These interactions act through Boosting energy before workouts and post-transcriptional machinery leading BMI for Teens the Cardiovaxcular of dynamic reactions to ever-altering annd signals Kalt, W. Whereas the study did not find any significant differences in anti-inflammatory cytokines with blueberry supplementation, it was however, reported that this null effect may be due to the shorter duration of the study and therefore, recommended further investigation. Mahdavi-Roshan, M, Salari, A, Ghorbani, Z, and Ashouri, A.

Polyphenols and cardiovascular health -

In the past few years, research on polyphenols has remarkably expanded and is unveiling several biological activities of these compounds.

Alas, the marketing departments of several industries are jumping ahead of solid scientific evidence; as a consequence, unsubstantiated claims are being made and whole foods or fortified, enriched, or enhanced foods are being created and sold. Science is beginning to corroborate some of these claims, but much more research is needed and several myths are to be disproven.

In this mini-review we critically discuss the current limitations of polyphenol research and we contend that, in addition to their putative antioxidant action, several biochemical and physiological processes might be influenced by polyphenols.

Keywords: Polyphenols , cardiovascular disease , microRNAs , biomarkers , Epidemiological , caloric intake , fats , proteins , antioxidant action , high-vegetable , nutraceuticals.

Title: Polyphenols and Cardiovascular Disease: A Critical Summary of the Evidence. Volume: 11 Issue: Abstract: Epidemiological studies are clear: diets in which plant foods provide the major portion of caloric intake, e. Visioli F. and Davalos A.

Polyphenols and Cardiovascular Disease: A Critical Summary of the Evidence Author s : F. Visioli and IMDEA-Food, Calle Faraday 7, Campus de Cantoblanco, Madrid, Spain. Davalos Volume 11, Issue 14, Page: [ - ] Pages: 5 DOI: Purchase PDF.

Mark Item. Mini-Reviews in Medicinal Chemistry. Title: Polyphenols and Cardiovascular Disease: A Critical Summary of the Evidence Volume: 11 Issue: 14 Author s : F.

Visioli and A. Davalos Affiliation: Keywords: Polyphenols , cardiovascular disease , microRNAs , biomarkers , Epidemiological , caloric intake , fats , proteins , antioxidant action , high-vegetable , nutraceuticals Abstract: Epidemiological studies are clear: diets in which plant foods provide the major portion of caloric intake, e.

Close Print this page. Export Options ×. Export File: RIS for EndNote, Reference Manager, ProCite. Content: Citation Only. Citation and Abstract. About this article ×. Cite this article as: Visioli F. Close About this journal. Related Journals Anti-Cancer Agents in Medicinal Chemistry.

Current Bioactive Compounds. Current Cancer Drug Targets. Current Cancer Therapy Reviews. Current Diabetes Reviews.

Current Drug Safety. Current Drug Targets. CH is a beneficial adaptive response that removes the effect of extrinsic or intrinsic stress to preserve cardiac function. However, excessive CH is deleterious and leads to adverse complications such as HF RES suppresses CH by regulating diverse signaling pathways in cardiomyocytes.

NFAT is a transcriptional factor that activates GATA4, which induces cell hypertrophy The benefits of calcineurin inhibitors have been shown in terms of preventing CH The study by Chan et al. Further examination revealed that RES inhibited CH processes by activating AMP-AMPK through upregulating liver kinase B1 LKB1 , the activating kinase of AMPK, leading to inhibition of p70S6K, eEF2, and NFAT signaling pathways Also, AMPK could inhibit CH through NFAT, NF-κB, and MAPK signal pathways RES could exert beneficial effects by regulating micro RNAs miRNAs , a central subgroup of non-coding RNAs, as an alternative molecular mechanism.

Fan et al. They showed that miR induces cardiomyocyte hypertrophy and disrupts cardiac function BRCA-1 is an essential gene for heart development and exerts cardioprotective effects in adult hearts Angiotensin II is one of the renin-angiotensin system hormones with a vital role in the progression and development of several CVDs, such as hypertension, CH, and HF Mashhadi et al.

showed that expression of AT1a Ang receptor was increased in the hypertrophic rat heart, indicating that the Ang receptor plays a vital role in the development of PO-induced cell hypertrophy.

Exercise intolerance is an essential feature of chronic HF, and identifying its underlying mechanism may help improve the quality of life of patients with HF Recent studies have shown that impaired skeletal muscle function, structure, and metabolism play an important role in exercise intolerance in HF patients In this way, some studies have shown that RES can improve rodents' skeletal muscle biogenesis, isometric force, and metabolism , Sung et al.

A significant improvement in HF mice's respiratory exchange ratio RER was observed. Decreased RER in HF mice indicates more use of fatty acids than glucose in metabolism, producing more ROS and increasing oxidative stress.

Treatment with RES elevated RER level, indicating that substrate utilization in the metabolic cycle shifted towards glucose; also, the total metabolic rate was increased after RES treatment Mechanistically, RES treatment increased phosphorylation and expression of IRS-1, Akt, and AMPKα, which were reduced in HF and enhanced insulin sensitivity of skeletal muscles.

This study also indicated that RES improved metabolism and insulin resistance in HF mice by altering the gut microbial community, which is associated with systemic metabolic rate and insulin sensitivity.

showed that RES enhanced the cecum bacterial profile, increasing glucose homeostasis and carbohydrate metabolism Curcumin [ 1E,6E -1,7-bis 4-hydroxymethoxyphenyl hepta-1,6-diene-3,5-dione] is a natural polyphenol substance extracted from turmeric that plays substantial roles in cellular function by regulating various signaling pathway.

Curcumin benefits various pathologic conditions and has anti-inflammatory and antioxidant effects According to these features, curcumin can be used as a therapeutic element in various diseases Several studies have reported the positive role of curcumin in attenuating CVDs, such as atherosclerosis, MI, and HF , Tang et al.

The results demonstrated the ameliorating of curcumin's role in cardiac remodeling and HF's diastolic dysfunction. Also, curcumin significantly reduced collagen deposition in heart tissue Table 1. The p, a histone acetyltransferase HAT enzyme, regulates the expression of multiple genes by chromatin remodeling.

P can also coactivate other transcriptional factors, such as GATA4 , , a member of the zinc-finger transcription factor family with high expression in cardiomyocytes and plays a critical role in cardiomyocyte differentiation GATA4 regulates the transcription of ANP, α- and β-myosin heavy chain α-MHC and β-MHC , which play a role in cardiac remodeling Therefore, it seems that overexpression of p induces cardiac remodeling by increasing the activation of GATA4 Several studies have reported curcumin as a natural pspecific HAT inhibitor that can improve cardiac remodeling in HF.

Morimoto et al. Mechanistically, curcumin reduced GATA4 and p binding but did not change their expression. Dickkopf-related protein 3 DKK-3 , a member of dickkopf glycoprotein, regulates cell proliferation. Also, DKK-3 could modulate the immune system by acting as a cytokine-like protein , DDK-3 is involved in cardiac remodeling and vascular smooth muscle differentiation, and several studies demonstrated the cardioprotective effects of DDK-3 Zhang et al.

showed that suppressing the expression of DDK-3 increases cardiac dysfunction and remodeling while augmenting the expression of DDK-3 improves cardiac function in an animal model of HFrEF Moreover, DDK-3 improves chronic HF conditions by suppressing c-Jun N-terminal kinase JNK signaling pathways by inhibiting p38 mitogen-activated protein kinase p38 It has been found that P38 and JNK signaling pathways are highly activated in HF and participate in cardiac remodeling , In addition, expression of DDK-3 increased in curcumin-treated mice, compared with untreated mice with HF.

Liu et al. studied the effects of curcumin on isoproterenol ISO -induced CH and the molecular mechanism behind it. It has been found that the mTOR signaling pathway exerted cardioprotective effects by decreasing autophagy Consistent with these studies, Bai et al.

Treatment with NCX inhibitor KB-R reversed the protective effects of curcumin on the myocardium and vessels. These results indicate that curcumin exerts cardioprotective effects by upregulating NCX expression in response to increased afterload Quercetin QCT is a natural flavonoid polyphenol widely found in fruits and vegetables such as onions, peppers, plums, mangos, and berries and is a potent anti-inflammatory, antioxidant, and anti-cancer component — Quercetin regulates several molecular pathways in cellular processes and exerts many beneficial effects on the cardiovascular system, such as anti-hypertensive and cardioprotective effects, by suppressing inflammation, oxidative stress, and apoptosis in the heart , Several studies investigated the mechanisms behind the cardioprotective effects of QCT.

showed that QCT inhibits the NF-κB pathway by activating peroxisome proliferator-activated receptor-γ PPARγ protein and preventing cardiac damage For further investigation, Chang et al.

administered QCT to improve cardiac function and hypertrophy in rats with TAC-induced HF. QCT decreased cardiac fibrosis by modulating TGF-β and MMPs, inflammatory cytokines TNF-α, IL, IL , and production of ROS by activating the expression of SIRT5 and IDH2 desuccinylation. Succinylation regulates mitochondrial metabolism and function; impaired succinylation and mitochondrial function lead to oxidative stress and inflammation.

This study showed that QCT regulates mitochondrial energy metabolism and improves oxidative stress by increasing succinylation through increasing expression of SIRT5 Anti-hypertrophic properties of quercetin have been reported in several studies — QCT can prevent cardiac remodeling in mice.

Wang et al. Also, quercetin attenuated ventricular wall thickness in mice, indicating the anti-hypertrophic effects of QCT SIRT3 is a type III histone deacetylase with anti-hypertrophic effects on the heart The expression of SIRT3 was increased by QCT, indicating that the anti-hypertrophic effects of QCT are related to the SIRT3-mediated signaling pathways.

PARP-1 is an up-regulated enzyme in hypertrophic hearts, and overexpression of SIRT3 inhibits its function Moreover, In vitro investigation showed that treating Ang II-induced H9c2 cells with QCT prevents hypertrophic response, restores impaired mitochondrial structure and function, reduces ROS generation, and decreases oxidative stress Oxidative stress and ROS play essential roles in the development of CH.

In this study, QCT treatment restored endogenous antioxidant enzyme CAT and SOD activity, increased sulfhydryl protein levels, and decreased H 2 O 2 a major ROS. Altogether this study revealed that QCT attenuates pre-existing CH by balancing oxidation and protecting mitochondria QCT also reduced oxidative stress in the heart tissue of AAC rats.

This study showed that rats with a QCT-supplemented diet have lower blood pressure and CH in pressure-overload stress conditions Table 1. Gallic acid 3, 4, 5-trihydroxy benzoic acid is a polyphenol component in green tea, blackberry, grapes, wine, mangoes, and walnuts.

It can be an anti-cancer, anti-allergic, anti-microbial, antioxidant, and anti-inflammatory factor , Gallic acid GA impacts the cardiovascular system, such as attenuating cardiac fibrosis, hypertension, oxidative stress, and eventually HF.

The antioxidative effects of gallic acid suppress cardiac hypertrophy and protect cardiomyocytes against damage , , An in vitro investigation conducted by Yan et al. In this experiment, GA increased cardiomyocyte autophagy by inhibiting ULK1 phosphorylation autophagy regulator , which leads to the degradation of unnecessary products and improved cardiac remodeling.

GA decreased inflammatory markers, myocardial superoxide products, and fibrosis factors in the heart of mice with HF. Collectively, GA exerts its cardioprotective effects and improves cardiac remodeling by activating autophagy through various pathways The levels of HF markers, such as ANP, BNP, and β-MHC, significantly decreased after GA treatment.

Pulmonary fibrosis is a severe complication of HF due to increased left atrial pressure, pulmonary edema, and fibrosis formation According to the anti-fibrotic effects of gallic acid in other studies, Jin et al. Expression of epithelial-mesenchymal transition EMT markers, including N-cadherin and SNAI1, was increased in the TAC group, and treatment with GA reduced their expression, suggesting the inhibitory role of GA in HF-induced pulmonary fibrosis by inhibiting the EMT process EMT participates in tissue repair and induces pulmonary fibrosis According to the well-established effects of GA on CVDs, Jin et al.

investigated mechanisms of GA affecting blood pressure and CH. Arterial remodeling and vascular contractibility were also reduced by GA treatment, indicating the regulatory effect of GA on vascular smooth muscle.

Collectively, GA alleviated hypertension and CH by suppressing Nox2 activity and Nox2-induced oxidative stress via inhibiting GATA4 expression Additionally, GA prevented ISO-induced CH and improved cardiac dysfunction by decreasing the expression of hypertrophy-related and fibrosis-related genes.

To investigate the role of JNK2 in cardiac fibrosis and hypertrophy, they transfected JNK2 into cardiomyocytes which led to increased Smad3 and collagen type I protein levels, inducing cell hypertrophy and fibrosis. Consequently, this study showed that GA prevents ISO-induced cardiac hypertrophy by regulating JNK2 signaling and Smad3 binding activity Table 1.

Estrogen has shown an influential role in protecting the cardiovascular system, especially in improving the pulmonary and cardiac function of pulmonary hypertension PH cases, by binding to estrogen receptor-β ERβ , Genistein, an isoflavone derived from soybean, functions as a natural estrogen, can bind to ERβ stronger than estrogen, and can exert anti-inflammatory and anti-cancer effects — According to the unwanted side effects of estrogen as a drug, genistein can be used instead of the pharmacological form of estrogen.

Also, several studies have shown that genistein intake can ameliorate cardiovascular risk factors such as hypertension and lipid profile Matori et al. This study confirms the beneficial cardiopulmonary effects of genistein in rats with PH Genistein has shown anti-hypertrophic effects in several studies.

Meng et al. Nitric oxide synthases NOS catalyze NO production from L-arginine. Neuronal nitric oxide synthase nNOS and endothelial nitric oxide synthase eNOS have anti-hypertrophic effects on the heart, but inducible nitric oxide synthase iNOS induces hypertrophy Maulik et al.

investigated the effects of genistein 0. Genistein exerts anti-hypertrophic effects via eNOS, nNOS, and antioxidant effects in ISO-induced CH rat models Recent studies have shown that genistein exerts parts of its effects by regulating the expression of miRNAs Gan et al.

Expression of the TIMP2 gene was increased in the ISO-induced CH heart, indicating pro-hypertrophic effects of TIMP2 Table 1.

Pterostilbene [4- 3,5dimethoxystyryl phenol] is a polyphenol structurally similar to RES and has potential pharmacological impacts such as anti-cancer, anti-inflammatory, antioxidant, and anti-apoptosis — Furthermore, Lacerda et al.

Enhancing the glutathione redox cycle was suggested as an underlying mechanism of the antioxidative effects of PTS The glutathione redox cycle protects the cell membrane from LPO and oxidative stress Phospholamban is a protein that regulates calcium channels in the heart, and SERCA is a calcium transporter in the cell.

Both these proteins play a significant role in calcium transportation and cardiac muscle contractility , Table 1. Kaempferol can protect cells against oxidative stress and inflammation and exerts various pharmacological effects such as anti-microbial, anti-diabetic, and anti-cancer Kaempferol exerts pleiotropic beneficial effects on the cardiovascular system, including ameliorating cardiac fibrosis, preventing HF, improving myocardial damage repair, and decreasing atherosclerosis , , Zhou et al.

Diabetes is one of the significant risk factors for HF development ; thus, according to the positive effects of KF on both the cardiovascular system and diabetes, Zhang et al.

Results of this study demonstrated that treatment with KF exerts significant cardioprotective effects in diabetic rats as it suppresses inflammation, oxidative stress, and apoptosis and alleviates blood glucose levels and serum cardiac markers Regarding the underlying mechanism, KF modulated the nuclear factor erythroid 2-related factor 2 Nrf2 signaling pathway, which protects cells against ROS, and the nuclear factor-light-chain-enhancer of activated B cells NF-κβ signaling pathway, which has a vital role in fibrosis.

The activity of antioxidant enzymes was increased, while the LPO level was decreased after treatment with KF. Expression of inflammatory factors, including NF-κβ p65, TNF-α, IL-6, IL-1β, p-IKKβ, and COX-2, significantly decreased. Cardiac apoptosis markers caspase-3 and Bax were decreased, while the anti-apoptotic marker Bcl-2 was increased in cardiac tissue after KF treatment.

The histopathological investigation revealed decreased destruction of myofibrils and lesser TUNEL-positive cells in the cardiac tissue of rats treated with KF Feng et al.

investigated the role of KF in CH and the molecular mechanism behind it. Interstitial fibrosis, oxidative stress, and apoptosis were also reduced after KF administration P38 and JNK are subfamilies of MAPKs and regulate cell apoptosis Table 1.

Recent studies have reported that LUT exerts cardioprotective effects against myocardial ischemia, coronary artery disease, and HF , Hu et al. PLB is a SERCA2a inhibitor whose phosphorylation suppresses activity This study verified the enhancing role of LUT on cardiac contractibility in HF Table 1.

Epigallocatechin gallate EGCG is a natural polyphenol flavonoid abundant in green tea and is known for its antioxidant properties. Several studies have shown that EGCG is vital in decreasing oxidative stress in the cardiovascular system For instance, a study by Sheng et al. showed that EGCG attenuates PO-induced CH by suppressing apoptosis and oxidative stress in rats The findings implied the role of EGCG in reducing oxidative stress and apoptosis; EGCG increased the expression of Bcl-2 and telomere repeat-binding factor 2 TRF2 , which are anti-apoptotic agents.

In addition, EGCG reduces oxidative stress in the heart by decreasing the level of MDA and increasing SOD activity According to the cardioprotective effects of EGCG, Muhammad et al. In this regard, Gao et al. investigated the effect of apigenin treatment on improving hypertension and hypertension-induced CH in Wistar-Kyoto rats.

Previous studies have reported that hypoxia-inducible factor HIF -1α mediates CH through its effect on HIMF hypoxia-induced mitogenic factor 38 , Apigenin can exert inhibitory effects on HIF-1α; therefore, Zhu et al. investigated the anti-hypertrophic effects of apigenin by inhibiting HIF-1α.

The result showed that apigenin decreased blood pressure, heart weight, and serum angiotensin II, indicating a positive role of apigenin in hypertension and CH. Levels of serum and myocardial-free fatty acids also decreased after apigenin treatment.

HIF-1α deregulates cardiac metabolism by inhibiting the expression of mitochondrial proteins involved in metabolisms, such as PPARα, CPT-1, and PDK Apigenin improved abnormal myocardial glucolipid metabolism by upregulating PPARα, CPT-1, and PDK-4 via suppressing HIF-1α.

This study revealed that apigenin's anti-hypertrophic effects are associated with its effect on HIF-1α Table 1. Caffeic acid CA is a natural flavonoid found in various foods and herbs, such as coffee, red wine, thyme, sage, and spearmint CA has a wide range of beneficial effects on cellular processes, such as modulating cell growth, proliferation, and anti-inflammatory effects; hence, this molecule could positively affect the cardiovascular system.

It is reported that intravenous administration of caffeic acid decreases blood pressure and improves cardiac function It also exerts cardioprotective effects by reducing MI-related oxidative stress According to the association of CA with the MAPK pathway and the role of this pathway in CH, Ren et al.

indicated inhibitory effects of CA on PO-induced CH. In addition, the treatment improved cardiac function and decreased cardiac fibrosis. The anti-inflammatory and antioxidant effects of delphinidin were well described ROS is a significant mediator of oxidative stress and has a vital role in the development of CH by regulating various signaling pathways and protein kinases NADPH oxidase NOX is an oxidoreductase enzyme and the leading producer of ROS in cardiac myocytes , Previous studies have shown that delphinidin exerts parts of its function by regulating NOX activity.

Chen et al. showed that treatment with a high dosage of delphinidin ameliorated CH and cardiac dysfunction and reduced oxidative stress and cardiac fibrosis in the heart.

Treatment with delphinidin prevented the increased expression of NOX by activating AMPK, a NOX inhibitor, in response to hypertrophic stimulators. Hesperidin 3,5,7-trihydroxyflavanone 7-rhamnoglucoside HES is a natural flavonoid with comprehensive pharmacological properties such as anti-inflammatory and antioxidant HES has beneficial cardioprotective effects, especially in attenuating CH It was indicated that treatment with HES improved hemodynamic state and attenuated left ventricular function.

HES preserved the function and structure of mitochondria, myofibril, and myocyte. Cardiac injury, apoptosis, and inflammatory markers were decreased, and oxidative stress was reduced in heart tissue by HES treatment.

PPAR-γ is a metabolism regulator which suppresses CH. Bhargava et al. showed that HES upregulated the expression of PPAR-γ, indicating that HES anti-hypertrophic effects arise from enhancing PPAR-γ expression Table 1.

Bioavailability is an essential issue regarding the clinical application of pharmacological substances. The concentration of RES is dose-depended, and the maximal concentration of 2.

Drug delivery systems and reformed formulation are novel ways to improve the bioavailability of RES in humans. RES has been shown to improve myocardial reperfusion, enhancing re-endothelialization and reducing inflammation.

Also, RES consumption before MI reduced infarct size and cardiac arrhythmia and relieved myocardial injury faster. RES can increase the viability and proliferation of cardiac stem cells, therefor transplanting RES-treated stem cells into an ischemic heart improved cardiac injury in the peri-infarct zone While curcumin could be administered as a drug, pure curcumin has low oral bioavailability due to its low absorption and rapid metabolism.

In this regard, Ray et al. Collectively, Ray et al. showed that an efficiently targeted delivery regimen for curcumin enhances its therapeutic effects, reduces CH, and improves cardiac function Additionally, Sungawa et al.

investigated the effectiveness of a novel surfactant-soluble oral drug delivery system DDS for curcumin to develop a therapeutic aid for patients with MI-induced HF. This DDS significantly enhanced gastrointestinal absorption and effectiveness of curcumin, as administration of 0.

In the meantime, no significant side effects were detected regarding DDS curcumin administration. The histopathologic examination showed that DDS curcumin suppressed myocardial cell hypertrophy and perivascular fibrosis.

However, the exact dosage of pure oral curcumin did not apply the same effects Creating a synthetic analog for curcumin is another way to increase its bioavailability to use it as an efficient therapeutic drug. Shimizu et al. examined the role of five different curcumin analogs in inhibiting pHAT.

Among these five analogues, GO-Y 1E, 4E -1,5-bis[3,5-bis methoxymethoxy phenyl]-1,4-pentadieneone inhibited pHAT and improved HF more efficiently than curcumin. The in-vivo investigation conducted by Shimizu et al. revealed that administration of 0.

HF treatment is based on improving symptoms and preventing further complications. Although these treatments effectively relieve symptoms, the survival rate has not met the desirable goal yet. Therefore, recent studies and clinical trials have focused on targeting the pathogenic mechanism of HF such as myocardial contractibility and metabolism, inflammation, oxidative stress, etc.

with new drugs , Therefore, Gal et al. investigated the role of RES on left ventricular function and cardiac inflammation in patients with HF. Moreover, the levels of NT-proBNP a marker of the severity of HF and galectin-3 were significantly lower in the RES-treated group compared to the placebo group.

Echocardiography results showed that treatment with RES significantly increased ejection fraction, left ventricular stroke volume, left ventricular end-systolic volume, and ventricular dilation, indicating positive effects of RES on cardiac remodeling.

The results showed that RES suppressed the expression of ATP synthesis-related genes via oxidative phosphorylation in leukocytes; however, this did not result in mitochondrial dysfunction.

This clinical study demonstrated that RES has anti-inflammatory effects and improves the quality of life, physical performance, cardiac function, and remodeling in patients with MI-induced HF In another similar study, Gal et al. evaluated the effects of RES on hemorheological parameters in HF patients.

They found that RES could significantly improve impaired red blood cell RBC aggregation resulting from HF, which may be attributed to the antioxidative effects of RES. Also, the result showed that RES significantly improved the results of the 6-minute walk test of HF patients Various cardiovascular disorders are associated with increased RBC aggregation, such as ischemic heart disease, diabetes, venous thrombosis, and HF Increased levels of inflammatory cytokines and oxidants in the blood due to HF are significant factors in RBC aggregation and hemorheological disturbances , Unstable angina, a subtype of acute coronary syndrome ACS , leads to cardiac complications, such as arrhythmia, MI, and eventually HF.

Inflammation is a critical factor in the progression of ACS, leading to further complications. According to the anti-inflammatory effects of curcumin, it can be used as a therapeutic drug in ACS, preventing complications such as HF. Dastani et al. This novel clinical trial showed no significant effect of curcumin on preventing cardiovascular complications of unstable angina, such as HF The results indicated that high curcumin absorption had no significant effects on left ventricular diastolic function but significantly suppressed increment in the plasma BNP levels The result revealed that nano-curcumin reduced atherosclerosis and hs-CRP levels as an inflammation indicator in diabetic heart patients However, future studies still need to investigate the theory more widely.

As reviewed earlier, polyphenols can play a critical role in attenuating HF and CH, as they can prevent cardiac remodeling mechanistically by blocking oxidative, inflammatory, apoptotic, and fibrotic-related pathways. Moreover, polyphenols are easily accessible and enriched within various natural plant-based sources and could be considered novel promising therapeutic approaches for HF.

Additionally, the conventional HF treatments' low survival rates have forced studies to search for other viable options as CVDs are growing globally. However, these studies are still in their infancy, and limited clinical data regarding the efficacy, side effects, and administration routes of polyphenol-based drugs for treating cardiovascular diseases such as HF and CH are available.

Despite the abundant presence of polyphenols in a human's regular nutritional diet, the poor solubility, low stability, rapid metabolism and elimination, and eventually, weak bioavailability are the rate-limiting factors for inhibiting these compounds from exerting their full cardioprotective effects Therefore, some recent studies have focused on enhancing the polyphenols' bioavailability, especially RES and curcumin, by employing nanoformulations, such as lipid-based nanoparticles liposomes , protein-based nanoformulations, polymers, micelles, and metal nanoparticles for drug delivery For instance, RES and curcumin co-delivery by polymeric micelles to doxorubicin-treated cardiomyocyte cell lines resulted in higher drug solubility and efficacy than non-polymeric forms and single-drug treatment Polymeric micelles used in these studies are biocompatible and FDA-approved.

Moreover, polymer-based drug delivery vehicles such as Poly D,L-lactic-co-glycolic acid PLGA nanoparticles demonstrated superior anti-atherosclerotic effects of curcumin-bioperine treatment compared to non-coated ones.

Pillai et al. reported that curcumin-bioperine coated with PLGA nanoparticles significantly reduced ox-LDL levels, downregulating the atherosclerotic plaque-related gene expression in vitro The efficacy of PLGA-encapsulated curcumin was also illustrated in vivo in later studies, where gold-capped curcumin encapsulated within PLGA demonstrated enhanced solubility, bioavailability, and eventually, improved anti-hypertrophic characteristics in hypertrophic Wistar rat models Aside from polymeric-based drug delivery, extensive studies were carried out on the efficacy of liposome-targeted therapy — Liposomes are phospholipid-based nanocarriers designed for both hydrophilic and hydrophobic drug delivery.

Liposome preparation progress in recent years has introduced the ligand surface-engineered and long-circulating liposomes, allowing stability and sustained drug release in target tissues and enhanced bioavailability The use of liposomes in CVDs has become a promising candidate for future safe drug delivery without cytotoxicity.

RES-contained liposomes were demonstrated to enhance the respiratory capacity of the cardiomyocytes in vitro Moreover, the transplantation of mitochondrial-activated cardiac progenitor cells by liposomal RES into the heart of the mouse models with cardiomyopathy resulted in reduced oxidative stress and apoptotic activities of the cardiomyocytes Considering their minimal side effects and significant therapeutic features, polyphenols have introduced themselves as intriguing options for future HF treatment.

However, due to the low bioavailability and stability of polyphenols in the circulating system, limited clinical trials have been conducted evaluating their impact on human HF, and most of the studies are in vitro and in vivo animal models. However, with recent advances in novel drug delivery systems, there is rising hope for translating nanoparticle delivery of these compounds to the clinical setting soon.

In conclusion, this study predominantly reviewed the therapeutic effects of polyphenol compounds and their underlying mechanisms in improving pathologic cardiac remodeling, leading to heart failure. Also, this study discusses the most recent advances and challenges in translating the antioxidative, anti-inflammatory, anti-apoptotic, and antifibrotic characteristics of these nutraceuticals into clinical settings.

The potential application of nano-drug delivery systems was also investigated regarding the limited solubility, stability, and bioavailability of the polyphenols in humans. Finally, further in-depth surveys are needed to understand better the involved molecular pathways of polyphenols in modulating cardiac remodeling and HF.

Also, there is a rising demand for viable strategies to better translate the in vitro and animal study results into the clinic. NH, AY, MS, YG, FA, RE, M-HA, MH, ZA, HM, MHJ, AM, and MR took part in creating the idea, design, and composing of the manuscript.

All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Tresserra-Rimbau cardovascular the University of Boosting energy before workouts in Increase mental energy. Consumption Polypphenols foods Polyphenols and cardiovascular health are rich in polyphenolic compounds has long been associated with health benefits related to cardiovascular function, including the modulation cardiovadcular various cardiovascular parameters such as, vascular and platelet function, blood pressure and the plasma lipid profile, with modulation of oxidative stress, inflammation, and endothelial function. However, according to the PREDIMED researchers, the epidemiologic findings have been inconclusive. Further randomized controlled trials are needed to confirm the promising protective effects of polyphenols on CVD and establish dietary recommendations and desired minimum levels of intake. Tresserra-Rimbau, E. Rimm, A.

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