Role of polyphenolic compounds and their nanoformulations: a comprehensive review on cross-talk between chronic kidney and cardiovascular diseases

Abstract

Chronic kidney disease (CKD) affects a huge portion of the world’s population and frequently leads to cardiovascular diseases (CVDs). It might be because of common risk factors between chronic kidney disease and cardiovascular diseases. Renal dysfunction caused by chronic kidney disease creates oxidative stress which in turn leads to cardiovascular diseases. Oxidative stress causes endothelial dysfunction and inflammation in heart which results in atherosclerosis. It ends in clogging of veins and arteries that causes cardiac stroke and myocardial infarction. To develop an innovative therapeutic approach and new drugs to treat these diseases, it is important to understand the pathophysiological mechanism behind the CKD and CVDs and their interrelationship. Natural phytoconstituents of plants such as polyphenolic compounds are well known for their medicinal value. Polyphenols are plant secondary metabolites with immense antioxidant properties, which can protect from free radical damage. Nowadays, polyphenols are generating a lot of buzz in the scientific community because of their potential health benefits especially in the case of heart and kidney diseases. This review provides a detailed account of the pathophysiological link between CKD and CVDs and the pharmacological potential of polyphenols and their nanoformulations in promoting cardiovascular and renal health.

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Naunyn-Schmiedeberg's Archives of Pharmacology
https://doi.org/10.1007/s00210-023-02410-y
REVIEW
Role ofpolyphenolic compounds andtheir nanoformulations:
acomprehensive review oncross‑talk betweenchronic kidney
andcardiovascular diseases
AnkitaRajput1· PalviSharma1· DavinderSingh1· SharabjitSingh1· PrabhjotKaur1· ShivaniAttri1· PallviMohana1·
HarneetpalKaur1· FarhanaRashid1· AsthaBhatia1· JoachimJankowski2· VanitaArora3· HardeepSinghTuli4·
SarojArora1
Received: 21 November 2022 / Accepted: 26 January 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
Chronic kidney disease(CKD) affects a huge portion of the world’s population and frequently leads to cardiovascular dis-
eases(CVDs). It mightbe because of common risk factors between chronic kidney disease and cardiovascular diseases. Renal
dysfunction caused by chronic kidney disease creates oxidative stress which in turn leads to cardiovascular diseases. Oxidative
stress causes endothelial dysfunction and inflammation in heart which results in atherosclerosis. It ends in clogging of veins
and arteries that causes cardiac stroke and myocardial infarction. To develop an innovative therapeutic approach and new drugs
to treat these diseases, it is important to understand the pathophysiological mechanism behind the CKD and CVDs and their
interrelationship. Natural phytoconstituents of plants such as polyphenolic compounds are well known for their medicinal
value. Polyphenols are plant secondary metabolites with immense antioxidant properties, which can protect from free radical
damage. Nowadays, polyphenols are generating a lot of buzz in the scientific community because of their potential health
benefits especially in the case of heart and kidney diseases. This review provides a detailed account of the pathophysiological
link between CKD and CVDs and the pharmacological potential of polyphenols and their nanoformulationsin promoting
cardiovascular and renal health.
Keywords Cardiovascular diseases· Chronic kidney disease· Polyphenols· Therapeutic potential· Nanoformulations·
Phytomedicine
Introduction
Kidney failure is an increasing public health issue that affects
both the elderly and young people all over the world (Hu etal.
2023). It is described as a change in structure and function of
the kidney that deteriorates health (Davranovna etal. 2022).
According to Gajjala and colleagues, kidney damage is sepa-
rated into five stages depending on the glomerular filtration
rate (GFR). GFR of less than 90ml/min/1.73 m2 is classified as
normal kidney function, whereas GFR of 60–89ml/min/1.73
m2 is classified as moderately diminished kidney function. In
third stage GFR is30–59ml/min/1.73 m2. In the fourth stage,
it declines to 15–29ml/min/1.73 m2 and in the fifth stage, it
is less than 15mlmin/1.73 m2 (Gajjala etal. 2015). The early
stages of chronic kidney disease are asymptomatic, while later
stages need transplantation or dialysis (Gajjala etal. 2015).
The final stage of nephropathy is kidney failure, often known
as an end-stage renal disease (ESRD) (Gerrits etal. 2023).
Chronic kidney disease (CKD) is emerging to be an important
Key points
• CVD and CKD shares various common risk factors such
as smoking, obesity, hypertension, diabetes mellitus, and
dyslipidaemia.
• Polyphenolic compounds attenuate oxidative stress and
ameliorates CVD and CKD.
• Nanoformulations of polyphenolic compounds improves their
pharmacological potential achieving enhanced efficacy.
* Saroj Arora
dr.sarojarora@gmail.com; saroj.botenv@gndu.ac.in
1 Department ofBotanical andEnvironmental Sciences, Guru
Nanak Dev University, Amritsar, Punjab, India
2 Institute forMolecular Cardiovascular Research, RWTH
Aachen University, Aachen, Germany
3 Sri Sukhmani Dental College & Hospital, Derabassi, Punjab,
India
4 Department ofBiotechnology, Maharishi Markandeshwar
Engineering College, Maharishi Markandeshwar (Deemed
tobe University), Mullana-Ambala133207, India

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chronic disease globally. It has been observed that patients
suffering from CKDs are diagnosed with chronic vascular
diseases (CVDs) (Yang etal. 2018). It might be due to similar
risk factors for CVDs and CKDs such as obesity, smoking,
higher systolic pressure, dyslipidemia, diabetes, and hyperten-
sion (Yang etal. 2018). It has been found that cardiovascular
morbid mortality is higher in CKD patients than in the general
population (Varian etal. 2023).
CVDs refer to a group of diseases affecting the heart mus-
cle and the circulatory system that supplies the blood to the
heart, brain, and other essential organs (Kumar etal. 2021).It
includes coronary heart disease, cerebrovascular disease,
peripheral arterial disease, rheumatic heart disease, congeni-
tal heart disease, cardiomyopathies, cardiac arrhythmias, deep
vein thrombosis, and pulmonary embolism (Zhou etal. 2021).
CVDs account for high morbidity and mortality all over the
world (Carney 2020). According to the reports of Global
Burden of Diseases (GBD), 64 million cases of CVDs were
recorded in 2015; among which 61 million cases were of coro-
nary heart disease (CHD) and the remaining cases included
cardiac stroke, rheumatic heart disease, and congenital heart
diseases (Roth etal. 2017). Major risk factors for CVDs are
hypertension, hypercholesterolemia, diabetes, alcohol con-
sumption, smoking, lack of physical activity, and obesity
(Mendez etal. 2022). Potential pathophysiological effects of
these factors involve increased cardiac electrical instability,
myocardial ischemia, plaque disruption, and thrombus for-
mation, contributing to clinical events such as arrhythmia,
myocardial infarction, cardiomyopathy, and cardiac stroke
(Kivimäki and Steptoe 2018; Vogel etal. 2019).
Numerous studies have revealed the health benefits of
polyphenols in recent years, with particular focus on their
protective effects against cardiovascular disease and renal
damage (Rana etal. 2022). Polyphenols have vasodilating
properties and can improve lipid profiles as well as reduce
the oxidation of low-density lipoproteins (Ahmadi etal.
2022). Polyphenols are considered to be major micronutri-
ents constituent of human diet, which are involved in many
antioxidant and biological activities and affect various
chronic disorders. Several studies have previously investi-
gated the effect of polyphenol-rich red grape juice, green tee,
coca, and white wine in patients with renal failure (Mirmiran
etal. 2021). Therefore, an attempt has been made to high-
light the link between cardiovascular diseases and chronic
kidneys disease so that patients suffering from these ailments
should know about the precautionary measures to take into
consideration. This review provides the detailed therapeutic
profile of polyphenols on CVD and CKD to encourage the
researcher to delve more into other possibilities of treatment
and strategies to combat such ailments and come with better
solution. Also, it will create awareness in general population
about the health benefits of polyphenolic compounds and
encourage to take polyphenolic rich diet.
Therefore, an attempt has been made to highlight the
therapeutic effect of polyphenols in cardiovascular diseases
and chronic kidneys disease.
Method
In this review article, the international research databases
including Academic Search, MEDLINE, Google Scholar,
JSTOR, Science Direct, (Education Resources Information
Center), Web of Science, SciVerse, SCOPUS, Directory of
Open Access Journals (DOAJ) database were searched using
the key words herbal medicine, obesity, renal failure, chronic
kidney disorders, cardiovascular diseases, inflammation,
polyphenols, flavonoids, and phytomedicine.
Common pathophysiology ofCKDs andCVD
The link between CKD and CVD has been well-documented
in the scientific literature. Traditional risk factors for both
CKD and CVD include smoking, obesity, hypertension, dia-
betes mellitus, and dyslipidaemia (Yang etal. 2018). As a
result, different pathophysiological pathways may be shared
by both of these diseases (Fig.1). So, understanding this link
can beimperative in developing drugs that treat both CVD
and CKD combined.
Neurohormones
Many biochemical compounds are released into the blood-
stream during heart failure, some of which are critical in
the early stages of the disease but later prove to be counter-
productive such as catecholamines (Di Fusco etal. 2022).
These hormones act on cardiomyocytes and cause ventricu-
lar remodelling of the heart and because of which stroke
volume is lowered and a surge of catecholamines enters the
bloodstream. However over time, they cause renal vasocon-
striction and a reduction in GFR (Xu etal. 2021).
RAAS system
The renin–angiotensin–aldosterone system(RAAS), regu-
latesblood pressureandfluidandelectrolytebalance, as well
as systemicvascular resistance (Kovács and Barta 2023).
Rennin breaks angiotensinogen and generates angiotensin I
which is modified into angiotensin II by angiotensin-convert-
ing enzyme (ACE) (Wang and Cheng 2020). Angiotensin II
(AT-II) exerts multiple effects (including vasoconstriction,
aldosterone synthesis, and anti-diuretic hormone (vasopres-
sin) secretion) via type1 and 2 angiotensin receptors (Yanai
etal. 2021). Transforming growth factor β (TGF- β), a media-
tor of interstitial fibrosis is up-regulated by activation of the

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type 1 angiotensin receptor resulting in cardiomyopathy and
renal failure (WHO 2015; Wong etal. 2014).
Aldosterone promotes sodium and water retention and
mediates increases in size and stiffness of endothelial
cells (Zhang etal. 2021). In myocardium, mineralocorti-
coid receptor activation contributes to extracellular matrix
deposition, fibrosis, diastolic dysfunction, and alterations
in cardiomyocyte calcium handling predisposing to delayed
after depolarizations (Aguilar etal. 2021). RAAS activation
promotes the progression of CKD, compounding renal and
cardiovascular dysfunction (Virzì etal. 2015).
Within vascular smooth muscle cells, cardiac myocytes,
especially renal tubular epithelial cells, AT-II results in the
production of superoxide, a reactive oxygen species and
produces oxidative stress (Virzì etal. 2015). This oxidative
stress can hasten the progression of renal injury which causes
endothelial dysfunction, cardiovascular and renal remodel-
ling, inflammation, and fibrosis (Tejchman etal. 2021).
Flow rate
It is based on the traditional notion that a decrease in cardiac
output causes a fall in renal perfusion pressure, which affects
GFR indirectly (Mascherini etal. 2023). A substantial
decline in function of the left ventricle puts arterial blood
pressure (BP) at risk, resulting in baroreceptor-mediated
activation of multiple neurohormones in the carotid sinus
and aortic arch (Kumar etal. 2018). Once, the RAAS is
activated the parasympathetic tone is suppressed and the
sympathetic tone is increased (Kumar etal. 2018).
Renal venous pressure
The relevance of estimating central venal pressure (CVP) and
its involvement in the management of heart failure patients
cannot be underestimated (Matsuto etal. 2023). Patients with
heart failure have a higher CVP, which raises renal venous
pressure, lowering gradients throughout the glomerular capil-
lary network and reduces GFR (Kumar etal. 2018).
Tubuloglomerular feedback
Adenosine is produced locally in the kidney during stress
and binds to receptors on afferent arterioles causing vaso-
constriction and lowering renal blood flow (Elbaum etal.
2023). The receptor’s stimulation causes an increase in
sodium resorption in the tubules, resulting in more salt and
water retention (Elbaum etal. 2023). Diuretic medication
given in case of acute decompensated heart failure delivers
sodium to the distal tubules stimulates additional adenosine
release from the macula densa, lowering glomerular filtra-
tion (Guo etal. 2023). Aside from that, people with heart
failure have higher levels of vasopressin (Gaudard etal.
2023). Vasopressin causes distal convulating tubule (DCT)
to absorb more water, resulting in volume retention (Gaud-
ard etal. 2023; Kumar etal. 2018).
Connecting link betweenCVD andCKD
Renal dysfunction is frequently linked to oxidative stress, as
levels of variousmarkers such as plasma F2-isoprostanes,
advanced oxidation protein products and malondialdehyde
are elevated in patients with varying degrees of renal dam-
age including end-stage renal failure (Deng etal. 2023).
High levels of oxidized low-density lipoprotein (LDL) have
also been reported to cause atherosclerosis (Ciccarelli etal.
2023). Atherosclerosis is a widespread artery disease that
develops in response to a variety of insults including dys-
lipidaemia, which is common in CKD patients and is the
leading cause of CVD (Jehanathan etal. 2023).
Fig. 1 Pathophysiological basis
of CVD and CKD

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The foundation for the development and progression of
atherosclerosis is a triad of oxidative stress, endothelial
dysfunction, and inflammation (Fig.2) (Pál etal. 2023).
Increased oxidative stress promotes endothelial dysfunction
by lowering the availability of nitric oxide (Pál etal. 2023).
Vascular permeability changes in these circumstances,
allowing LDL cholesterol to enter the intima, where it is
oxidized and transformed into a highly atherogenic mol-
ecule that triggers an inflammatory response within the
vessel (Yamagata 2023). As a result, leukocyte adhesion
molecules are expressed causing circulating inflammatory
cells to bind and migrate into the subendothelial space.
By absorbing oxidized LDL and forming a fatty streak,
monocytes are transformed into foam cells (Im etal.
2021). Smooth muscle cells migrate from the media to
the intima as lesions progress where they proliferate and
produce extracellular matrix-like collagen and elastin and
this leads to the formation of afibrous capthat encloses
the atherosclerotic lesion (Badin 2019). Acute inflamma-
tory processes favour the release of extracellular matrix
modulators from macrophages and other inflammatory cells
which causes cap weakening, consequently plaque ruptures
(Vergallo R and Crea 2020). It leads theprocoagulantlipid
core and blood to come into contact leading tothrombus
formationassociated with clinical outcomes such as stroke
and myocardial infarction (Vergallo R and Crea 2020).
Polyphenols: classication andtheir sources
Polyphenols are the common plant-based constituents of
food. They are mainly derived from phenylpropanoid and
phenylpropanoid-acetate backbones (Zhang etal. 2021).
Fig. 2 Illustration of connecting
link between chronic kidney
disease, oxidative stress, and
cardiovascular diseases
Fig. 3 Basic structures of
various classes of polyphenolic
compounds

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Table 1 Classification of polyphenols
S. No Class/Subclass Examples Sources References
1 Flavanoids
Flavones Luteolin, Apigenin, Chrysin Baicalein Parsley, celery, millet, wheat, skin of citrus fruit, Pars-
ley, thyme, celery, sweet red peppers, honey, propolis
Archivio etal. 2007, Moon etal. 2006, Manach etal.
2005
Flavonones Hesperetin, Naringenin Tomatoes, mint, citrus fruit, grape fruit, Hertog etal. 1993
Flavonols Quercetin,Kaempferol,Galangin Fisetin, Myricetin,
Morin, Hyperoside, Heliosin
Onions, curly kale, leeks, broccoli, blueberries, red
wine, tea, Apples, Buckwheat tea, cherries
Neo etal. 2008, Manach and Donovan 2004
Flavanonols Taxifolin, Fustin onions, French maritime bark, tamarind seeds, milk
thistle
Asmi etal. 2017
Flavan-3-ols Catechin, Epicatechin, Epigallocatechin, Epicatechin-
3-gallate, Epigallocatechin-3-gallate, Proanthocya-
nidins
Green tea infusion, Red wine, Chocolate, Green tea
extract, Black tea, Grapeseed extract, cocoa,bilberry,
hawthorn
Archivio etal. 2007, Moon etal. 2006
Isoflavones Genistein, Genistin, Daidzein Daidzin, Biochanin A,
Formononetin,
Soybean, red clover, alfalfa, peas Moon etal. 2006
Neoflavonoids Dalbergin, Calophyllolide, Inophyllum Calophyllum species, Dalbergia sisso Choudhary etal. 2016, Donnelly and Boland 1995
Chalcones Isoliquiritigenin, Flavokawain AFlavokawain B, Fla-
vokawain CGymnogrammene
Hops, beer Moon etal. 2006
Anthocynidins Cynidin, Pelargonidin, Peonidin Delphinidin, Petunidin,
Malvidin
Orange juice, red wine, red grape juice Vitaglione etal. 2007, Bub etal. 2001
Anthocyanins Cyanidin-3-glucoside, Cyanidin-3-rutinoside, Cyanin,
Pelargonidin-3-glucoside
Cherries, grapes, berries, red cabbage Moon etal. 2006
2 Phenolic Acids
Benzoic acids 4-Hydroxybenzoic acid, Salicylic acid, Vanilic acid Gal-
lic acid, Protocatechuic acid, Ellagic acid, Hydrolyz-
able tannins
black tea, red wine Cartron etal. 2003, Shahrzad etal. 2001
Hydroxycinnamic acids Caffeic acid, p–Coumaric acid Ferulic acid, Sinapic
acid Cinamic acid, Curcumin Chlorogenic acids,
Chlorogenic acid, 5-Caffeoylquinic acid, Caffeoylferu-
loylquinic acids, Alpha-cyano-4-hydroxycinnamic
acid
Coffee, red wine, apple cidar Nardini etal. 2002 DuPont etal. 2002 Caccetta etal.
2000
3 Stilbenoids
Stilbenoids trans-Resveratrol, trans-Piceatannol, trans-Piceid, trans-
Pterostilbene, Cajanotone Cajanamide
Red grapes, wine, blueberries, peanuts, dark chocolate,
Cajanus cajan, sorghum
Zhang etal. 2012
4 Other polyphenols
Stilbenes Resveratol, 3,5-(Dihydroxyphenyl) thylbenzene-1,1-diol Red wine Vitrac etal. 2002
Lignans Sesamol, Sesamin Linseed Adlercreutz and Mazur 1997
Xanthones Mangostin, Lichexanthone lichens Le Pogam and Boustie 2016
Chromones Chamaechromone, Efloxatem Dysoxylum binectariferum, Senna siamea, Aquilaria
sinensis Tian etal. 2020, Matos etal. 2015
Anthraquinones Emodin, Alizarin Plants of family Rubiaceae Diaz etal. 2018

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They include a wide range of compounds with one phenol
ring such as phenolic acids and phenolic alcohols as well as
molecules with several hydroxyl groups on aromatic rings
(Nagar etal. 2020). Polyphenols are classified into several
classes according to the number of phenol rings that they
contain and to the structural components that hold these
rings together (Tijjani etal. 2020). This basic framework
allows several different replacement structures resulting in
major classes of polyphenols such as flavonoids, phenolic
acids, stilbenoids and some other polyphenols as shown in
Fig.3. The polyphenols are categorized into various classes
and subclasses as discussed in Table1.
Pharmacological potentials ofpolyphenols
Flavones
Flavones are a class of flavonoids. Flavone backbone is an
important backbone for the synthesis of many compounds act-
ing at different targets to provide pharmacological properties,
for example, Oroxylin A (neuroprotection), Nobiletin (anti-
inflammation), Chrysin (antioxidant), Tricetinidin (asthma),
Baicalein (anti-ulcer), Acacetin (cardiovascular system), Api-
genin (anti-microbial), Luteolin (malaria), Diosmetin (dia-
betes), Flavopiridol (cancer). Of all the flavones, apigenin is
the most studies phenol and is most widely dispersed in the
plant kingdom. Chamomile, made from the dried flowers of
Matricaria chamomilla, is one of the most popular sources of
apigenin drink as a single ingredient herbal tea (Etheridge and
Derbyshire 2020). Apigenin has been tested against several dis-
eased conditions viz. spinal cord injury in rats, lung-ischemia
in rats, liver ischemia in rats, oxygen–glucose deprivation in rat
hippocampal neurons, and myocardial ischemia in Langendroff-
perfused rat hearts (Buwa etal. 2016; Bougioukas etal. 2014).
Apigenin (20mg/kg) downregulated the expression of
cluster ofdifferentiation38 (CD38) in Zuker rats having
diabetic kidney disease (Ogura etal. 2020). Apigenin sig-
nificantly reduced renal injury including tubulointerstitial
fibrosis, tubular cell damage and pro-inflammatory gene
expression (Ogura etal. 2020). Apigenin (20µM) also
increased phosphorylation of AMPK and reduced TGF-β1
induced phosphorylation of Extracellular signal-regulated
protein kinases 1/2 (ERK1/2) in normal rat kidney fibroblast
(NRK-49F) (Li etal. 2020). Potassium oxonate-induced
hyperuricemic nephropathy in mice was attenuated by api-
genin through co-inhibiting uric acid reabsorption and the
Wnt/β catenin pathway (Li etal. 2019a, b, c). It inhibits
the renal urate transporter 1 (URATE1) and glucose trans-
porter 9 (GLUT9) in mice. Human renal epithelial (HK2)
cells treated with a 200-mM concentration of apigenin show
suppressed oxidative stress and increased gene expres-
sion of Nuclear Factor Erythroid like 2 (Nrf-2) and Heme
Oxygenase-1 (HO-1) (Zhang etal. 2019a, b, c). Further, this
was confirmed by treating the culture with LY294002 small
interfering RNA (siRNA), which inhibited the phosphati-
dylinositol 3-kinase-Akt (PI3K/Akt) pathway and which
attenuated the apigenin-induced protective effect on high
glucose-induced injury (Zhang etal. 2019a, b, c).
Flavanones
Several flavanones are discovered in the last two decades out
of which Naringenin, Hesperitin and Eriodictyol are well
known (Ávila-Gálvez etal. 2021). Naringenin is a lipophilic
flavanone widely present in citrus fruits such as oranges and
grapes which contain plenty (1.47–11.15mg/100g) of pure
naringenin (Mahato etal. 2019).
Naringenin (100mg/kg) reduced the doxorubicin (10mg/
kg) induced renal fibrosis by increasing the levels of antioxi-
dant enzymes and decreasing nitric oxides in the kidney of
Wistar rats (Khan etal. 2020). In a 2-kidney, 1-clip (2K1C)
renal nephropathy rat model, naringenin (200mg/kg) lowered
AT-II levels in peripheral blood without altering the blood
pressure and also modulates the mesangial expansion, inter-
stitial fibrosis and arteriolar thickening in nonclipped kidneys
(Wang etal. 2019).
Naringenin is reported to protect hypoxia-induced cell
death (160µM) of cardiomyocytes (H9c2 cells) and strepto-
zotocin-induced cytotoxicity (100µM) in pancreatic beta-cells
(MIN6 cells) (Wang etal. 2019; Tang etal. 2017). Naringenin
supplementation downregulates the expression of endoplas-
mic reticulum protein markers including phosphorylation of
Protein kinase-like endoplasmic reticulum kinase (p-PERK),
phosphorylation of the eukaryotic initiation factor 2alpha
(p-elf2α), Aortic thromboembolism 4 (ATE4) and Cyclophos-
phamide (CHOP) in renal toxicity induced hyperglycaemic
rats (Rajappa etal. 2019; Khan etal. 2021). Medium lethal
oral doses (LD50) of naringenin are > 5000mg/kg (Ortiz‐
Andrade etal. 2008). It can induce concentration-dependent
peroxidation of liver membrane lipids along with double-
stranded breaks in liver nuclei (Rahmani etal. 2022). Narin-
genin is an important flavonoid possessing numerous physico-
chemical, pharmacokinetic and pharmacodynamic properties.
Flavanols
Flavanols are typically found as oligomers or polymers in
their polymerized forms among a variety of plant-derived
food products like fruits, vegetables and beverages (Silva
etal. 2022). Plants produce three types of flavanols: flavan-
4-ols, flavan-3,4-diols, and flavan-3-ols. Flavan-3-ol mol-
ecules have chiral centres on positions 2 and 3, yielding four
diastereoisomers (Silva etal. 2022). In plants, there are four
major monomer forms of flavan-3-ol, collectively known as

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"catechins": ( +)-epicatechin, (-)-epicatechin (Epi), ( +)-cat-
echin (Cat), and (-)-catechin (Bernatova 2018).
Epicatechin is a naturally occurring flavan-3-ol mono-
mer present mainly in green tea, cocoa, fruits, vegetables,
and cereals as important secondary metabolites (Prakash
etal. 2019). Current scientific knowledge has revealed vari-
ous health benefits owing to its various activities such as
antioxidant, anti-inflammatory potential, ability to improve
muscle performance, reducing the symptoms of cardiovas-
cular and nephropathic disorders, preventing diabetes, and
protecting the nervous system (Abdulkhaleq etal. 2017; Qu
etal. 2021). According to different absorption and bioavail-
ability studies, epicatechin is well absorbed in the gastro-
intestinal tract, followed by various metabolic processes,
with peak concentrations of epicatechin and its metabolites
between 60 and 120min after administration (Bernatova
2018; Borges etal. 2018). As reported, in senior males
with epidemic cases of CHD and CVD, epicatechin intake
proves to be a positive health benefit (Dower etal. 2016).
It protects endothelial cells and mitochondrial function,
lowers oxidative stress, and plays a preventive role in CVD
(Dower etal. 2016). According to numerous studies, the
mechanism behind this includes the involvement of epicat-
echin in nitric oxide-mediated endothelial function and the
Nrf2 pathway (Qu etal. 2021). Although flavanols’ phar-
macological methods of action are unknown, however, they
are believed to involve increased bioactivity of nitric oxide
(NO), regulation of the immune system, and improved
endothelium homeostatic vascular repair (Al-Dashti etal.
2018). Invivo, flavanols inhibited arginase activity in
human red blood cells and rat kidneys, indicating that a
flavanol-rich intervention can decrease arginase activity in
human red blood cells and rat kidneys (Oteiza etal. 2021).
It dramatically boosts nitric oxide synthase (NOS) activity
in the heart and blood vessels and improves NO-depend-
ent vasodilation (Kluknavsky etal. 2016). Furthermore,
epicatechin regulates important markers involved in the
endothelial dysfunction as well as inflammation pathways,
such as tumor necrosis factor-alpha (TNF-α), Interleukin-1
(IL-1), and Soluble E-selectin (sE-selectin), resulting in a
protective impact in hypertensive individuals with cardio-
related disease (Dower etal. 2015). The stimulation of
4-aminopyridine and glutamate-sensitive K+ channels via
the modulation of calcium (Ca (2 +))-activated potassium
channel (BKCa) and ATP-sensitive K + (KATP) channels
in vascular smooth muscle cells causes relaxation of the
human internal mammary artery (HIMA) and it is one of
the evident roles of epicatechin (Novakovic etal. 2015).
Epicatechin also works as a vasodilator in isolated human
vein grafts, reducing acetylcholine-induced aortic con-
striction and preventing Cyclooxygenase 2 (COX-2) rises
(Marinko etal. 2018). In the invivo study of isoproterenol-
induced myocardial infarcted rats, epicatechin suppressed
lysosomal lipid peroxidation, stopped lysosomal enzyme
leakage, and decreased myocardial damage (Prince 2013).
The dietary supplementation of epicatechin reduced
kidney injury in rats chronically treated with the NO syn-
thase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME)
and protected mice from developing mitochondrial injury
in cisplatin-induced nephropathy (Gómez-Guzmán etal.
2011; Tanabe etal. 2012). Also, it has been reported that in
fructose-fed rats, invivo (–)-epicatechin intake prevented
fibrosis of the kidney and changes in podocytes, as well as
reduction of superoxide anion production, abnormalities in
nitric oxide metabolism, and inflammatory symptoms in the
renal cortex (Prince etal. 2016).
Tea, obtained from the leaves and buds of the plant
named Camellia sinensis, possesses several biologically
active polyphenolic flavonoids with epigallocatechin-
3-gallate (EGCG) as the major constituent (Ahammed and
Li 2022). Green tea catechins have a variety of biological
roles, including anti-inflammatory, anti-oxidative, and anti-
carcinogenic properties, which may account for some of
their cardioprotective properties (Rakha etal. 2022). Dur-
ing reperfusion, intravenous administration of 10mg/kg
EGCG dramatically reduced IkappaB kinase (IκB) activity,
resulting in decreased IκBα degradation and nuclear factor
kappa-light-chain-enhancer (NFκB) activity and reduced
c-Jun phosphorylation and as a result, activating Activation
Protein (AP-1) (Suzuki etal. 2006). It was further validated
with findings, reporting that oral administration of green tea
polyphenols (20mg/kg/d) for 60days reduced NFκB activ-
ity in murine cardiac transplants (Saeed etal. 2015). The
EGCG pre-treatment has been reported to counteracts doxo-
rubicin (DOX)-induced cardiotoxicity in rats by decreasing
oxidative stress, inflammation, and apoptotic signals as well
as activating pro-survival pathways (Yao etal. 2017). By
Fig. 4 Schematic representation of the mechanism of cardioprotective
properties of ECCG

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modulating oxidative stress, keeping a check on balance
between apoptotic markers and maintaining DNA integ-
rity, EGCG protected against cardiac damage and main-
tained cardiac health (Yoon etal. 2014). In addition, the
literature suggests that taking EGCG supplements early in
the course of diabetic nephropathy (DN) can help reduce
disease development (Mohan etal. 2020). Based on vari-
ous findings, it is possible to conclude that EGCG's ability
to activate the Nrf2/ARE signalling pathway at multiple
stages, i.e., by downregulating Kelch-like ECH-association
protein-1 (Keap1) and boosting nuclear Nrf2 levels by dis-
rupting the Nrf2-Keap1 interaction, is primarily responsible
for its beneficial effect in DN mitigation Fig.4. The EGCG
supplementation may be more advantageous at an early
stage of DN when aberrant Nrf2 accumulation develops,
which needs to be confirmed further (Tanaka etal. 2019).
Flavanonols
Flavanonols, also known as 3-hydroxyflavanone or 2,3-dihy-
droflavonol are a group of flavonoids with the backbone
3-hydroxy-2,3-dihydro-2-phenylchromen-4-one and the vari-
ous examples of flavanonols class are Taxifolin (or Dihydro-
quercetin), Aromadedrin (or Dihydrokaempferol) and Enge-
letin (or Dihydrokaempferol-3-rhamnoside) (Cacciola etal.
2021). Taxifolin is a bioactive catechol-type flavonoid found
in a variety of plants, including herbs, that has pleiotropic
properties such as anti-oxidant and anti-glycation properties
(Tanaka etal. 2019). Also, Taxifolin is prevalent flavanonol
present in plant named Pseudotsuga taxifolia, a member of
Pinaceae family (Bhardwaj etal. 2021). Taxifolin is known to
alleviate the cerebral ischemia–reperfusion injury by impair-
ing the excess production of reactive oxygen species (Guo
etal. 2015). It also prevented the release of cytochrome c
from mitochondria into the cytoplasm by blocking caspase-3
and caspase-9 activation, restoring mitochondrial membrane
potential, and regulating the expression of proteins involved
in the intrinsic apoptosis pathway (Saito etal. 2017). Taxifolin
controls a number of pharmacological activities, including
anti-oxidation, mitochondrial protection, and the production
of advanced glycation end products (AGEs). It's now being
studied as a possible treatment for cardiovascular disease,
neuropsychological problems, and cancer (Feng etal. 2021;
Ahmed etal. 2020). Invitro and invivo investigations showed
that taxifolin inhibited the activation of NF-κB via the C-Fos
signalling pathway. In addition, taxifolin inhibited the produc-
tion of IL-6, IL-1, and TNF-α (Zhang etal. 2019a, b, c).
Isoflavones
Isoflavones are secondary metabolites, abundantly found in
plants that predominantly belong to Papilonoidae, a subfam-
ily of Leguminosae. They are mainly derived via the classical
phenylpropanoid pathway (Ahmed etal. 2020). According
to reported data, the biological activities of isoflavones are
influenced by the allocation of the number and position of
hydroxyl groups attached to the two aromatic rings (López-
Yerena etal. 2020). The most studied isoflavones are biocha-
nin A, genistein, daidzein, glycitein, Equol (40,7-dihydroxy-
isoflavan), and formononetin, etc (Promden etal. 2014). In
addition, numerous studies reported that isoflavones possessed
additional health benefits such as decreases cardiovascular
risk, osteoporosis, the severity of bone resorption and decreas-
ing renal dysfunctions (López-Yerena etal. 2020). Isoflavones
have various invitro and invivo pharmacological activities
such as anti-diabetic, anticancer, antimutagenic, antioxidant,
antiproliferative, and estrogenic effects (Ahmed etal. 2020).
Cardiovascular diseases are gradually increasing every
year because of aging and changes in lifestyle (Silva and
Lopes 2020). A reported data showed that ingesting 60mg
of isoflavones per day decreased cardiovascular diseases in
menopausal women by reducing the stiffness of blood ves-
sels (Qin etal. 2015, 2014). Genistein modulates the conver-
sion of myofibroblasts and as a result, exhibits an essential
role in suppressing fibrosis in endomyocardial fibrosis (Yang
etal. 2018). Along with genistein, daidzein also improves
the risk factor of cardiovascular disease effectively (Chen
etal. 2019). It regulates the genotype of estrogen recep-
tors, that further decreases the level of plasma triglyceride
and uric acid, therefore reducing the risk factors of cardio-
vascular disease (Bai etal. 2019). Bai etal. 2019 reported
that Biochanin A (BCA) significantly reduces myocardial
injury by suppressing the release of aspartate aminotrans-
ferase (AST), creatine kinase-MB (CK-MB), and lactate
dehydrogenase (LDH) in myocardial ischemia/reperfusion
(MI/R) rats through the myocardial cell membrane (Jheng
etal. 2020). BCA also suppresses MI/R-induced inflamma-
tory responses by reducing the serum levels of IL-1β, IL-18,
IL-6, and TNF-α in rats (Jheng etal. 2020).
The reported study showed that isoflavones decreased uri-
nary protein excretion and relieved renal histopathological
damage by modulating the expressions of Wnt4, β-catenin
and TGF-β1 (Li etal. 2017a, c; Liu etal. 2018). Genistein
improved renal dysfunction by regulating the expression of
sirtuin 1 (SIRT1) engaged in the treatment of various dis-
eases in the cells and showed cytoprotective effects using
anti-apoptosis, antioxidative, and anti-inflammatory mecha-
nisms (Liu etal. 2014). Along with this, the intake of soy-
bean daidzein was also reported to improve renal function in
pre-hypertension menopausal women (Kim 2021).
Benzoic acids
Benzoic acid is also known as phenylformic acid, benzene
carboxylic acid, benzene formic acid, carboxybenzene, or

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phenylcarboxylic acid (Velika and Kron 2012). It is widely used
as antibacterial and antifungal preservatives and flavoring agents
in food, cosmetic, hygiene, and pharmaceutical products (Del
Olmo etal. 2017). There are various derivatives of benzoic acid
(Fig.5). One of the examples of benzoic acids is gallic acid.
GA is a member of the gallotannin family of plant poly-
phenols (Guerreiro etal. 2022). It can be found in fruits,
vegetables, tea leaves, grapes, blackberries and gallnuts. It
has antioxidant (Wang etal. 2014), antiallergic, (Wang etal.
2014), antibacterial, anticancer (Mansouri etal. 2013), anti-
ulcer and neuroprotective activities (Doan etal. 2015). It has
also been proven to have positive benefits in animal mod-
els of metabolic disorders (Chao etal. 2014). GA also pos-
sesses antihyperglycemic and lipid homeostatic properties
Fig. 5 Various derivatives of
benzoic acid
Fig. 6 Mechanism of hyperten-
sive activity of GA

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1 3
(Xu etal. 2021). While there is substantial evidence that GA
is a cardioprotective agent (Akbari 2020).
As per experimental studies, GA appears to protect
against CVDs by increasing antioxidant enzyme capacity,
inhibiting lipid peroxidation and lowering serum levels of
cardiac marker enzymes, modulating hemodynamic param-
eters, recovering electrocardiogram aberrations, and preserv-
ing histopathological changes (Mojadami etal. 2021).
The effect of GA treatment for 1week recovered renal
function and pathological abnormalities in Diabetic
nephropathy (DN) caused by Methylglyoxal (MG) via
decreased microRNAs-associated with DN, fibrosis, Endo-
plasmic Reticulum (ER) stress, and enhanced glyoxalase
1 (GLO1) activity, as well as Nrf2 activity adjustment as
depicted in Fig.6 (Neto-Neves etal. 2021).
Hydroxycinnamic acids
Hydroxycinnamic acids (HCAs) are important phytochemi-
cals possessing significant biological properties (Neto-Neves
etal. 2021). Results of studies in animal models and invitro
experiments of ferulic acid (derivative of Hydroxycinnamic
acid) suggest its high therapeutic and preventive potential
against several pathological disorders such as cardiovascu-
lar diseases including cardioprotective and antihypertensive
actions and on the metabolism of lipids, diabetes, and throm-
bosis (Coman and Vodnar 2020; Rao etal. 2021).
Ferulic acid (FA) is an abundant dietary antioxidant
which may offer beneficial effects against cancer, cardiovas-
cular diseases, diabetes, neurodegenerative and Alzheimer’s
disease (Rao etal. 2021). The results of studies in animal
models and invitro experiments of ferulic acid suggest its
high therapeutic and preventive potential against cardiovas-
cular diseases (Neto-Neves etal. 2021).
Lignans
The shikimic acid biosynthetic route produces lignans,
which are 1,4-diarylbutan compounds (Durazzo etal. 2019).
Oilseeds such as flax, soy, rapeseed, and sesame; wholegrain
cereals such as wheat, oats, rye, and barley; legumes; vari-
ous vegetables and fruits (particularly berries); beverages
(i.e., coffee, tea, and wine); and, more recently, dairy prod-
ucts, meat, and fish have all been found to contain lignans
(Durazzo etal. 2019). Yeung and colleagues (Yeung etal.
2020) have found that lignan-rich diets, which include veg-
etables, fruits, and whole grain products, may help to pre-
vent chronic diseases, notably hormone-dependent cancer
and cardiovascular diseases (Rodríguez-García etal. 2019).
In a study conducted by Puukila and colleagues in 2017,
pre-treatment with secoisolariciresinol diglucoside (25mg/
kg) significantly reduced the right ventricular hypertro-
phy, ROS levels, lipid peroxidation, catalase, superoxide
dismutase, and glutathione peroxidase activity as well as
plasma levels of Alanine aminotransferase (ALT) and AST
(Puukila etal. 2017). In another study, 6h after cecalliga-
tionand puncture (CLP) surgery, mice were given lignan
secoisolariciresinol diglucoside (LGM2605) at a dose of
100mg/kg body weight intravenously to minimise cardiac
ROS build up and restore heart function. In primary cardio-
myocytes taken from adult C57BL/6 mice that had under-
gone CLP and been treated with LGM2605, assessment of
mitochondrial respiration (Seahorse XF) revealed restored
basal and maximal respiration as well as retained oxygen
consumption rate (OCR) consistent with spare capacity.
LGM2605 restored mitochondrial abundance, boosted
mitochondrial calcium uptake, and retained mitochondrial
membrane potential, according to additional analyses aimed
at identifying the molecular mechanisms that would explain
improved cardiac performance (Kokkinaki etal. 2019).
In a study conducted by Huang and colleagues, SDG’s
effect on Janus kinase2(JAK2)/signal transducer and acti-
vator of transcription3(STAT3) (mediating the protective
effect of SDG) was investigated. Findings of this study
revealed that treatment with H2O2 reduced cell viability
and induced apoptosis in H9C2 rat cardiomyocytes. SDG
significantly reduced the effect of H2O2 in a dose-dependent
manner. H2O2 curtailed the expression of phosphorylated
STAT3 and inhibited the levels of B-cell lymphoma-extra-
large and induced myeloid leukemia cell differentiation pro-
tein, which are the STAT3 target genes. On the other hand,
SDG rescued the phosphorylation of STAT3 and increased
the levels of STAT3 target genes. Treatment with SDG
alone led to a dose-dependent increased phosphorylation
of JAK2 and STAT3, without activating Src. Furthermore,
the anti-apoptotic effects of SDG were partially suppressed
by a JAK2/STAT3 inhibitor. In addition, molecular docking
revealed that SDG may bind to the protein kinase domain
of JAK2, at a binding energy of -8.258kcal/mol. Molecu-
lar dynamics simulations revealed that JAK2-SDG binding
was stable. Hence, it can be concluded that activation of
the JAK2/STAT3 signalling pathway contributed to the anti-
apoptotic property of SDG, which can be potential JAK2
activator (Huang etal. 2018).
As was previously mentioned, oxidative stress, inflamma-
tion, diabetes, dyslipidemia, and hypertension are some of the
main causes of heart conditions like stock, coronary artery
disease, and peripheral artery disease (Deng etal. 2023). Myo-
cardial infarction and stroke, two of the main causes of death,
are influenced and encouraged by these conditions (Cicca-
relli etal. 2023). SDG and its metabolites may modulate the
serum total cholesterol, low-density lipoprotein, total choles-
terol, and high-density lipoprotein ratio, lowering the risk of
androgenic complications and preventing oxidative damage,
and acting as a potential cardiovascular protector by mediat-
ing the mechanisms (Huang etal. 2018). SDG (600mg) was

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1 3
found to significantly reduce the aforementioned parameters
in human studies as well (Imran etal. 2015). Other studies
have shown that the anti-cardiovascular properties of SDG
are related to enterolactone-mediated increased production of
vascular endothelial growth factor, endothelial NO synthase,
and HO-1-mediated myocardial angiogenesis (Imran etal.
2015). A significantly lower risk of total CHD was associated
with higher dietary intake of matairesinol, secoisolaricires-
inol, pinoresinol, and lariciresinol both as a group and on an
individual basis (Hu etal. 2021).
Anthocyanins
Anthocyanins are glycosylated polyhydroxy and polymeth-
oxy derivatives of flavilium salts that belong to the flavonoid
family and have a unique carbon structure of C3 – C6 – C3.
The protective benefits of flavonoids, anthocyanins, on recog-
nised indicators of CVD risk such as NO, inflammation, and
endothelial dysfunction are supported by mechanistic studies
(Kalt etal. 2020). Anthocyanin isolates and anthocyanin-rich
flavonoid mixtures may offer protection against DNA cleav-
age, estrogenic activity (altering the development of hormone-
dependent disease symptoms), enzyme inhibition, increased
cytokine production (thus regulating immune responses), anti-
inflammatory activity, lipid peroxidation, decreased capillary
permeability and fragility, and membrane strengthening (Das
etal. 2019; Champ and Kundu-Champ 2019).
Long-term eating causes anthocyanins to accumulate in
cardiac or vascular tissues; yet, animal studies have indicated
that anthocyanins influence vascular responsiveness (Dan-
ielewski etal. 2020). In patients with vascular disorders,
low-dose anthocyanin therapies have been linked to consid-
erable reductions in ischemia; blood pressure; cholesterol
levels; inflammatory status (Alam etal. 2021). Extracts of
grape pomace regulates the cholesterol 7α-hydroxylase and
sterol 27-hydroxylase at transcriptional level(key enzymes
in CVDs) (Ferri etal. 2016). In comparison to the antho-
cyanin-free control, corn-derived anthocyanins made the
myocardium less vulnerable to ischemia reperfusion injury
proved in both exvivo and invivo studies (Alam etal. 2021;
Toufektsian etal. 2008).
Anthocyanins, appear to inhibit endothelial cell pro-
duction of this form of monocyte adhesion throughout the
inflammatory phase (Zhang etal. 2021). Also, anthocyanins
have been found to inhibit the release of many molecules
involved in inflammatory regulation, including vascular
endothelial growth factor and intracellular adhesion mol-
ecule-1 (Aboonabi and Aboonabi 2020).
C-reactive protein (CRP), an acute phase reactant whose
interaction with endothelial cells, which stimulates adhesion
molecule production, may be one mechanistic link to athero-
sclerosis (Gorabi etal. 2022). Data from the National Health
and Nutrition Examination Survey (NHANES) demonstrate a
substantial inverse relationship between blood CRP and antho-
cyanin intake among adults in the USA (Tufail etal. 2022).
Three anthocyanin monomers (40 or 200mg/kg) were
reported to suppress body lipid accumulation, reduce weight
gain, leptin secretion, decrease insulin resistance, and adipo-
cyte size (Wu etal. 2013). Anthocyanins (100mg/kg b.w.)
were reported to reduce serum triglyceride levels and pre-
vent development of atheromatous changes in the thoracic
aorta (Xue etal. 2023). Moreover, anthocyanins could sig-
nificantly increase PPARα protein expression in the liver,
implying that its hypolipidemic effect may be due to the
enhancement of fatty acid catabolism (Xue etal. 2023).
Neoflavonoids
Neoflavonoids are a unique class of naturally occurring fla-
vonoids present in a wide range of plant families, including
Fabaceae, Clusiaceae, Leguminosae, Rubiceae, Passiflo-
raceae (Mas-Capdevila etal. 2020). The most evaluated neo-
flavonoid compounds are coumarin, latifolin, melanoxylonins
D, and dalnigrin (Kumar etal. 2020). Neoflavonoids exhibit
numerous pharmacological activities such as antioxidant,
anti-allergic, anti-androgen, anti-osteoporosis, anti-inflam-
matory, antitumor etc. (Kumar etal. 2020).
Latifolin has been found to protect cardiac injury caused
by pituitrin or isoproterenol by reducing oxidative stress and
activating the Nrf2 signalling pathway (Kumar etal. 2020).
Latifolin has been reported to protect against myocardial
damage by inhibiting the expression of keap-1 and upregu-
late the expression of HO-1 and NAD(P)H quinone oxidore-
ductase-1 (NQO1) in myocardial tissue (Li etal. 2017;Li
etal. 2020).
Melanoxylonins D, isolated from the heartwood of Dal-
bergia melanoxylon, possess cardioprotective activity by
reducing myeloperoxidase protein in H9c2 cells undergo-
ing ischemia/reoxygenation damage and eventual cardiac
failure (Sun and Wang 2020; Liu etal. 2021). (7R)-(-)-3′,5-
dihydroxy-4′,2,4-trimethoxy-dalbergiquinol, an another
neoflavonoid isolated from the heartwood of Dalbergia
melanoxylon showed cardioprotective effect on hypoxia/
reoxygenation injury in H9c2 by reducing level of lactate
dehydrogenase and malondialdehyde activity and enhancing
superoxide dismutase activity (Rudrapal etal. 2021).
Chalcones
Chalcones (1,3-diaryl-2-propen-1-ones) are secondary
metabolites belonging to the group of flavonoids, ubiqui-
tous in medicinal and edible plants (Rudrapal etal. 2021;
Batovska and Todorova 2010). Major examples of chal-
cones include phloridzin, arbutin, phloretin and chalconar-
ingenin (Panche etal. 2016).Chalcones have potential in
treating cardiovascular system related problems due to their

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1 3
antioxidant activity (Batovska and Todorova 2010; Mahapa-
tra and Bharti 2016). Mahapatra and Bharti, 2016 reported
that chalcones such as tinctormine, lonchocarpin, xantho-
humol, xanthohumol B, desmethylxanthohumol, xanthoan-
gelol, xanthoangelol E, isobavachalcone, derricin, lupeol-
based chalcones etc. have been reported to act against targets
of cardiovascular problems (Mahapatra and Bharti 2016).
Isobavachalcone is a natural chalcone compound derived
from dried ripe fruit ofPsoralea corylifolia effectively
ameliorated renal damage and improved kidney pathologi-
cal appearances, prevented apoptosis induced by streptozo-
tocin in the glomerular tissue invivo and blocked the high
glucose-induced growth inhibitory effect in human renal glo-
merular endothelial cells invitro by reducing pro-inflamma-
tory mediator production and blocking the NF-κB pathway
in the damaged renal tissues (Dong etal. 2020).
Licochalcone possessed antinephritic activity by reducing
the amount of protein level in urine of nephritic mice with
glomerular disease (Kataya etal. 2011). Another chalcone,
butein obtained from Rhusspecies ameliorated renal con-
centrating ability in cisplatin-induced acute renal failure in
rats by restoring renal functional parameters (Opiyo etal.
2021). 4-hydroxyderricin (4-HD) and xanthoangelol (XA)
chalcones intake inhibit arteriosclerosis, and reduces cho-
lesterol level in blood (Oh etal. 2019).
Pinocembrin is a major flavonoid found in rhizomes of
Boesenbergia pandurata possess nephroprotective activity
due to its antioxidant and anti-apoptotic nature (Promsan
etal. 2016). Pinocembrin is reported to exert protective
effects against human renal proximal tubular cells apoptosis
by ameliorating colistin-induced mitochondrial impairment,
gentamicin-induced nephrotoxicity, subsequently leading to
improved renal function (Worakajit etal. 2021). Moreover,
colistin-activated cytotoxicity including ROS generation, loss
of membrane potential and upregulation of apoptotic proteins
expression such as cytochrome C and caspase-3 were also
suppressed in pinocembrin treatment (Worakajit etal. 2021).
Isoliquritigenin, a chalcone present in Liquorice extracts
is currently used as a phosphodiesterase III inhibitor for the
treatment of CVD (Hasan etal. 2021). Isoliquritigenin is a
natural antioxidant may protect heart against ischemic injury
via modulating cellular redox status and regulating cardio-
protective signalling pathways (Das etal. 2020). Isoliquriti-
genin exerted a remarkable Reno-protective effect against
Cisplatin (CSP)-induced renal toxicity by abrogating oxida-
tive stress and apoptosis (Rui-Zhi etal. 2022).
It was reported that butein prevents occurrence of kidney
problems such as kidney stones which occurs in the human
body during hyperuricemia by inhibiting xanthine oxidase
activity (Umamaheswari and etal.., 2011).The pharma-
cological potential of some of the otherpolyphenolic com-
pounds is summarized in Table2.
Nanoformulations ofpolyphenolic
compounds fortreatment ofCVD andCKD
Numerous studies have indicated that polyphenols have a wide
range of biological effects.Researchers' interest in these adapt-
able, naturally occurring substances is expanding as a result of
their critical function in regulating illness development linked
to nearly all of the body's major systems, including the car-
diovascular, neurological, and gastrointestinal systems (Fraga
etal. 2019). However, inadequate bioavailability as a result of
poor water solubility and quick metabolism severely restricts
their clinical application (Caballero etal. 2021). One intrigu-
ing strategy for maximizing polyphenols' medicinal potential
is nanotechnology. Sensitive polyphenolic chemicals can be
added to nanocarriers to prevent physiological deterioration,
enable longer release, boost bioavailability, and enable targeted
drug delivery. There is mounting evidence that nanomedicine
may be able to improve polyphenols' poor pharmacokinet-
ics and increase the effectiveness of their therapeutic effects
(Anand etal. 2022; Patra and Das2018). Organic nanocarri-
ers (micelle and vesicle nanocarriers, liposomes, polymeric
nanogels, and dendrimers) and inorganic nanoparticle (NPs)
are the two main types of nanostructured nanocarrier systems
used in drug delivery (Lombardo etal. 2019). The ability of
a drug molecule to accumulate at the sites of action, resulting
in a greater therapeutic index, is referred to as drug targeting
(Gao and Zhang 2015; Lundy etal. 2016).
Need fornanoformulations andtheir future
perspectives inthetreatment ofCVD andCKD
Non-functionalized therapies are unable to specifically tar-
get the heart and are frequently eliminated in the reticuloen-
dothelial organs. In comparison to free form, medication
encapsulation inside Nanoparticles (NPs) improves drug
persistence and circulatory half-lives lives (Lombardo etal.
2019). The main cause of abrupt development of acute coro-
nary syndromes in atherosclerosis is ruptures of macrophage-
rich atherosclerotic plaques in the coronary arteries (Libby
etal. 2019). In general, tailored therapeutic approaches can
lessen dose-dependent deleterious effects in distant organs by
inhibiting macrophages' activity (Peng etal. 2020).
Novel nanocarrier-based formulations have the poten-
tial to overcome the limitations of conventional formula-
tions by reducing dose, dosing frequency, dose-dependent
adverse effects, and improving efficacy (Patel etal. 2020).
Nano-formulations are now widely used for treatment that
is both effective and safe. These nano-formulations improve
the characteristics of traditional medications while being
tailored to the individual delivery site (Jeevanandam etal.
2016). Some of the nanoformulations of the polyphenolic
compounds have been summarized in the Table3.

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Eect ofpolyphenolic rich diet onCVD
andCKD
CVD
In a randomized control study conducted by Noad and col-
leagues, it has been reported that participants that consumed
more polyphenol-rich foods for 8weeks, such as berries,
and dark chocolate, experienced a notable improvement in
endothelium-dependent vasodilation. This study demonstrated
that a diet enriched with polyphenols (epicatechin, vitamin
C, lutein, zeaxanthin, beta carotene, alpha carotene, beta-
cryptoxanthin, lycopene) may reduce cardiovascular risk and
improve microvascular function by significant improvement in
an established marker (systolic blood pressure, diastolic blood
pressure, body mass index, total cholesterol, high density lipo-
protein, low density protein, triglycerides) of cardiovascular
risk in hypertensive participants (Noad etal. 2016).
In another clinical study conducted by Mendonca and col-
leagues it was found that the intake offlavonoidsshowed an
Table 2 Summary of pharmacological potential of polyphenolic compounds
S.no Compounds Pharmacological role Model References
1. Quercetin Cardioprotective potential - Patel etal. 2018
2. Hesperidin Cardioprotective potential Human trials Mas-Capdevila etal. 2020
3. Naringenin Cardioprotective potential In-vitro cell lines study using MDA-MB-231
cells
Zhao etal. 2019
4. Kaempferol Cardioprotective potential In-vitro Cell lines study on the cells collected
from heart of 1–3-day-old neonatal Sprague–
Dawley rats
Tang etal. 2015
5. Fisetin Cardioprotective potential in vitromodel of MI/IRI in mammalian cardiac
cells
Rodius etal. 2020
6. Myricetin Cardioprotective potential - Wang etal. 2019
7. Morin Protective effect against
diabetic nephropathy
In vivo study in Wistar rats Aleisa etal. 2013
8. Hyperoside Cardioprotective potential In vivo study in mice Wang etal. 2018a, b
9. Taxifolin Cardioprotective potential - Das etal. 2021
10. Catechins Cardioprotective potential - Chen etal. 2016
11. Epicatechin Cardioprotective potential - Bernatova 2018
12. Epicatechin-3-gallate Cardioprotective potential In vivo study in male Sprague–Dawley rats Li etal. 2008
13. Epigallocatechin- 3-O-Gallate Cardioprotective potential - Jagtap etal. 2009
14. Proanthocyanidins Cardioprotective potential - Kruger etal. 2014
15. Genistein Cardioprotective potential In vivo preclinical and clinical trials Altavilla etal. 2004
16. Biochanin-A Cardioprotective potential - Govindasami etal. 2020
17. Isoliquiritigenin Diabetic cardiomyopathy In vivo mice model Gu etal. 2020
18. Cyanidin Cardioprotective potential In-vitro study on H9c2 cardiac myoblast cell
lines
Qian etal. 2018
19. Cyanidin-3-glucoside Cardioprotective potential In-vitro human umbilical vein cell line (EA.
hy926)
Sivasinprasasn etal. 2016
20. Cyanidin-3-rutinoside Cardioprotective potential In vivo study on male Wistar-Kyoto rats Thilavech etal. 2018
21. Piceatannol Cardioprotective potential - Tang and Chan 2014
22. Gallic acid Cardioprotective potential - Akbari 2020
23. Protocatechuic acid Diabetic nephropathy In-vitro cell lines study on human mesangial cells Ma etal. 2018
24. Caffeic Acid Cardiovascular potential - Silva and Lopes 2020
25. p-Coumaric acid Diabetic nephropathy In vivo study on female adult Sprague–Dawley
rats
Mani etal. 2021
26. Ferulic acid Diabetic nephropathy In vivo study on rats Choi etal. 2011
27. Sinapic Acid Diabetic nephropathy In vivo study on rats Alaofi etal. 2020
28. Curcumin Cardioprotective potential - Wongcharoen andPhrom-
mintikul 2009
29. Chlorogenic acid Diabetic nephropathy In vivo study on maleSprague–Dawley rats Bao etal. 2018
30. Caffeoyl Quinic Acid Nephropathy In vivo study on Sprague–Dawley rats He etal. 2011

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Table 3 Nanoformulations developed from polyphenolic compound for the treatment of the CVD and CKD
Polyphephenols Formulations Therapeutic
effect
Mechanism References
1 Curcumin Curcumin nanoemulsion Cardioprotective Inhibits acetylcholinestrase and 3-hydroxy-3-methylgutaryl
coenzyme A reductase
Rachmawati etal. 2016
Curcumin/P Reduces diabetic cardiomyopathy and alleviates the pathological
and morphological destruction of myocardial cells
Tong etal. 2018
Curcumin-polymer based nanoparticle Reduces lipid peroxidation, myocardial levels of MDA, nitric
oxide and total oxidative status
Boarescu etal. 2019
AC-lipo Reduces total cholesterol and LDL; Reduces lipid disposition Li etal. 2019a, b, c
Curcumin-mesoporous silica material Reduces MDA levels and increases SOD, GSH and Catalase
levels in cardiac tissue
Yadav etal. 2019
Curcumin-PEG-PDLLA Effective against ischemia–reperfusion induced oxidative stress
and myocardial injury
Li etal. 2017a, c
PLGA nanoparticle encapsulated
curcumin
Decreases the B-type atrial natriuretic peptide Du Preez etal. 2019
Curcumin/CMC-peptide Improves cardiovascular response by reducing liver fat disposi-
tion
Ray etal. 2016
Curcumin-loaded PEG-PDLLA NPs Prevents the CK-MB leakage from cardiomyocytes Zhang etal. 2019a, b, c
Curcumin-nisin poly lactic acid NP Improves ECG patterns, reduces serum myeloperoxidase levels,
reduces ROS and MDA levels; downregulates cardiac troponin
I levels; Inhibits cardiac hypertrophy
Nabofa etal. 2018
Curcumin-NPs Renoprotective Reduces serum creatinine, urea levels and alleviates the histo-
logical damage in renal tubules; Attenuated oxidative stress in
renal tissues
Chen etal. 2017
2 Tilianin Tilianin-loaded PEG-PPS micelles Cardioprotective Prevents myocardial infarction, coronary heart disease, hyperten-
sion and atherosclerosis by reducing the expression of Toll like
receptor 4 and NF-κB p65 protein expressions
Wang etal. 2018a, b
3 Puerarin PUE@PEG-PE micelles Cardioprotective Reduces the ROS level, Bax expression and Caspase-3- activity;
increases Bcl-2 expression
Li etal. 2018
PUE@TPP/PEG-PE micelles Treats acute mycocardial infarction Li etal. 2019a, b, c
RGD/PEG-PUE-SLN Ameliorates myocardial infarction Dong etal. 2017
Pue-SLNs Renoprotective Enhances the suppression of ICAM-1 and TNFα in diabetic rat
kidney
Luo etal. 2013; Pan etal. 2015
4 Naringenin Naringenin lipid nanoemulsions Cardioprotective Inhibits adhesion and transmigration of monocyte through
endothelial cells, reduces nuclear translocation of nuclear fac-
tor kappa B, produced MCP1 and ultimately reduces endothe-
lium inflammation
Fuior etal. 2019
5 Baicalin BN-PEG-NLC Cardioprotective Reduces the infarct size in the acute mycocardial infarction Zhang etal. 2016a, b

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Table 3 (continued)
Polyphephenols Formulations Therapeutic
effect
Mechanism References
6 Quercetin mRQ Cardioprotective Attenuated cardiotoxicity Cote etal. 2015
Quercetin loaded PLGA Prevents atherosclerosis and other CVDs; suppresses oxidatives stress Giannouli etal 2018
PLGA-quercetin Improves controlled release of quercetin; enhances cell enlist-
ment, attachment, expansion and articulation of heart proteins
in local myocardium
Lozano etal 2019
Gold-quercetin nanoparticles Renoprotective Reduces insulin resistance; restore lipid imbalance; inhibits
TLR4/NF-κB and oxidative stress; increases superoxide dis-
mutase activity
Xu etal. 2017
7 Breviscapine Bre-LE Cardioprotective Removes blood stasis and promotes blood circulation; formulation Xiong etal. 2010
Bre_NLC Renoprotective Decreases MDA levels and increases SOD levels in renal cortex Gao etal. 2017
8 Resveratrol RSV-NC Cardioprotective Reduces both systolic and diastolic blood pressures and alleviates
insulin resistance
Shahraki etal. 2017
mRC Helps in ROS scavenging and apoptosis prevention Carlson etal. 2014
RS-SLN Increases heart rate, ejection fractions and fractional shortening Zhang etal. 2019a, b, c
Res NPs Renoprotective Attenuates NLRP3 inflammasome and induces autophagy Lin etal. 2017
9 Epigalltocatechin-3-Gallate L-Enano Cardioprotective Improves the targeted delivery of the ECCG prevent atheroscle-
rosis
Zhang etal. 2016a, b
CSNLCE Zhang etal. 2013
PLGA encapsulated ECCG NPs Renoprotective Reduces TNFα, IL-6 and IL-1 level I kidney tissues; Modulation
of NFκB and Nrf2 exression; ROS Scavenging
Widiatmaja etal. 2022
10 Magnolol Magnolol NPs Cardioprotective Supression of TNFα induced vascular cell adhesion molecule 1
(VCAM-1) expression in endothelial cells
Lee etal. 2017
EPC-encapsulated (0.01mg/ml) DPPC-
encapsulated magnolol (0.01/ml)
Enhanced inhibition of the proliferation of vascular smooth
muscle cells (VSMCs)
Chen and Wu 2008
11 Tanshinone IIA Discoidal recombinant HDL Cardioprotective Ameliorates atherosclerotic lesions Zhang etal. 2013
Spherical recombinant HDL
TPP-TPGS/TN/LPNs Reduces adverse cardiac remodeling and dysfunction Zhang etal. 2018
IIA-NP Enhanced mitochondrial targeted efficacy Mao etal. 2018
Abbreviations: Curcumin/P, curcumin/PBLG-PEG-PBLG (poly (gamma-benzyl-l-glutamate)-poly(ethylene glycol)-poly(gamma-benzyl-l-glutamate) (PBLG-PEG-PBLG)); AC-Lipo,
liposomes loaded with atorvastatin calcium and curcumin; curcumin-PEG-PDLLA, curcumin-poly(ethylene glycol) methyl ether-block-poly(d,l-lactide); curcumin/CMC-peptide, curcumin
encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte-specific homing peptide; curcumin-loaded PEG-PDLLA NPs, curcumin-loaded monomethoxy poly
(ethylene glycol)-b-poly (DL-lactide) nanoparticles; PLGA, poly lactic-co-glycolide; P-Rg3, BB-lip, berberine liposomes; PEG-PPS, poly(propylene sulfide)-co-poly(ethylene glycol); PUE@
PEG-PE, puerarin-loaded 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; TPP, triphenylphosphonium; RGD/PEG-PUE- SLN, RGD-modified and
PEGylated solid lipid nanoparticles loaded with puerarin; BN-PEG-NLC, baicalin-loaded PEGylated nanostructured lipid carriers; mRQ, resveratrol and quercetin in Pluronic®F-127 micelles;
Bre-LE, breviscapine lipid emulsion; RSV-NC, resveratrol nanocapsule; mRC, resveratrol–curcumin at a molar ratio of 5:1 in F127 micelles; RS-SL, a solid lipid nanoparticle loaded with res-
veratrol; L-Enano, ligand-epigallocatechin-3-gallate-loaded nanoparticles; CSNLCE, chitosan-coated EGCG encapsulated nanostructured lipid carriers; EPC, 1,2-diacyl-sn-glycero-3-phospho-
choline; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; TPP-TPGS/TN/LPNs, triphenylphosphonium-d-α-tocopheryl polyethylene glycol 1000 succinate surface-modified, tanshinone-
loaded LPNs; IIA-NP, tanshinone IIA nanoparticles

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inverse association with risk of cardiovascular events in a
prospective cohort of Spanish middle-aged adult university
graduates (Mendonça etal. 2019).
CKD
Increased systemic inflammation and oxidative stress have
been previously described as well-established unconventional
important players in the aetiology of atherosclerosis. They
are also engaged in the dysregulation of innate immunity in
haemodialysis (HD) patients. A clinical study was conducted
by Shema-Didi and colleagues, to investigate the effect of
1-year intake of pomegranate juice (polyphenolic source) on
inflammation, oxidative stress, as well as long-term clinical
outcomes. In this randomized placebo controlled double-
blind trial, total 101 chronic HD patients were enrolled and
received 100cc of pomegranate juice during each dialysis,
or matching placebo, three times a week for 1year. It was
found that consuming pomegranate juice reduced the levels
of polymorphonuclear leukocyte priming, protein oxidation,
lipid oxidation, and inflammatory indicators significantly
over time. Three months after the intervention, these posi-
tive benefits were eliminated. Consuming pomegranate juice
dramatically reduced the likelihood of experiencing a second
infection-related hospitalisation. Furthermore, 25% of the
patients had improvement in the pomegranate juice group
and only 5% experienced progression in the atherosclerotic
process, while more than 50% of patients in the placebo
group showed progression and none showed any improve-
ment. Long-term consumption of pomegranate juice slows
the course of atherosclerosis, boosts innate immunity, and
lowers morbidity in HD patients (Shema-Didi etal. 2012).
Synergistic eect ofpolyphenolic
compounds
In a study conducted by Chtourou and colleagues, the
effects of naringin (N), chlorogenic acid (C), and quercetin
(Q) combinations (NCQ:- 5:1:5) were examined on renal
fibrosis in twelve-month-old 30Wistar rats (450g ± 40g)
rats with diabetes induced by streptozotocin (STZ) and its
underlying mechanisms over a period of ten weeks. It was
reported that the oxidative defence system of kidneys of
treated rats had improved. A number of indicators, such as
blood urea nitrogen, creatinine, and uric acid, were exam-
ined. The evaluation of antioxidant parameters revealed that
reduced glutathione levels, superoxide dismutase, catalase,
glutathione peroxidase, Na+-K+-ATPase activity, nitric
oxide generation, protein carbonyl, advanced oxidation pro-
tein products, lipid peroxidation, and all other parameters
were significantly balanced and closer to control values.
Furthermore, NCQ reversed kidney fibrosis and damage
as shown by histological analysis and molecular biology
examination of the expression of matrix metalloproteinase,
TGF-, TNF, and tumor protein (p53) (Chtourou etal. 2022).
Literature survey revealed that very less research has been
done on evaluating the combinations of the polyphenolic
compounds on CVD as well as CKD. Using various poly-
phenol combinations may have positive outcomes. Addition-
ally,developing suitablenanoformulations of effectivecom-
binations can be quite advantageous. Hence more research
should be encouraged.
Conclusion
CVDs and CKD have common pathophysiological path-
ways that interconnect them at certain points. Hence,
patients with CKD have chances of developing CVDs. One
of the main connecting links between CKD and CVD is
the process of atherosclerosis that occurs in response to
oxidative stress generated by renal dysfunction and leads
to heart attack and other heart diseases. Polyphenols pos-
sesses the ability to scavenge oxidative stress, modulate
various biochemical, hormonal and anti-inflammatory
markers. Presently research is going on investigating
their cardioprotective and renoprotective potential. Fur-
ther, nanoformulations of polyphenolic compounds have
been found to be more effective in treating CVD and CKD.
Despite this enormous research on pharmacological poten-
tial of polyphenols in CVD as well as CKD, awareness
among common people is not adequate. We believe that by
highlighting their various beneficial effects to the reader,
we are trying to encourage them to utilize polyphenols as
complimentary therapy for CVD to allopathic drugs except
in those cases wherefactorsresponsible for these chronic
disorders are other than oxidative stress, inflammation and
dyslipidaemia. In this review, we attempted to highlight
the therapeutic potential of the polyphenolic compounds
and their nanoformulations in heart and kidney diseases
in simple manner for easy understanding.
Acknowledgements The authors are highly grateful to Guru Nanak
Dev University for their support.
Author contribution Ankita Rajput, Palvi Sharma, Davinder Singh,
Sharabjit Singh, Prabhjot Kaur, Shivani Attri, Pallvi Mohana, Harneet-
pal Kaur, and Farhana Rashid contributed in writing manuscript; Astha
Bhatia, Jaochim Jankowski, Hardeep Tuli, and Vanita Arora helped in
editing the manuscript and gave suggestions and Saroj Arora conceived
the idea.
Data availability Not applicable.
Declarations
Ethical approval Not applicable.

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Competing interests The authors declare no competing interests.
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