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V. Ramesh et al.
polyphenolics exhibit strong anti-inammatory, antioxidant,
blood thinning effect and reduce cholesterol [5]. Carotenoids
have anticarcinogenic and hypocholesterolemic properties
[4, 6].
3 Role ofNutraceuticals inLifestyle
Diseases
Lifestyle changes have culminated in chronic illness resulting in major nancial burden and psychological burden on
entire population [1]. The forthcoming paragraphs aim to
summarize the effect of selected nutraceuticals against lifestyle disorders such as hypertension, obesity, diabetes mellitus, Parkinson’s, Alzheimer’s, cancer, and osteoporosis.
3.1 Neurological Disorders
The main neurodegenerative disorders (NDDs), such as
Alzheimer’s disease (AD), Parkinson’s disease (PD), motor
neuron disease, Huntington’s disease, and prion disease are
primarily characterized by decrease in neurotransmitters,
which ultimately cause a loss of motor, sensory, and cognitive function leading to decrement in the neuronal numbers
or integrity, obstructing neuronal communication. PD and
AD can cause dementia and depression, leading to an
increase in mortality and morbidity, which is a signicant
nancial burden on society as a lifestyle-related disorder. By
the year 2050, it is expected that approximately 47 million
people worldwide would have dementia (cognitive decline)
and other NDDs [11].
AD is a chronic, irreversible neurodegenerative disorder
and amyloid-(β) peptide-containing extracellular amyloid
plaques and hyperphosphorylated tau (p-tau) proteincontaining intracellular neurobrillary tangles (NFT) are the
two major hallmarks of the disease [12]. Together with AD,
PD accounts for major NDDs in the population. PD-affected
brain is distinguished by presence of parkin, α-synuclein,
and other proteins which are collectively known as Lewy
bodies present in the cytoplasm of dead neurons located in
various regions of the brain [13].
Nutraceuticals acts at various target to modulate protein
synthesis and protect against dysfunctional mitochondria,
endoplasmic reticulum stress. They also exert antioxidant,
anti-inammatory, antihyperlipidemic, and neuroprotective
effects, resulting in the prevention of neurodegenerative disorders. They decrease β-site amyloid precursor proteincleaving enzyme 1 (BACE-1), Aβ aggregation, and
deposition, enhance neuroplasticity, inhibit acetylcholinesterase (AChE), downregulate amyloid precursor protein
(APP) gene expression, and inhibit glycogen synthase kinase
(GSK) signaling. Nutraceuticals such as vitamins, dietary
bers, CoQ10, creatine, lipoic acid, herbs, and phytoconstituents are easily available, inexpensive with minimal side
effects, and offer an alternative method for prophylactic and
therapeutic management of neurological disorders [14].
3.1.1 Role ofNutraceuticals inParkinson’s
Disease
Several nutraceuticals such as vitamins (Vitamin A, C, D,
and E), fatty acid (MUFA and PUFA), herbs (Plantago
ovata, Mucuna pruriens, Scutellaria baicalensis), phytoconstituents (curcumin, resveratrol, epigallocatechin-3-gallate,
genistein, lycopene, and vincamine), and miscellaneous
(CoQ10, Mito Q, creatine, lipoic acid, and N-acetyl cysteine)
play a signicant part in the management of Alzheimer’s disease [11, 13–16].
3.1.1.1 Vitamins
Vitamin supplements such as vitamins A, C, D, and E are
typical type of nutraceuticals utilized in the management of
Parkinson’s disease. Vitamins C and E work synergistically
to prevent oxidation and restore antioxidative function in
PD patients. Levodopa (L-Dopa) is more readily absorbed
by older PD patients when taken along with vitamin
C.Vitamin D regulates dopamine levels, controls calcium
homeostasis, increases glutathione levels, reduces nitric
oxide synthase (NOS) levels, and exhibits antiapoptotic
activity. β-carotene, a carotenoid found in vitamin A, prevents the buildup of intracellular α-synuclein and also acts
as an antioxidant. It decreases C/EBP homologous protein
caspase-12 and binding immunoglobulin protein (BIP)/
Grp78 expression [14, 15].
3.1.1.2 Fatty Acids
Lack of PUFAand MUFA, such as alpha-linolenic acid, linoleic acid, and docosahexaenoic acid, are strongly linked to
impaired brain function. Omega-3 fatty acids from sh
reduce reactive oxygen species (ROS) formation and enhance
free radical scavenging properties. They also reduce neutrophil and monocyte chemotaxis, minimize the production of
proinammatory cytokines, and exert a neuroprotective
effect in dopamine deciency. MUFA can lower plasma cholesterol and triglycerides [11].
3.1.1.3 Herbs
Plantago ovata is used along with Levodopa/carbidopa to
improve L-Dopa proles and also alleviate constipation in
PD patients. The seed powder of Mucuna pruriens is a natural source of L-Dopa and contains two neuroprotective
agents, namely CoQ 10 and Nicotine Adenine Dinucleotide
(NADH). NADH increases dopamine levels by enhancing
the expression of tyrosine hydrolase and mitochondrial complex I. Scutellaria baicalensis contains baicalein that inhibits apoptosis, activates autophagy, improves antioxidant,
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restores dopamine levels, and reduces inammation by suppressing inammatory cytokines. It ultimately reduces neurotoxicity and brillations by the formation of an oligomer
of α-synuclein [16].
3.1.1.4 Phytoconstituents
Phytoconstituents such as polyphenols have signicant benecial effects in PD by enhancing motor and gait abnormalities, preserving dopaminergic neurons, and preventive free
radicals. Curcumin and curcuminoid, owing to their powerful antioxidant properties, protect neurons from protein oxidation and maintain mitochondrial complex I activity by
suppressing α-synuclein aggregation. Resveratrol inhibits
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and suppress the expression of inammatory mediators
like tumor necrosis factor-alpha (TNF-α) and interleukin
1-α, (IL-1). It also regulates the expression of Bcl-2associated X protein (BAX) and B-cell lymphoma protein 2
(Bcl-2) at both mRNA and protein levels, contributing to its
antiapoptotic activity. Oxyresveratrol exhibits potent free
radical scavenging activity by suppressing intracellular ROS
in neuronal cells [16]. Epigallocatechin- 3- gallate reduces
neurotoxicity by increasing dopamine levels, improving
motor function, regulating protein kinase C activity, and
inducing endogenous antioxidant defense systems. They also
modulate the ROS-NO pathway to protect the substantia
nigra dopaminergic neurons against oxidative stress caused
by iron, which can lead to neuronal death [13].
Estrogen has neuroprotective effects in both PD and postmenopausal women. Estrogen-decient individuals are more
prone to get PD, and phytoestrogens supplement such as soy
products, nuts, and grains which are structurally similar to
estradiol, confer protection against PD.Genistein is a rich
phytoestrogen and acts as a transcription activator to upregulate antioxidative and antiapoptotic genes. Ginseng contains
ginsenosides Rg1 which exhibits antiapoptotic effect, cytochrome c release inhibition and stimulates PI3k/Akt/mTOR
pathway. Its antioxidant activity regulates glutathione levels
and oxidative stress-mediated nuclear factor kappa B (NFκB) pathway, maintains mitochondrial function, and reduces
iron levels by regulating the expression of iron transport proteins such as ferroportin 1 and divalent metal transport [16].
Vincamine helps to increase dopamine production,
reduces neuronal damage, decreases the production of ROS
and iron-chelating molecules, increases vasodilation activity, relaxes the muscles surrounding the capillaries in neurons, and increases the ow of nutrients and glucose to the
brain by producing more adenosine triphosphate (ATP) via
the Kreb’s cycle. Lycopene exhibits neuroprotective action
by increasing dopamine levels in the striatum. Its antioxidant effect is accompanied by an increase in the activity of
superoxide dismutase (SOD) and NADH dehydrogenase, as
well as a reduction in glutathione and malondialdehyde
concentrations [14].
3.1.1.5 Miscellaneous
CoQ10 or Ubiquinone exhibits antioxidant and free radical
scavenging activity, suppresses lipid peroxidation, and acts
as a redox component of the mitochondrial electron transport chain in neuronal cells. Creatine has neuroprotective
properties as it counteracts ATP depletion by increasing
intracellular phosphocreatine levels and acts as an antioxidant [13, 16]. Mito Q (Triphenylphosphine) has antioxidant
properties and maintains respiratory chain function [14].
Lipoic acid is a powerful antioxidant and acts as an antiinammatory agent by inhibiting TNF-α and NF-κB. Its
neuroprotection is due to increase in intracellular cysteine
levels, thereby increasing glutathione levels. N-acetylcysteine
acts as a direct glutathione precursor and antioxidant that
stimulates mitochondrial complex I and IV activities in neuronal cells [13].
3.1.2 Role ofNutraceuticals inAlzheimer’s
Disease
Several nutraceuticals such as vitamins (Vitamin B complex,
C, D, and E) phytoconstituents (isoavones, anthocyanidins,
and avones), and miscellaneous (CoQ10, Omega-3 fatty
acids, vayacog, souvenaid, cerefolin NAC, and axona) play a
signicant part in the management of Alzheimer’s disease
[11, 14–18].
3.1.2.1 Vitamins
The antioxidative properties of vitamins C and E help to protect the aging brain from pathologies associated with
AD. The cognitive status of older adults is improved by
25-hydroxy vitamin D3 and B vitamins maintain the integrity of the nervous and hematopoietic systems. Pyridoxin,
folate, and cobalamin maintain normal brain function, energy
production, and the repair of damaged cells. High levels of
homocysteine are neurotoxic and supplementing with B vitamins, including vitamin B6, helps to lower blood homocysteine levels [15].
3.1.2.2 Phytoconstituents
Flavonoids are polyphenolic compounds classied into six
subgroups: avonols, avanonols, avones, isoavones, avanones, and anthocyanidins. Several neurological processes
are inuenced by avonoids and their metabolites. Flavonoids
alter cerebral blood ow, upregulate synaptic plasticityrelated proteins and antioxidant enzymes, along with suppression of AD neuropathological process. Grape juice is a
avonol which reduces glutamate toxicity, platelet aggregation, lipid peroxidation and improves endothelial function.
The intake of these supplements improves cerebral hemodynamic as well as visual and cognitive performance [15].
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Oxyresveratrol found in grapes inhibits BACE-1and reduces
beta-amyloid production [16]. Garlic (Allium sativum)
has neuroprotective and antioxidant properties. Curcumin
owing to its anti-inammatory and antioxidant properties,
lowers Aβ plaque development by blocking the BACE-1
enzyme [17].
Isoavones (Genistein, Daidzein, Glycitin) enhance cholinergic function by increasing choline intake and stimulating acetylcholine release by potassium. It activates estrogen
receptor beta in the brain to enhance visual memory, spatial
memory, and learning ability. Anthocyanidins (Pelargonidin,
Cyanidin, Malvidin) are found in blueberries, bilberries,
cranberries, elderberries, raspberry seeds, and strawberries
exhibit anti-inammatory, antioxidant, improve brain function, and protect genomic DNA integrity, and increase structural and synaptic plasticity. Flavones (Luteolin, Apigenin)
are found in rosemary, celery, and parsley and enhance the
GABAergic and glutamatergic transmission, improve neuronal viability, protect neurons from beta-mediated toxicity
caused by copper, and also have anti-inammatory properties. Bioavonoids, found in capers, apples, onions, and
green tea, protect endothelial cells from oxidative stress,
exhibit cytoprotective properties, and improve hippocampal
synaptic plasticity and memory. Crocin is the main chemical
compound identied in saffron, which is involved in improving learning and memory in AD, and has antioxidant activity
[14, 15].
3.1.2.3 Miscellaneous
CoQ10 supplements reduce AD-related oxidative stress,
inammation, and AChE activity. Alpha-lipoic acid is a powerful antioxidant that helps glucose metabolism and utilization in the brain of AD patients. Omega-3 fatty acids enhance
nootropic activity and stop brain atrophy in AD-related conditions. They also exhibit anti-inammatory effects by suppressing microglia and astrocytes through the peroxisome
proliferator-activated receptor delta (PPAR-δ) and Jun
N-terminal kinase (JNK) signaling pathways, inhibiting the
β-secretase enzyme, increasing neurotransmitter synthesis,
and improves neurogenesis by increasing neurotrophic
growth factors. Neurocognitive function in patients with AD
is improved by taking neutral amino acid supplements.
Memory, brain wave activity, and brain metabolism were all
improved by phosphatidyl serine [11, 15].
The following marketed products, such as vayacog, souvenaid, cerefolin NAC, and axona are used in treating
AD. Vayacog is combined with omega-3 fatty acids and
phosphatidylserine, to supplement with lipids necessary for
neuronal cell membrane uidity and integrity. Omega-3 fatty
acids, uridine monophosphate, choline, and B vitamins in
souvenaid improve synaptic function. Vitamin B2, B6, B12,
and L-methyl folate present in cerefolin NAC are used to the
prevent neuroinammation, oxidative stress, and cognitive
impairments causing vitamin B12 and folate deciencies.
Axona, a coconut oil fraction contains caprylic triglyceride,
provides energy and nootropic effects in the brain of AD
patients [18].
3.2 Role ofNutraceuticals inHypertension
Cardiovascular disease is the leading cause of mortality
worldwide and is predicted to increase rapidly in the next
two decades. The most signicant pathophysiologic contributor to cardiovascular disease is the development of hypertension, and it is predicted that nearly 90% of people will
develop hypertension in their lifetime. Many nutraceuticals
such as probiotics, CoQ10, melatonin, vitamins C and D,
potassium, cocoa avonoids, L-arginine, beetroot juice, axseed, aged garlic extract, green tea, and resveratrol have
proved to be effective in lowering the blood pressure [19–23]
(Table1).
3.2.1 Dietary Fibers
Soluble ber consumption improves endothelium-mediated
vasodilation, viability of coronary artery endothelial cells
and reduces intracellular free radical generation. Soluble
bers and gut microbiota activate membrane-type receptor
for bile acids (TGR5) and farnesoid X receptor (FXR),
enhancing glucose, cholesterol, lipid, and energy metabolism by increasing bile acid excretion. Trimethylamine produced by gut microbiota is converted into toxic
trimethylamine-N-oxide (TMAO) by avin monooxygenase
and excretes toxic metabolites through the kidney.
Accumulating a high level of TMAO in serum leads to an
increase in the risk of developing cardiovascular disease like
stroke and myocardial infarction. Therefore, high-dietary
bers are recommended to minimize serum TMAO levels.
Fibers like arabinoxylans and pectins increase the synthesis
of key antioxidant enzymes by stimulating the transcription
factor Nrf2, causing a decrease in lipid peroxidation and free
radial generation, inhibiting the glutathione level, enhancing
the inducible nitric oxide synthase (iNOS) activity in the cardiac cell leading to chronic blood pressure reduction.
Secoisolariciresinol diglucoside found mainly in axseed, is
an essential lignan, with rich ber content and acts as an
angiotensin-converting enzyme (ACE) inhibitor [20, 22].
3.2.2 Prebiotics andProbiotics
Prebiotics exert antihypertensive activity by enhancing
hepatic insulin sensitivity and reducing the production of
cholesterol, fatty acid, and triacylglycerol. A decrease in
SCFAs lead to hypertension onset which can be rectied by
supplementation with dietary ber producing SCFAs, thus
activating the G protein-coupled receptor 41 and olfactory
receptor 78 present in blood vessels, through modulation of
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Table 1 Role of nutraceuticals for the management of hypertension [19–23]
Sl. no Nutraceuticals Mechanism of action
1 Prebiotics Reduce the synthesis of triacylglycerol, fatty acid, and cholesterol
SCFAs activate the Olfr78 and Gpr41 receptor present in blood vessels, through modulation of renin release
2 Ascorbic acid Improve in NO
Enhancement endothelial function and arterial compliance
3 Vitamin D
supplementation
4 Magnesium Increase prostaglandin E production
5 PUFAs Suppress thromboxane A2 synthesis
6 Sour tea (Hibiscus
sabdariffa)
7 Saffron
8 Ginger Blocks voltage-dependent calcium channels
9 Cinnamon, turmeric,
paprika, saffron,
black and red pepper
10 Extra virgin olive oil Antihypertension action by eNOS
11 Grape seed and red
wine extracts
12 Lycopene Powerful antioxidant and important in preventing cardiovascular disease
13 Quercetin Potent antioxidant
14 Catechin Decrease blood pressure
15 Soy isoavones Promotes vasodilation
16 Cocoa avonols Antihypertensive effect via increasing NO synthesis
Modulates vascular tone
Regulates blood pressure
Anti-inammatory
Induces vasodilation
Exert vasodilatory effect
PGH2 and TXA2 antagonist
Release NO
Antioxidant activity
Vasorelaxation via activation of K+ channels and inhibition of Ca2+ channels
Antihyperlipidemic activity
Anti-inammatory property
Antioxidant activity
NOS enzyme stimulation to cause endothelial relaxation
Inhibit COX 1 and 2, prostaglandin E2 (PGE2), and TNF-α
Inhibit calcium channel
Antioxidant
Downregulate ACE
Increase eNOS activity and NO serum levels
Promotes the production of NO
Inhibit ACE activity
Reduce ROS formation
Suppress the inammatory mediators via downregulation of intracellular adhesion molecule (ICAM-1)
Increase the regulation of detoxication enzymes
Enhancement DNA repair
Enhance the antioxidant activity
Reduce inammation
Decrease endogenously produced asymmetric dimethylarginine by inhibiting NO synthesis
Inhibit platelet aggregation
Antioxidant
Decrease blood pressure by improving endothelial function
Decrease lipid peroxidation
Enhanced SOD activity
Increase in NO levels
Antiatherosclerotic action
Vasodilator
Antiplatelet activity
Anti-inammatory
Platelet activation
Decrease in vascular oxidative stress
Anti-inammatory
Improves endothelial function
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Table 1
(continued)
Sl. no Nutraceuticals Mechanism of action
17 Epicatechin and
18 Garlic (H
19 CoQ10 Act as mitochondrial electron transporter
20 Valyl-prolyl-l-
21
catechin
S, allicin
diallydisulde
diallyltrisulde
methylallyltrisulde)
proline and
Isoleucyl-prolylproline
α -linolenic acid
2
Suppress glycoprotein IIb/IIIa expression- antiplatelet action
Cardioprotective signaling molecule
Protect the cell against apoptosis, oxidative stress and necrosis
Inhibit platelet aggregation
Enhances vasodilatation and brinolysis
Antioxidant activity
Decrease proinammatory cytokines
ACE inhibitor
Antihypertensive action by suppressing soluble epoxide hydrolase
V. Ramesh et al.
renin release. For example, fermentation of insoluble ber
oligosaccharides, is prebiotic that helps in the synthesis of
human colonic bacteria and short-chain fatty acids (SCFAs)
like butyrate, propionate, and acetate. Probiotics reduce total
and low-density lipoprotein cholesterol, insulin resistance,
glucose and regulates ACE, thereby reducing blood pressure
[20, 22].
3.2.3 Vitamins
Vitamins A, C, D, and E are majorly involved in regulating
BP.Vitamin C is a potent antioxidant and displays a synergistic effect with antihypertensive drugs, such as amlodipine.
It reduces blood pressure by improving endothelial function
which decreases the binding afnity to angiotensin II type 1
receptor and increases nitric oxide (NO) activity. Vitamin E
has, anti-inammatory antioxidant, cardioprotective effect,
and antihypertensive activity by increasing endothelial nitric
oxide synthase (eNOS), and decreasing NADPH levels.
Vitamin D exerts cardiovascular protective effects, by
improving vascular tone, modulating blood pressure, increasing high-density lipoprotein (HDL) levels, and exhibiting
anti-inammatory activity [21, 22].
3.2.4 Minerals
The main minerals involved in the regulation of BP are calcium, magnesium, and potassium. Potassium exerts antihypertensive effect by increasing baroreex sensitivity,
natriuresis, modulates sodium-potassium ATPase in the vascular smooth muscle cells, reduces sensitivity to angiotensin
II and catecholamines, and decreases NADPH oxidase.
Other mechanisms include enhancing antioxidant and antiinammatory, suppressing insulin resistance, decreasing
asymmetric dimethylarginine, reducing intracellular sodium,
and producing TNF-β. High levels of magnesium prevent
calcication of atherosclerotic plaques, induce vasodilation,
and also act as a natural calcium channel blocker, reducing
intracellular sodium and calcium contents thus decreasing
blood pressure. Calcium supplementation reduces the frequency occurrence of preeclampsia in pregnant women
[21,22].
3.2.5 Fatty Acids
PUFAs namely as omega-3 fatty acid and omega-6 fatty acid
are found in cottonseed, hemp seed, salmon, safower, soybean, ax oil, mustard oil, corn oil, and evening prime rose
oil. Flaxseed is rich in omega-3 fatty acids and acts as cardioprotective factor by blocking prostaglandin H2 receptors
(PGH2) and decreasing the synthesis of thromboxane A2
(TXA2). It also exerts antioxidant and free radicals scavenging activity, producing vasodilation by activating potassium
channels, and inhibiting the calcium channel and ACE [22].
3.2.6 Herbs
Herbs like saffron, ginger, cinnamon, curcumin, paprika, turmeric, and pepper act by increasing eNOS activity, modulating detoxication enzymes and exert antioxidant,
antihypertensive, along with calcium channel-blocking
effects. Flavonoids such as resveratrol, epicatechin, and
quercetin possess potent antioxidant, anti-inammatory,
antiatherosclerotic, antiproliferative, vasodilator, and antiplatelet aggregation, as well as blood pressure lowering
properties [22].
3.2.7 Phytoconstituents
Polyphenols, anthocyanins, alkaloids, pectin, and wax are
involved in the management of blood pressure. Hibiscus sab-
dariffa (Polyphenols and anthocyanins) exerts ACE inhibitor
and has cardioprotective, vasodilator effect through the
endothelium-derived nitric oxide-cyclic guanosine monophosphate (cGMP) relaxant pathway. Cocoa beans
(Theobroma cacao) commonly used in beverages and choco-
late, contain methyl-xanthine like theophylline, theobromine,
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and caffeine. Flavonoids such as epicatechin, catechin, procyanidins, quercetin, and isoquercitrin promote NO synthesis and encourage ow-mediated dilatation along with
antiplatelet activity by downregulating glycoprotein IIb/IIIa
expression and normalizing the lipid prole, and glucose
level [19].
Garlic (Allium sativum) contains hydrogen sulde, diallyl
disulde, diallyl trisulde, and methylallyl trisulde which
inhibit platelet aggregation, improve vasodilation and brinolysis, and protect the cell from oxidative stress, apoptosis,
and necrosis. Aged dry garlic extract contains sulfur compounds, avonoids, and allicin which exerts calcium channelblocking and ACE inhibitory activities. They enhance arterial
compliance by decreasing sensitivity to catecholamines and
increasing the synthesis of NO and bradykinin [19].
Betalain owing to its electron-donating properties have
the ability to quench oxidative stress-induced hypertension.
Lycopene, a hydrophobic carotenoid constituent of tomato,
exerts antihypertensive properties by improving endothelial
function, increasing NO levels, and acts as an antioxidant.
Olive leaves contain triterpenoids, oleanolic acid, hydroxytyrosol, and consumption of olive oil helps in lowering
blood pressure. Polyphenols increase plasma nitrite/nitrate
levels and decrease serum asymmetric dimethylarginine
levels, thereby increasing NO levels and decreasing blood
pressure [19].
3.2.8 Miscellaneous
Nonnutrient supplements, such as CoQ10, pycnogenol,
and melatonin, are not necessarily taken with food. CoQ10
has antioxidant properties, mitochondrial electron transporter, and coenzyme for mitochondrial enzymes and its
deciency is implicated in hypertension and cardiovascular disease. It suppresses production and action of proinammatory cytokines such as C-reactive protein, TNF-α
and IL-6. Pinus pinaster, marketed as Pycnogenol functions as a natural ACE inhibitor, protects against oxidative
stress on cell membranes, boosts NO, enhances endothelial
function and blood ow in the renal cortex, and has a positive impact on hypertension. Melatonin, a dark hormone
secreted from the pineal gland, appears to ameliorate
hypertension through central and peripheral mechanisms
by improving endothelial function, NO metabolism, and
antioxidant activity [19].
ALA lowers blood pressure by altering circulating oxylipin by inhibiting soluble epoxide hydrolase. L-arginine, a
basic amino acid, and substrate for NOS participates in the
synthesis of endothelium-derived relaxing factor. Milkderived tripeptide has benecial effects on hypertension
because of its peptide sequences, high potassium, and calcium content. Valyl-prolyl-proline and isoleucyl-prolylproline act as ACE inhibitor and attenuate the development
of hypertension.
3.3 Role ofNutraceuticals inObesity
Obesity is a chronic disease that has a wide range of complications and can affect different physiological functions.
Obesity is increasing dramatically in both men and women
of all ages. Excessive consumption of foods with high fat and
calories, along with sedentary lifestyles, is one of the factors
that contribute to obesity. Consequently, a low-calorie diet
and appropriate exercise help reduce obesity [24].
Several nutraceuticals such as dietary bers (glucomannan and psyllium ber), Prebiotics, probiotics, minerals (calcium), fatty acids (PUFA and DHA), herbs (Murrayakoenigii,
Momordica charantia, Caralluma mbriata, Paulliniacupana,
Panax ginseng, Ginkgo biloba, Hieracium sp., Morus nigra,
Prunus armeniaca, Rhus verniciua, Taraxacum ofcinale,
Garcinia mangostana, Cordyceps militaris, Sorghum
bicolor, fenugreek, black gram, chili pepper, ginger, tur-
meric, bottle gourd, amla, green tea, apple, and annurca
esh) and phytoconstituents (capsaicin, curcumin, polyphenols, gingerol, shogaol, and baicalin) show a signicant part
in the management of obesity. Nutraceuticals act against
obesity by the following mechanisms; increasing the bile
acid synthesis and low-density lipoprotein (LDL) clearance,
decreasing the absorption of fat, upregulation of LDL receptors, inhibiting insulin resistance and α-amylase, regulating
lipase activity, modulating AMP-activated protein kinase
(AMPK), peroxisome proliferator-activated receptor gamma
(PPAR-γ), and mitogen-activated protein kinases (MAPK)
pathways along with anti-inammatory and antioxidant
activity [3, 24, 25] (Fig.2).
3.3.1 Dietary Fibers
Dietary bers modify food structure, digestive processes,
and appetite cues, improving energy balance and body
weight management in humans. Dietary bers bind with bile
acids and catalyze an increase in bile acid genesis, a decrease
in hepatic cholesterol, upregulation of the LDL receptor, and
a rise in the clearance of LDL.Fiber increases intraluminal
viscosity and inhibits the assimilation of macronutrients,
which traps cholesterol in the small intestine and makes people feel fuller for longer, resulting in lower calorie consumption [25].
Dietary ber is easily digested by the local microbiota in
the colon, leading to bacterial proliferation and SCFA such
as acetate and propionate, in which propionate decreases the
hepatic cholesterol synthesis. SCFA may play an important
part in energy balance, and insulin resistance through the
stimulation of the G-protein-coupled free fatty acid receptor
(FFA). In particular, FFA2 and FFA3 stimulation in the colon
increases the synthesis of anorectic gut peptides like Peptide
YY (PYY) and Glucagon-like peptide-1 (GLP-1) with an
appetite suppressant effect by reducing food intake. FFA3
activation in adipocytes also boosts leptin expression.
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Fig. 2 Role of nutraceuticals for the management of obesity
Prebiotics change the gut microbiota composition and
increase endogenous GLP-1, L-cell number, and leptin sensitivity, which manage energy homeostasis. Glucomannan is
a hydrosoluble ber, with a high-density structure that exerts
hypocholesterolemic activity. Psyllium ber attenuates lowdensity lipoprotein levels. β-glucans increase HDL cholesterol and decrease LDL cholesterol levels [25].
3.3.2 Minerals andFatty Acids
Calcium-rich foods (milk, yogurt, and cheese) help in the
control of body weight and reduction of adipose tissue. Fish
contains arginine, which increases the endogenous synthesis of NO exerts a vasodilatory effect, thus causing a reduction in blood pressure. PUFAs reduce hyperglycemia,
hyperinsulinemia, and have anti-obese action by downregulating PPAR-α. DHA acts as an anti-inammatory factor
that inhibits obesity. MUFA can lower plasma cholesterol
and triglyceride levels. In order to treat fatty liver and a disturbed fat metabolism, choline lipotropic agents are
employed [3, 24].
3.3.3 Phytoconstituents
Flavonoids exert cardioprotective action by reducing NO,
ROS, platelet aggregation, lipid peroxidation, and proinammatory cytokines. Fenugreek (steroidal sapogenins, galactomannans, and isoleucine), ginger (6-gingerol, 6-shogaol),
bottle gourd, and amla exhibit antihyperglycemic, antihyper-
lipidemic, immunomodulatory, antioxidant, and anti-inammatory activity by decreasing the serum triglycerides, total
cholesterol, and LDL level, increasing HDL level, and activating AMPK signaling pathway. Momordica charantia,
Cordycepsmilitaris (cordycepin), green tea (epigallocatechin3-gallate), Caralluma mbriata (pregnane glycosides, a-
vone glycosides, and avonoids), and Sorghum bicolor
decrease the adipose tissue deposition, risk of hypertension,
and cardiovascular disorders, increase insulin sensitivity, and
modulate the gene expression via MAPK, PI3K-Akt, and
insulin signaling pathway. Paulliniacupana, ginger, tiliro-
side, baicalin, and baicalein reduce obesity by inducing
expression of uncoupling protein 1 (UCP-1) and adiponectin
signaling via the activation of AMPK and PPARγ. Panax
ginseng (Ginsenoside Rg1) induces UCP-1 expression by
modulating the transcription factor PR-domain containing
16 (PRDM16) and peroxisome proliferator- activated receptor gamma coactivator 1-alpha (PGC1α) [24,26].
Flavonoids such as capsaicin, curcumin, curcuminoid,
cranberry, and rose have adipocyte browning property,
reduce inammation, and modulate cytokines like TNF-α,
cyclooxygenase-2 (COX-2), and interleukins 1 and 6 (IL1&6) which constraint the activity of UDP-glucuronosyl
transferase and CYP-450. Murrayakoenigii, black gram, and
chili pepper (capsaicin) exhibit antihypertensive, antiinammatory, antioxidant, and antihyperglycemic properties
by elevating the hepatic glycogen level, reducing the
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Fig. 3 Role of nutraceuticals in diabetes mellitus with their possible mechanism of action
gluconeogenic enzymatic activity, inhibiting insulin resistance and α-amylase thus counteracting obesity. Ginkgo
biloba, Hieracium sp., Morus nigra, Prunus armeniaca,
Rhus verniciua, Taraxacum ofcinale, and annurca esh
(polyphenols) inhibit lipase activity by reducing the adipocyte volume, fat accumulation, fat mass, and lipid peroxidation thus preventing obesity [3, 21, 26, 27]. Apple (oligomeric
procyanidin) acts effectively in the cholesterol uptake
process [28].
rate which would signicantly affect the nancial state of
global health care [29].
Phytochemicals, dietary supplements, functional foods,
bioactive components, lipids, protein, vitamins, and minerals
are signicant nutraceuticals that have been proved to be
effective in management and prevention of diabetes mellitus
[27, 30–33]. In diabetes mellitus, nutraceuticals mainly target α-amylase, α-glucosidase, dipeptidyl peptidase-IV
(DPP-IV), aldose reductase, PPAR-γ, AMPK, and glucose
transporter protein type-4 (GLUT4) to reduce hyperglycemic condition (Fig.3) [34].
3.4 Role ofNutraceuticals inDiabetes
Mellitus
All over the world, diabetes mellitus is becoming more common. As a result of increasing population, aging, urbanization, and related lifestyle changes, it is predicted that high
percentage of the world’s adult community is prone to have
diabetes mellitus. However, diabetes itself is a multimorbid
metabolic disorder that can damage and impair various
organs, ensuing in a poor quality of life and a higher death
3.4.1 Dietary Fibers andPrebiotics
Insoluble and soluble bers are two different types of dietary
bers and have unique role in maintaining blood glucose levels. Soluble bers are β-glucans, inulin, and pectin. β-glucans
are abundant in the cell walls of fungi, yeast, oats, and barley
which reduce postprandial glycemia and delay glucose
absorption and stomach emptying by modulating PI3K/AKT
pathway. It also decreases LDL level and increases HDL
level, thus curbing the risk of CVD in type 2 diabetes mellitus (T2DM). It also acts as a prebiotic and generates SCFA
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primarily propionate and acetate. Propionate promotes gluconeogenesis, inhibits hepatic cholesterol synthesis, and is
associated with insulin secretion [30].
Inulin and fructooligosaccharides occur in plants and
fruits like bananas, chicory root, garlic, wheat, and onions.
Inulin consumption improves blood glucose management
and has antioxidant properties. A unique colonic fermentation property of high-performance inulin can alter the gut
microbiota composition favoring growth of Bidobacteria.
After fermentation, it tends to support propionate production,
which reduces acetate-to-propionate, resulting in lowering
the risk factors related to T2DM by reducing LDL and total
serum cholesterol. Dietary bers (psyllium) exert hypoglycemic effect in diabetic patients and lower lipid levels in hyperlipidemic conditions. Nopal (Opuntia cus-indica) regulates
postprandial blood glucose peaks in T2DM.Arabinoxylan, a
key component of whole grains exerts diabetic-related antiinammatory properties and antidiabetic property by
decreasing the absorption of glucose and total cholesterol.
Pectins are linear polymer of galacturonic acid that reduces
fasting glucose and cholesterol concentrations [30].
Insoluble dietary bers include lignin, cellulose, xyloglucans, xylans, mannans, and glucomannans and act as physical barriers, thus modulating the motility of digestive
products in GIT.Intake of high-insoluble dietary bers helps
in modulating the glycated hemoglobin A1c (HbA1c) levels
thereby minimizing the risk of development of T2DM [30].
All prebiotics are bers and get fermented in colon and
stimulate the growth of Lactobacilli, Bidobacteriaceae, and
Faecalibacterium family, which exerts anti-inammatory
property. A high level of Akkermansia muciniphila increases
number of L-cells synthesis of GLP-1 and GLP-2 which is
associated with healthy glucose metabolism and gut barrier
function [30].
3.4.2 Vitamins
Vitamin D and calcium supplementation aid in improving
insulin sensitivity and preventing diabetes by suppressing
parathyroid hormone (PTH) secretion. Vitamin H (chromium
picolinate and biotin) may improve blood glucose management by enhancing insulin activity and glucokinase enzyme
[31, 32].
3.4.3 Minerals
Minerals such as chromium, selenoprotein, zinc, magnesium, and vanadium, are used to manage diabetes mellitus.
Chromium enhances both β-cell and tissue sensitivity by
upregulation of insulin receptor and improving insulin binding. Selenoprotein prevents the likelihood of developing
metabolic diseases, through its antioxidant and cytoprotective properties. Zinc partially exhibits an antioxidant property
and is benecial for antiaging and antidiabetic activity.
Before the discovery of insulin in 1922, vanadium was used
to enhance insulin sensitivity to control blood glucose levels.
Oral magnesium supplements help to restore magnesium
deciencies and improve oxidative stress, inammation, and
insulin resistance in T2DM [32, 33].
3.4.4 Fatty Acids
Regular consumption of sh provides DHA and EPA fatty
acids that regulate satiety and appetite by counteracting insulin resistance and plasma leptin level. Omega-6 fatty acids
overcome insulin sensitivity syndrome by modulating genes
related to lipid, glucose, and insulin homeostasis through
PPARs [33]. Olive oil exerts antidiabetic, anti-inammatory,
antioxidative properties and improves mitochondrial function [35].
3.4.5 Herbs
Botanicals such as Biophytum sensitivum, Caesalpinia bonducella, Catharanthus roseus, Eugenia jambolana, Citrullus
colocynthis, Helicteres isora, Scoparia dulcis, Tinospora
cardifolia, Cucurbita maxima, and Acacia arabiaca exhibit
antidiabetic activity through stimulation of pancreatic β-cell
to release insulin. Punica granatum and Cassia auriculata
inhibit intestinal α-glucosidase activity leading to antihyperglycemic effects. Ocimum sanctum exhibits antidiabetic
activity by inhibiting cortisol levels. Murraya koenigii,
Casearia esculenta, Coccinia indica, Cassia auriculata, and
Brassica juncea suppress glycogen phosphorylase activity,
leading to a suppression of glycogenolysis and neoglycogenesis, establishing hypoglycemic activity. Ipomoea batatas
reduces insulin resistance, and inhibits maltase. Cucurbita
maxima exerts hypoglycemic action and regenerates damaged pancreatic cells [36, 37].
3.4.6 Phytoconstituents
Activation of AMPK suppresses the synthesis of both fatty
acid and cholesterol in the liver. AMPK activation also
reduces lipogenesis and lipolysis in adipocytes. Berberine,
epigallocatechin gallate, and caffeine reduce body weight,
plasma triglyceride by suppressing lipogenesis-related genes
and promoting gene associated with ATP production in muscle tissue and adipocytes [34].
PPAR-γ modulates gene associated with inammation,
lipid metabolism, and glucose homeostasis. Activation of
PPAR-γ enhances the expression and mobilization of the
glucose transporters GLUT-1 and GLUT-4 to the cell surface, thus increasing glucose uptake into liver and muscle
cells. PPAR-γ agonists suppress TNF-α and enhance adiponectin levels thus improving insulin sensitivity. Natural
products such as rutin of Noni fruit (Morindacitrifolia L.),
narcissoside, nicotioroside, honokiol, and catechin upregulate expression of adiponectin and PPAR-γ. Green tea
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consumption counteracts T2DM risk by promoting insulin
sensitivity and PPAR-γ activation. Sargahydroquinoic acid,
sargaquinoic acid, and amorfrutins are novel PPAR-α/γ dual
agonists. Quercetin and kaempferol from Euonymus alatus,
improve insulin-mediated glucose uptake [35].
The DPP-IV enzyme causes degradation and inactivation
of many glucose-regulating incretin hormones, including
GLP-1 and GIP, enhances insulin production in pancreatic
β-cells. The phytoconstituents such as resveratrol, luteolin,
apigenin, avone, myrcenol, linalool, α-elemol, and
β-eudesmol have signicant interactions with PPAR-γ and
DPP-IV targets [34].
Apple extracts contain phlorizin from peels and esh,
which acts as a hypoglycemic factor [28]. The cardioprotective
and antidiabetic effects of soy proteins such as solcon S and
solgen 40 reduce insulin resistance, and dyslipidemia in diabetic postmenopausal women. The main polyphenolic compound in coffee and chlorogenic acid is similar to acarbose and
acts by inhibiting intestinal glucose transport and glucose6-phosphate translocase, an enzyme involved in gluconeogenesis and glycogenolysis, by reducing the absorption of
carbohydrates. Robinetinidol and setinidol present in Acacia
mearnsii, inhibit lipase and exert antidiabetic activity. The
hydroxy chalcone compound in cinnamon inhibits an enzyme
called tyrosine phosphatase that targets the insulin receptor,
and has the potential to enhance insulin signaling [36, 38].
3.4.7 Miscellaneous
ALA is a PPAR-γ agonist, antioxidant, and improves insulin
sensitivity by tissue uptake of glucose via GLUT-4. It also
reduces microvascular diabetic complications such as cataract formation, vascular damage, and polyneuropathy.
Carnitine (L-Carnitine, Acetyl L-Carnitine) aids in the breakdown of fatty acids and the binding of acyl residues in the
body and is useful in preventing diabetic ketoacidosis.
N-Acetyl Cysteine enhances glutathione synthesis, decreases
the progression of vascular damage, maintains RBC intact
form, diminishes structural changes in T2DM, and exhibits
antiglycation activity. Consumption of cow milk and donkey
milk helps to maintain normoglycemia. Trypsin, pepsin, and
pancreatin present in the milk improves damaged β-cell viability. Alcalase and pepsin found in eggs inhibit α-glucosidase
and DPP-IV [36, 39].
Watermelon, cucumbers, pumpkins, and muskmelons
contain L-citrulline which is crucial for urea cycle by recoupling uncoupled e-NOS. Nutraceuticals such as zinc, glycine, lipoic acid, broccoli sprouts, taurine, and
N-acetylcysteine reduce dicarbonyl stress by promoting
Nrf2 activation. Inositol has a role in reverting of diabetesinduced neuropathy and maintaining the normal blood cholesterol level and integrity of cell membrane. Spirulina
(phycocyanin) has numerous health advantages especially
antioxidant and antidiabetic activity by an increase in insulin
production and reduction in the glucose absorption and
HbA1c levels [39, 40].
3.5 Role ofNutraceuticals inCancer
Nutraceuticals are efcient in the prevention of cancer rather
than treatment and may be used as an adjuvant in cancer
treatment by preventing metastasis, invasion, and drug resistance. They are also known to cause proteasome and epigenetic alterations that prevent and treat cancer. Common cancer
molecular targets that nutraceuticals can affect are the growth
factor receptors (Fig. 4), mainly protein kinases such as
phosphoinositide 3-kinase (PI3K), mammalian target of
rapamycin (mTOR), AMPK, breakpoint cluster regionAbelson murine leukemia viral oncogene (BCR-ABL); proinammatory mediators namely interleukins, TNF-α,
COX-2, and 5-lipoxygenase (5-LOX); epidermal growth factor receptor (EGFR) like vascular endothelial growth factor
receptor (VEGFR) and insulin-like growth factor 1 receptor
(IGF1-R). It also includes transcription factors like signal
transducer and activator of transcription 3 (STAT3), nuclear
factor erythroid 2-related factor 2 (Nrf2), activator protein 1
(AP-1), PPAR-γ, β-catenin, NF-κB, sonic hedgehog along
with dietary supplements (vitamin E, L-glutamine, and
omega-3 fatty acid), bers, and phytoconstituents, (turmeric,
saffron, black pepper) [41].
3.5.1 Dietary Fibers
Dietary bers, namely vegetables, fruits, whole grains,
legumes, nuts, seeds, wholemeal, brown rice, high-ber
cereals, muesli, and oats exhibit anticancer activity. Dietary
ber has an essential role in antineoplastic functions due to
physical, prebiotic, and metabolic effects. It reduces the
intestinal transit time by increasing the stool bulk and binds
the carcinogens to the stool, which favors the elimination of
fecal carcinogens. Colonic bacteria convert ber into SCFA,
which has anti-inammatory, antioxidant, and anticancer
properties. SCFAs with cholestyramine inhibit bile acid
reabsorption and prevent liver cancer. Dietary bers alleviate
breast cancer by preventing intestinal reabsorption of estrogens, inhibiting β-d-glucuronidase activity by hydrolysis of
conjugated estrogen, increasing fecal excretion, elevating the
sex hormone-binding globulin levels, modulating the insulin
production and glucagon-like peptide, then lowering the
level of leptin. Phytoestrogens like genistein, resveratrol,
enterolactone, and enterodiol, act as a competitive inhibitor
of estrogen receptor, induce cancer cells differentiation, and
reduce angiogenesis. Probiotics prevent cancer cell proliferation by improving host immunity and modulating apoptosis
and cell differentiation [42].
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