence of CVDs worldwide, with a high level of morbidity and mortality, and excessive side effects of current therapies, the optimized alternative approaches are necessary for the prevention and/or treatment of these diseases. A large group of plant-derived bioactive compounds are used as alternative therapies for CVDs, which are summarized in this paper. They can be tailor-made to match the character and cultural preferences, to meet those lofty objectives, global and country-wide tasks to sell healthier, primarily plant-based diets. The role and significance of bioactive compounds for CVD treatment is still being explored, and its consequences must be established. Some polyphenols and flavonols used as bioactive compounds have been shown to reduce CVD risk factors. Their antioxidant and anti-inflammatory properties are the most important characteristics that make them favorable candidates for CVDs treatment. Along with the detailed properties of bioactive compounds used in CVDs, the current review provides an overview of the therapeutic advantages of nanoformulations along with recent advancements in this field.

The advantages of nano-delivery systems of bioactive compounds, recent preclinical studies, clinical trials, and nano-theranostic approaches are also discussed in this review, in order to offer a clearer understanding of the connection between bioactive compounds and CVD prevention, diagnostics, and treatment. Although the reported success of preclinical studies is related to the effectivity of nanoformulations and theranostic nanoplatforms, the translational approach to clinical sectors remains poorly explored, as the therapeutic applications of nano-phytomedicines in CVDs are still in their initial clinical phases. Nanotechnologies will provide a new window in the area of CVDs with the opportunity to achieve effective treatment, better prognosis, and fewer adverse effects on non-target tissues. However, further research is required for the development of low-cost nanoformulations and their effective usage, along with research in the toxicological approach.