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High-Altitude Medicinal Plants as Promising Source of Phytochemical Antioxidants to Combat Lifestyle-Associated Oxidative Stress-Induced Disorders

Authors:
  • GB Pant National Institute of Himalayan Environment

Abstract

Oxidative stress, driven by reactive oxygen, nitrogen, and sulphur species (ROS, RNS, RSS), poses a significant threat to cellular integrity and human health. Generated during mitochondrial respiration, inflammation, UV exposure and pollution, these species damage cells and contribute to pathologies like cardiovascular issues, neurodegeneration, cancer, and metabolic syndromes. Lifestyle factors exert a substantial influence on oxidative stress levels, with mitochondria emerging as pivotal players in ROS generation and cellular equilibrium. Phytochemicals, abundant in plants, such as carotenoids, ascorbic acid, tocopherols and polyphenols, offer diverse antioxidant mechanisms. They scavenge free radicals, chelate metal ions, and modulate cellular signalling pathways to mitigate oxidative damage. Furthermore, plants thriving in high-altitude regions are adapted to extreme conditions, and synthesize secondary metabolites, like flavonoids and phenolic compounds in bulk quantities, which act to form a robust antioxidant defence against oxidative stress, including UV radiation and temperature fluctuations. These plants are promising sources for drug development, offering innovative strategies by which to manage oxidative stress-related ailments and enhance human health. Understanding and harnessing the antioxidant potential of phytochemicals from high-altitude plants represent crucial steps in combating oxidative stress-induced disorders and promoting overall wellbeing. This study offers a comprehensive summary of the production and physio-pathological aspects of lifestyle-induced oxidative stress disorders and explores the potential of phytochemicals as promising antioxidants. Additionally, it presents an appraisal of high-altitude medicinal plants as significant sources of antioxidants, highlighting their potential for drug development and the creation of innovative antioxidant therapeutic approaches.
Pharmaceuticals 2024, 17, 975. https://doi.org/10.3390/ph17080975 www.mdpi.com/journal/pharmaceuticals
Review
High-Altitude Medicinal Plants as Promising Source of
Phytochemical Antioxidants to Combat Lifestyle-Associated
Oxidative Stress-Induced Disorders
Mohammad Vikas Ashraf
1,†
, Sajid Khan
2,†
, Surya Misri
3
, Kailash S. Gaira
4
, Sandeep Rawat
4
, Balwant Rawat
5
,
M. A. Hannan Khan
6
, Ali Asghar Shah
6
, Mohd Asgher
2,
* and Shoeb Ahmad
1,
*
1
Department of Biotechnology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah
University, Rajouri 185234, Jammu and Kashmir, India; vikasashraf@bgsbu.ac.in
2
Department of Botany, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University,
Rajouri 185234, Jammu and Kashmir, India; sajidkhan717@gmail.com
3
Section of Microbiology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University,
Rajouri 185234, Jammu and Kashmir, India; suryamisri23@gmail.com
4
Sikkim Regional Centre, G.B. Pant National Institute of Himalayan environment, Pangthang,
Gangtok 737101, Sikkim, India; kgaira@gmail.com (K.S.G.); sandeep_rawat15@redimail.com (S.R.)
5
School of Agriculture, Graphic Era University, Dehradun 24800, Utarakhand, India;
balwantkam@gmail.com
6
Department of Zoology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University,
Rajouri 185234, Jammu and Kashmir, India; drmahkhan@bgsbu.ac.in (M.A.H.K.);
aashah@bgsbu.ac.in (A.A.S.)
* Correspondence: asghermohd@gmail.com (M.A.); shoebahmad@bgsbu.ac.in (S.A.);
Tel.: +91-9622-184-466 (M.A.); +91-7889-964-623 (S.A.)
These authors contributed equally to this work.
Abstract: Oxidative stress, driven by reactive oxygen, nitrogen, and sulphur species (ROS, RNS,
RSS), poses a signicant threat to cellular integrity and human health. Generated during mitochon-
drial respiration, inammation, UV exposure and pollution, these species damage cells and contrib-
ute to pathologies like cardiovascular issues, neurodegeneration, cancer, and metabolic syndromes.
Lifestyle factors exert a substantial inuence on oxidative stress levels, with mitochondria emerging
as pivotal players in ROS generation and cellular equilibrium. Phytochemicals, abundant in plants,
such as carotenoids, ascorbic acid, tocopherols and polyphenols, oer diverse antioxidant mecha-
nisms. They scavenge free radicals, chelate metal ions, and modulate cellular signalling pathways
to mitigate oxidative damage. Furthermore, plants thriving in high-altitude regions are adapted to
extreme conditions, and synthesize secondary metabolites, like avonoids and phenolic com-
pounds in bulk quantities, which act to form a robust antioxidant defence against oxidative stress,
including UV radiation and temperature uctuations. These plants are promising sources for drug
development, oering innovative strategies by which to manage oxidative stress-related ailments
and enhance human health. Understanding and harnessing the antioxidant potential of phytochem-
icals from high-altitude plants represent crucial steps in combating oxidative stress-induced disor-
ders and promoting overall wellbeing. This study oers a comprehensive summary of the produc-
tion and physio-pathological aspects of lifestyle-induced oxidative stress disorders and explores the
potential of phytochemicals as promising antioxidants. Additionally, it presents an appraisal of
high-altitude medicinal plants as signicant sources of antioxidants, highlighting their potential for
drug development and the creation of innovative antioxidant therapeutic approaches.
Keywords: antioxidant; high-altitude medicinal plants; lifestyle-associated disorders; oxidative
stress; phytochemicals; ROS
Citation: Ashraf, M.V.; Khan, S.;
Misri, S.; Gaira, K.S.; Rawat, S.;
Rawat, B.; Khan, M.A.H.; Shah, A.A.;
Asgher, M.; Ahmad, S. High-
Altitude Medicinal Plants as
Promising Source of Phytochemical
Antioxidants to Combat
Lifestyle-Associated Oxidative
Stress-Induced Disorders.
Pharmaceuticals 2024, 17, 975.
hps://doi.org/10.3390/ph17080975
Academic Editors: Agnieszka
Ludwiczuk and Syota Kagawa
Received: 22 June 2024
Revised: 14 July 2024
Accepted: 18 July 2024
Published: 23 July 2024
Copyright: © 2024 by the authors. Li-
censee MDPI, Basel, Swierland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (hps://cre-
ativecommons.org/licenses/by/4.0/).
Pharmaceuticals 2024, 17, 975 2 of 61
1. Introduction
Oxidative stress (OS) within organisms arises when there is an imbalance between
the production of reactive oxygen species (ROS) and the body’s ability to neutralize them
[1]. ROS are generated during cellular metabolism, particularly in processes like the res-
piratory chain and tricarboxylic acid (TCA) cycle within mitochondria. ROS, including
hydrogen peroxide (H
2
O
2
) and superoxide anion (O
2
•−
), play essential roles in physiolog-
ical functions such as cellular defence and signalling [2]. However, disproportion between
ROS production and neutralization can lead to oxidative stress, which is implicated in
various pathological conditions [3]. This imbalance, where an excess of reactive molecules
overwhelms the body’s innate defence mechanisms, damages cellular structures and es-
sential molecules like lipids, proteins and DNA. As a result, this leads to the development
and progression of multiple diseases [4]. While ROS, when present in controlled, low con-
centrations, serve as signalling molecules facilitating cellular functions and oering cellu-
lar protection, their excessive production, as seen in conditions like inammation, can
spur the generation of additional highly reactive species, such as superoxide radical (O
2
•−
),
hydroperoxyl radical (HO
2
), singlet oxygen (1O
2
), ozone (O
3
), nitric oxide (NO), nitrogen
dioxide (NO
2
), sulphur dioxide (SO
2
), and sulphur trioxide (SO
3
) [5]. These reactive spe-
cies react with cellular components, modifying their normal structure and function. No-
tably, the oxidative modication of essential enzymes or regulatory sites is critical, chang-
ing their redox potential, that trigger alterations in cell signalling pathways and induce
programmed cell death [6]. Evidently, oxidative stress and inammation are closely
linked. Oxidative stress can trigger inammation, while inammation can, in turn, am-
plify OS. This creates a harmful cycle that promotes cell damage and a pro-inammatory
environment [7].
Oxidative stress stands as a central mechanism in the pathogenesis of a spectrum of
health disorders, spanning cardiovascular, neurodegenerative, and metabolic conditions
such as obesity, diabetes and many others [8] (Figure 1). Its pivotal role is evident in the
disruption of cell membrane integrity through induced lipid peroxidation, contributing
signicantly to the progression of cardiovascular complications like atherosclerosis, en-
dothelial dysfunction, and plaque formation, as well as neuronal membrane damage,
which underlies various neurodegenerative diseases [9].
Figure 1. Oxidative stress-induced health modalities (The illustration was created using BioRender
at www.biorender.com.)
Pharmaceuticals 2024, 17, 975 3 of 61
Moreover, the impact of ROS extends beyond membrane disruption, inuencing crit-
ical proteins and enzymes and thereby compromising essential cellular functions and sig-
nalling pathways. This includes the matrix metalloproteinases (MMPs) activation in car-
diovascular ailments and the initiation of protein misfolding and aggregation, character-
istic of neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases [10]. Fur-
thermore, oxidative stress triggers an inammatory cascade, marked by the release of pro-
inammatory mediators, perpetuating a cycle that exacerbates cellular damage and dis-
ease progression. Notably, oxidative stress causes adipose tissue inammation and dys-
function, increasing pro-inammatory cytokines and adipokines, which lead to insulin
resistance and disrupted lipid metabolism leading to obesity [11]. In diabetes, oxidative
stress impairs insulin signalling and damages pancreatic β-cells, reducing glucose uptake
and insulin secretion, thereby worsening the disease [12]. Understanding the intricate in-
terplay between oxidative stress and its associated inammatory responses is paramount,
as it not only elucidates the underlying mechanisms of disease but also oers promising
avenues for therapeutic intervention in combating these debilitating health conditions.
Phytochemicals, particularly those derived from high-altitude medicinal plants, have
emerged as potent antioxidants with the potential to counteract oxidative stress and its
associated health disorders by scavenging harmful free radicals in the body [13]. Their
diverse mechanisms of action also include anti-inammatory eects, modulation of cellu-
lar signalling pathways, and enhancement of immune function. High altitude medicinal
plants have adapted to extreme environmental conditions such as low oxygen levels, in-
tense ultraviolet radiation and temperature uctuations. These harsh conditions stimulate
the production of bioactive compounds within these plants, making them rich sources of
phytochemicals with unique properties [14]. The exploration of high-altitude medicinal
plants not only preserves cultural traditions but also harnesses their therapeutic potential
for modern medicine, particularly in combating oxidative stress-related diseases and dis-
covering novel pharmaceutical compounds. Though high-altitude regions harbour a vast
array of plant species and genetic diversity, much of this biodiversity remains unexplored
and underutilized [15]. This untapped reservoir of biological diversity oers immense po-
tential for discovering new bioactive compounds and understanding evolutionary adap-
tations to extreme environments. Therefore, exploring high-altitude medicinal plants as
sources of potent antioxidants not only advances our understanding of natural defence
mechanisms but also paves the way for developing innovative therapeutic strategies to
overcome oxidative stress-related diseases [16]. This study highlights and summarizes the
production and physio-pathological aspects of oxidative imbalance and emphasizes the
role of phytochemicals in mitigating these eects. Further, this study provides a compre-
hensive tabulation of more than 160 high-altitude medicinal plants along with their re-
ported phytochemicals, which could be very useful in harnessing their potential to combat
lifestyle-associated, oxidative stress-induced disorders and could serve as a starting point
for the exploration of alternate medicine for combating these diseases.
1.1. Oxidative Stress: Source, Mechanism and Lifestyle-Related Diseases
1.1.1. Source of Oxidative Stress
Oxidative stress occurs when highly reactive species, such as superoxide radical
(O2•−), hydroperoxyl radical (HO2), singlet oxygen (1O2), and ozone (O3); reactive nitrogen
species (RNS) like nitric oxide (NO) and nitrogen dioxide (NO2); and reactive sulphur
species (RSS) like sulphur dioxide (SO2) and sulphur trioxide (SO3), overwhelm the natu-
ral antioxidant defence system of a body. This leads to cellular damage and dysfunction,
which can contribute to a wide array of diseases [17]. These reactive species are continu-
ously produced within cells at low levels during normal metabolic processes, which are
safely neutralized by cellular machinery, but can also stem from contact to external factors
such as radiation (such as X-rays and UV), air pollutants, ozone, cigaree smoke, bacteria,
viruses, drugs and various forms of cellular stress, whether acute or chronic [18].
Pharmaceuticals 2024, 17, 975 4 of 61
These reactive species include both non-radicals and free radical oxidants. Free radi-
cals are particularly unstable due to having unpaired electrons in their outer electron or-
bit. This instability drives them to react with other molecules, causing oxidation and sub-
sequent harm to crucial biological molecules such as nucleic acids (DNA, RNA), lipids
and proteins [19].
The key intercellular origin of these reactive species includes endoplasmic reticulum,
mitochondria, peroxisomes, lysosomes, plasma membrane and, cytosol [20]. ROS, formed
from the chemical reactions involving molecular oxygen, encompass free radicals such as
superoxide anions (O2•−) and hydroxyl radicals (OH), alongside non-radical oxidants like
hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). Reactive nitrogen species, on
the other hand, include peroxynitrite radical (ONOO), and nitric oxide (NO). Recently
identied reactive sulphur species (RSS) include thiol radical (RS) and RSS formed
through reactions between ROS and thiols. RSS exhibit both radical and non-radical prop-
erties, and they have a particular anity for sulphur-containing molecules, such as pep-
tides and proteins, triggering oxidation and reduction reactions [20].
Enzymes of the mitochondrial electron transport respiratory chain are major contrib-
utors to ROS production [21]. Furthermore, various other enzymes catalyse chemical re-
actions that contribute to ROS formation. These include homologs of phospholipase A2
(PLA2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, cyclooxygenase
(COX), uncoupled nitric oxide (NOS), xanthine oxidase (XO), glucose oxidase (GOXs),
myeloperoxidase (MPO) and, lipoxygenases (LOXs) [22].
NADPH oxidase (NOX), initially identied in the phagosomes of immune cells, has
several homologs with diverse intracellular localizations. Some homologs, like DUOX2
and NOX1, play major roles in various inammatory conditions and tumours. Xanthine
oxidase, primarily expressed in the small intestinal mucosa and liver, catalyses ROS pro-
duction both on the outer surface of the plasma membrane and in the cytoplasm [23].
Lipoxygenases are non-heme iron enzymes that accumulate ROS by oxidizing arachidonic
acid (AA), whereas myeloperoxidase, a heme protein that localizes lysosomes, contributes
to ROS production in immune cells [24].
1.1.2. Mechanism of ROS Production
Mitochondria is the main endogenous source of ROS because of its involvement in
ATP synthesis through oxidative phosphorylation. This process involves the reduction of
molecular oxygen (O2) to water (H2O) in the electron transport chain (ETC) [10]. Superox-
ide (O2) production within mitochondria is a signicant contributor to cellular ROS.
Seven primary sites of superoxide production have been identied in mammalian cells
[6]. Ranked by their highest capacity, these include the ubiquinone binding sites in com-
plex I (site IQ) and complex III (site IIIQo); glycerol 3-phosphate dehydrogenase (GPDH);
the avin in complex I (site IF); electron transferring avoprotein: Q oxidoreductase (ET-
FQOR), involved in fay acid beta-oxidation; and pyruvate and 2-oxoglutarate dehydro-
genases. Most of these complexes release O2 into the mitochondrial matrix, except for
complex III site and GPDH. Within the mitochondrial membrane, three types of superox-
ide dismutase (SOD) exist: copper superoxide dismutase (Cu-SOD), manganese superox-
ide dismutase (Mn-SOD), and zinc superoxide dismutase (Zn-SOD). Mn-SOD catalyses
the conversion of O2 into H2O2. Hydrogen peroxide can then be converted into a hy-
droxyl radical by the enzyme aconitase through the Fenton reaction. Copper and zinc
SODs function primarily in the inter-membrane space to convert superoxide into less ROS
[25] (Figure 2).
Pharmaceuticals 2024, 17, 975 5 of 61
Figure 2. Source, mechanism of production of ROS leading to oxidative stress and its repercussions
along with cellular antioxidant defence. (The illustration was created using BioRender www.bio-
render.com.) [*: Free radical; Nrf2: Nuclear factor erythroid 2-related factor 2; ARE: Antioxidant Re-
sponse Element; Mn: Manganese; Cu: Copper; Fe: Iron; OH: Hydroxyl radical; SOD: Superoxide
Dismutase; NQO1: NAD(P)H quinone dehydrogenase 1; HO-1: Heme Oxygenase-1; GSTs: Gluta-
thione S-transferases; MDA: Malondialdehyde; TBARS: Thiobarbituric Acid Reactive Substances;
ROS: Reactive Oxygen Species; RO: Reactive Oxygen; O
2
: Oxygen; Keap1: Kelch-like ECH-associ-
ated protein 1; sMaf: Small Maf proteins; H
2
O
2
: Hydrogen Peroxide]
An alternative pathway for generating ROS involves the mitochondrial cytochrome
catalytic cycle, which includes enzymes like cytochrome P450. These enzymes process a
broad variety of organic compounds, such as steroids, lipids and, xenobiotics, leading to
the production of dierent reactive byproducts, including hydrogen peroxide and super-
oxide radicals [2]. Additionally, in mammals, various protein complexes, such as nicotin-
amide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R), dihydroorotate de-
hydrogenase (DHODH), succinate dehydrogenase (SDH) from complex II, and monoam-
ine oxidases (MAO), generate ROS [5]. Numerous antioxidant defence systems safeguard
mitochondria from the detrimental eects of ROS. These include endogenous antioxidants
like glutathione peroxidases (GPXs), thioredoxin peroxidases (TRXPs), SODs, peroxire-
doxins (PRDXs), glutathione (GSH), thioredoxin-2 (TRX2), glutaredoxin-2 (GRX2), cyto-
chrome C oxidase (complex IV), and coenzyme Q. Additionally, exogenous antioxidants,
such as ascorbic acid, vitamin E, and phytochemicals (carotenes, phenols, etc.), play cru-
cial roles in this protective mechanism [5] (Figure 2). Excessive production of ROS is asso-
ciated with numerous human disorders. These include myocardial dysfunction, inam-
mation, diabetes, neurodegenerative disease, aging, chronic kidney disease and DNA
damage leading to cancer. ROS can cause damage to genomic and mitochondrial DNA,
leading to mutations in somatic cells, genomic instability, activation of oncogenes, sup-
pression of tumour suppressor genes, and disruptions in various metabolic and signalling
pathways. Compensatory mechanisms may initially be activated but can ultimately con-
tribute to cellular damage and the development of various pathological conditions [2].
Pharmaceuticals 2024, 17, 975 6 of 61
1.1.3. Lifestyle-Associated Oxidative Stress-Induced Disorders
Besides many other external factors, lifestyle factors, such as lack of physical activity,
smoking, poor dietary habits, and excessive alcohol intake, predominately sponsors the
onset of oxidative stress-related disorders (Figure 1). These behaviours result in the over-
production of ROS, overwhelming the body’s antioxidant defences and leading to oxida-
tive stress [26]. In cardiovascular diseases, oxidative stress damages blood vessels and
promotes atherosclerosis. In neurodegenerative disorders, ROS-induced neuronal dam-
age accelerates conditions like Parkinson’s and Alzheimer’s diseases [27]. For metabolic
disorders, oxidative stress disrupts insulin signalling and lipid metabolism, fostering obe-
sity and diabetes [28]. Addressing these lifestyle factors is crucial for preventing and man-
aging these oxidative stress-related diseases.
Cardiovascular Diseases
1. Atherosclerosis
Oxidative stress stages the oxidation process of LDL cholesterol, giving rise to oxi-
dized LDL (oxLDL). Within the arterial wall, macrophages ingest oxLDL, which triggers
foam cell formation and initiates an inammatory reaction. This response triggers the re-
lease of chemokines, and cytokines, which recruit additional immune cells to the site of
inammation. Further, oxidative stress enhances endothelial dysfunction, promoting vas-
oconstriction and platelet aggregation, which contribute to plaque formation and narrow-
ing of arteries [29].
2. Hypertension
Oxidative stress diminishes the availability of nitric oxide (NO), a powerful vasodi-
lator, by scavenging it and promoting its inactivation. This results in endothelial dysfunc-
tion and impaired vasodilation, contributing to increased peripheral vascular resistance
and hypertension. Moreover, ROS can activate the renin–angiotensin–aldosterone system
(RAAS), that leads to vasoconstriction and sodium retention, further exacerbating hyper-
tension [30].
3. Myocardial Infarction
Oxidative stress stages the development and progression of plaque and atheroscle-
rosis instability, thereby increasing the risk of plaque rupture and thrombosis. ROS can
directly damage cardiomyocytes and impair myocardial contractility. Additionally, oxi-
dative stress activates inammatory pathways, promoting myocardial inammation and
brosis, which can lead to cardiac remodelling and dysfunction [31].
Neurodegenerative Diseases
1. Alzheimer’s Disease (AD)
Oxidative stress induces the accumulation of hyperphosphorylated tau proteins and,
β-amyloid (Aβ) peptides, leading to the formation of senile plaques and neurobrillary
tangles, respectively. ROS also disrupts calcium homeostasis, mitochondrial function, and
synaptic transmission, contributing to neuronal dysfunction and cell death. Inammatory
mediators, including cytokines and microglial activation, further exacerbate neuroinam-
mation and neuronal damage in AD [32].
2. Parkinson’s Disease (PD)
Oxidative stress promotes the misfolding and accumulation of α-synuclein protein,
forming Lewy bodies, the pathological hallmark of PD. ROS-induced mitochondrial dys-
function leads to impaired energy production, increased oxidative damage, and neuronal
cell death, particularly in dopaminergic neurons of the substantia nigra. Additionally, ox-
idative stress activates microglia and astrocytes, triggering neuroinammation and neu-
rodegeneration in PD [33].
Pharmaceuticals 2024, 17, 975 7 of 61
Cancer
1. DNA Damage and Mutation
Oxidative stress induces DNA lesions, including strand breaks, base modications
and DNA–protein cross-links. Unrepaired DNA damage can lead to mutations in tumour
suppressor genes and oncogenes, promoting the initiation and progression of tumours.
Additionally, ROS-mediated activation of signalling pathways, such as nuclear factor-
kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), further drives tumour
growth, invasion, and metastasis [34].
2. Tumour Angiogenesis
Oxidative stress promotes the production of angiogenic factors, such as vascular en-
dothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α), which
stimulate the formation of new blood vessels to support tumour growth and metastasis.
ROS-mediated activation of pro-angiogenic pathways and inhibition of anti-angiogenic
factors contribute to tumour angiogenesis and neovascularization [35].
Metabolic Disorders
1. Insulin Resistance
Oxidative stress impairs insulin signalling pathways by promoting serine phosphor-
ylation of insulin receptor substrate 1 (IRS-1), inhibiting its association with the insulin
receptor and downstream activation of phosphatidylinositol 3-kinase (PI3K) and Akt. This
leads to decreased glucose uptake and glycogen synthesis, and increased gluconeogenesis
and lipolysis, leading to insulin resistance and hyperglycaemia in type 2 diabetes [36].
2. Obesity
Oxidative stress promotes adipocyte dysfunction and inammation by activating
pro-inammatory pathways, such as NF-κB and c-Jun N-terminal kinase (JNK). ROS in-
duce the secretion of pro-inammatory cytokines, such as tumour necrosis factor-alpha
(TNF-α) and interleukin-6 (IL-6), from adipose tissue macrophages and adipocytes, caus-
ing a persistent inammatory condition that leads to insulin resistance, dyslipidemia, and
overall metabolic dysfunction [37].
1.2. Antioxidant Defence Systems
Antioxidants play a pivotal part in preventing or delaying the oxidation of target
molecules caused by ROS, which in turn leads to oxidative stress. These compounds act
as defenders by donating electrons to free radicals, neutralizing their harmful eects on
lipids, proteins, DNA, and other biomolecules [38]. They serve as scavengers within bio-
logical systems and are essential defence mechanisms against oxidative stress [4].
Antioxidants can originate from external sources, known as exogenous antioxidants,
which are mainly obtained through food, as well as from internal sources, referred to as
endogenous antioxidants, which are produced within the body [39]. Endogenous antiox-
idants can be enzymatic or non-enzymatic in nature [40]. Enzymatic antioxidants are a
specic category of antioxidant systems present in the human body. These enzymes pos-
sess antioxidant activity and are capable of acquiring dierent valences, allowing them to
transfer electrons to neighbouring free radicals, thereby facilitating their breakdown and
neutralization [41]. Some examples of enzymatic antioxidants include glutathione reduc-
tase (GR), superoxide dismutase, catalase (CAT), and glutathione peroxidase (GPx) [42].
Glutathione reductase aids in the production of reduced glutathione, which helps coun-
teract the oxidative damage caused by ROS [43]. Similarly, SOD plays a crucial role in
neutralizing free radical species by converting superoxide radicals into hydrogen perox-
ide [25,44]. Non-enzymatic endogenous antioxidants are produced within the body
through various metabolic pathways and physiological processes. Therefore, these anti-
oxidants are essential for neutralizing ROS and protecting cells from oxidative damage
Pharmaceuticals 2024, 17, 975 8 of 61
[45]. Some examples of non-enzymatic endogenous antioxidants are glutathione (GSH),
uric acid, bilirubin, melatonin and alpha-lipoic acid (Figure 3).
Figure 3. Endogenous and exogenous sources of antioxidants. (The illustration was created using
BioRender www.biorender.com.)
Exogenous antioxidants refer to the types of antioxidants that originate outside the
body and can be supplied to the body primarily through diet or supplements. These anti-
oxidants encompass various essential nutrients like vitamin C, vitamin E, omega-3 and
omega-6 fay acids [46]. Additionally, they may include certain plant-derived phyto-
chemicals such as polyphenols, including avonoids, as well as trace elements like zinc
and manganese [16]. Synthetic antioxidants like butyl hydroxyanisole may also be classi-
ed as exogenous antioxidants, as they aid in preventing lipid oxidation [40].
Phytochemicals are low molecular weight non-enzymatic compounds produced by
plants and possess numerous medicinal and therapeutic properties [47,48]. Certain phy-
tochemicals possess antioxidant properties and actively engage with oxidative radicals,
neutralizing their harmful eects through various mechanisms. These include scavenging
free radicals by electron transfer and chelating metal ions that trigger ROS production.
Dierent groups of phytochemicals such as avonoids, ascorbic acid and carotenoids, ex-
hibit diverse antioxidant activities against dierent ROS.
Medicinal plants that thrive at high altitudes possess inherent protective processes
against the detrimental results of ROS [49]. They produce enzymatic antioxidants like
SOD and CAT, as well as non-enzymatic antioxidants such as tannins, avonoids, and
ascorbic acid in bulk quantities to mitigate harsh environmental stress factors [50]. How-
ever, due to challenges associated with their isolation and the risk of denaturation, plant-
derived enzymatic antioxidants are typically not employed for therapeutic purposes [51].
Some plants possess genetic capabilities to synthesize phytochemicals that eectively neu-
tralize toxic ROS [47]. Additionally, exposure to various environmental stresses stimulates
the production of phytochemicals, which act as countermeasures against ROS [50]. These
secondary metabolites, derived from essential metabolic pathways, exert protective eects
by preventing the oxidation of plant proteins, lipids, and DNA through passive or active
resistance mechanisms [52].
This study provides a summary of major oxidative stress-induced health disorders
and mechanistic details of phytochemicals being used as antioxidants. This study also
aims to focus upon high altitude medicinal plants as the bulk producers of antioxidants
Pharmaceuticals 2024, 17, 975 9 of 61
and as a potential source of plant-derived therapeutic agents against lifestyle-induced ox-
idative stress-related diseases.
2. Phytochemicals as Antioxidants
Phytochemicals are non-enzymatic compounds, with low molecular weight, that
abundantly exist in plants [53]. These biologically active substances have gained recogni-
tion for their medicinal and therapeutic properties. The World Health Organization
(WHO) has acknowledged the use of these plant-derived compounds in the treatment of
various human diseases, highlighting their signicance in healthcare [48]. Numerous phy-
tochemicals possess antioxidant properties and actively engage with oxidative radicals
such as ROS, neutralizing their harmful eects by scavenging free radicals by electron
transfer and chelating metal ions that trigger ROS production [47]. Many phytochemicals,
such as avonoids, ascorbic acid and carotenoids, show diverse mechanisms by which to
counter the eects of ROS and to therefore mitigate OS [13]. These phytochemicals oer
immense potential for inhibiting and treating oxidative stress, contributing to the overall
wellbeing and health of individuals.
2.1. Carotenoids
Carotenoids are lipophilic pigments found in plant plastids. They are responsible for
the vibrant colours seen in various fruits and vegetables [54]. Carotenes, having a beta-
ionone ring, also serve as a crucial source for the synthesis of vitamin A [55]. Almost 1200
natural carotenoids have been identied and characterized so far, along with their struc-
tures and biological sources (hp://carotenoiddb.jp; accessed on 7 June 2024), with beta-
carotene being the most extensively studied among them [56]. The chemical structure of
carotenoids consists of 40 carbon atoms arranged in a specic paern of double bonds,
which contributes to their antioxidant properties [57].
Carotenoids can be broadly classied into two categories: carotenes, which contain
carbon and hydrogen atoms, and xanthophylls, which contain at least one oxygen atom
[58]. Carotenes include alpha-carotene, beta-carotene, lutein, and lycopene, while xantho-
phylls encompass canthaxanthin, antheraxanthin, zeaxanthin, and others [59].
The antioxidant action of carotenoids primarily involves their ability to react with
peroxyl radicals and singlet oxygen species, thereby preventing oxidative damage to lipid
membranes [60]. Singlet oxygen species transfer their energy to nearby carotenoid mole-
cules, allowing the oxygen molecule to return to its non-toxic state. The excited carotenoid
molecule then dissipates its energy to the surrounding solvent, returning to its ground
state and enabling it to react with other free radicals [61].
Carotenoids have demonstrated eectiveness against various diseases associated
with oxidative stress, including Alzheimer’s disease [62]. Certain carotenoids, such as
beta-carotene, have been found to bind eciently to receptors associated with Alzheimer’s
disease, such as histone and p53 receptors [63]. Carotenoids also play a protective role
against photo-oxidative damage to the skin caused by UV radiation. By leveraging their
antioxidant properties, carotenoids, like lycopene and beta-carotene, can help suppress
and inhibit skin diseases, mitigating the risk of dermatoses and cutaneous malignancy
[60]. Additionally, carotenoids show potential in inhibiting the progression of health ab-
normalities such as rheumatoid arthritis and have cardiovascular protective eects [64].
Lutein and zeaxanthin, key carotenoids concentrated in the macula of the eye, play critical
roles in eye health by acting as antioxidants and blue light lters. These compounds pro-
tect retinal cells by neutralizing ROS and reducing oxidative stress, which are known con-
tributors to age-related macular degeneration (AMD). Mechanistically, lutein and zeaxan-
thin absorb blue light wavelengths, particularly those most damaging to the retina (400–
500 nm), thereby preventing phototoxicity and subsequent cellular damage. Their pres-
ence in the macular pigment also enhances visual performance by improving contrast sen-
sitivity and by reducing glare. Scientic evidence supports their eectiveness in
Pharmaceuticals 2024, 17, 975 10 of 61
maintaining retinal integrity and potentially slowing the progression of AMD, underscor-
ing their importance in preserving long-term eye function and vision [65].
Overall, carotenoids serve as valuable antioxidants, contributing to the prevention
and management of various diseases linked to oxidative stress.
2.2. Ascorbic Acid (AsA)
Ascorbic acid (AsA), popularly known as vitamin C, plays an important role in the
non-enzymatic defence mechanisms against ROS [66]. This class of antioxidant com-
pounds consists of low molecular weight substances that act as reducing agents [67].
Plants produce ascorbic acid through the Smirno-Wheeler pathway, involving the con-
version of mannose and lactose in their D and L forms. Additionally, the Wolucka–Van
pathway serves as an alternative route for synthesizing ascorbic acid in plants. Mitochon-
dria, particularly in the photosynthetic tissues of plants, serve as key sites for the produc-
tion of ascorbic acid, which exists in two forms: semi-dehydroascorbyl radical and dehy-
droascorbate [68].
Ascorbic acid (vitamin C) plays a pivotal role in the ascorbate–glutathione cycle in
plants, serving as a primary antioxidant by scavenging ROS such as hydrogen peroxide
[69]. It undergoes oxidation to monodehydroascorbate (MDHA) and dehydroascorbate
(DHA) during ROS detoxication. DHA is then reduced back to ascorbic acid by dehy-
droascorbate reductase (DHAR), with the assistance of glutathione, thereby replenishing
the cellular pool of active ascorbate. Additionally, ascorbic acid regenerates oxidized vit-
amin E (tocopherol and tocotrienol) by reducing tocopheroxyl radicals (vitamin E), pro-
longing vitamin E’s antioxidant function in protecting cellular membranes from oxidative
damage. This cycle ensures eective antioxidant defence and redox homeostasis, essential
for plant resilience against environmental stressors [70].
Within plants, free radicals are generated as a result of metabolic activities in the
presence of oxygen or exposure to UV radiation [19]. Ascorbic acid acts as an antioxidant
by scavenging ROS, including hydrogen peroxide, superoxide anion, and hydroxyl radi-
cal, forming monodehydroascorbate. By doing so, it protects essential biomolecules such
as unsaturated fay acids, proteins, and DNA from damage [71]. The antioxidant activity
of ascorbic acid contributes to the prevention of various cardiovascular disorders and gas-
tric problems. It enhances the concentration of nitric oxide in the vascular endothelium,
thus aiding in the prevention of hypertension. Moreover, ascorbic acid promotes the ab-
sorption of iron in the small intestine, oering potential inhibition of gastric issues associ-
ated with Helicobacter pylori infection [72].
Overall, ascorbic acid serves as a vital antioxidant in plants, safeguarding against ox-
idative damage and contributing to the prevention of cardiovascular and gastric ailments
in humans [73].
2.3. Tocopherols and Tocotrienols
Tocopherols and tocotrienols are isoforms of vitamin E, consisting of four types: al-
pha, beta, gamma, and delta [74]. These phytochemicals possess a hydrophobic nature
and contain a prenyl group [75]. They exhibit signicant antioxidant activity and play a
crucial role in preventing various cardiovascular diseases, neurodegenerative diseases,
like Alzheimer’s, and aging [76]. The antioxidant characteristics of tocopherols and to-
cotrienols are aributed to the occurrence of a chromanol ring in their structure. This ring
contains a hydroxyl group that combats free radicals by donating hydrogen atoms [77].
Among the various forms of vitamin E, both alpha tocopherols and tocotrienols are
particularly active in preventing lipid peroxidation caused by free radicals, thereby pro-
tecting cell membranes from damage [78]. The alpha forms of tocopherols and tocotrienols
work by inhibiting the generation of free radicals, while the gamma forms are eective in
capturing and neutralizing the impacts of ROS. Collectively, these vitamin E isoforms con-
tribute to the body’s defence against oxidative stress and its detrimental eects [77].
Pharmaceuticals 2024, 17, 975 11 of 61
2.4. Polyphenols
Polyphenols are a prominent class of phytochemicals, which play a major role as an-
tioxidants [79]. They are synthesized by plants as a result of shikimic acid pathway from
amino acids phenylalanine or tyrosine [80]. Polyphenols exhibit varying molecular
weights depending upon the degree of polymerization (small molecules such as quercetin
have a molecular weight of 302.24 Da, while, as tannins, they can reach several thousand
kDa due to their polymeric nature) and exert antioxidant eects by acting as reducing
agents [81]. They donate hydrogen atoms to the ROS produced, thus, scavenging the free
radical species [82]. Important polyphenols present in the plants, which perform antioxi-
dant activity, are avonoids, phenolic acids and lignans [83–85].
Flavonoids are a major group of plant phenolic compounds, characterized by the
presence of a avan nucleus in their chemical structure [86]. They have 2 benzene rings
denoted by ring A and ring B connected to a third pyran ring that is ring C [87]. These
phytochemicals play a major role in preventing the peroxidation of lipids by using pro-
cesses such as electron transfer or chelation of metal ions [88]. The B ring that is present
in the molecular structure of avonoids engage a major role in the scavenging of free rad-
icals. The B ring contains hydroxyl groups, which stabilize the free radical species, such
as hydroxyl or peroxynitrite, by transferring either electrons or hydrogen atoms to them
[89]. Flavonoids further prevent oxidative stress by chelating metal ions such as copper or
ferric ions which stimulate the production of ROS in the body [89]. Dierent types of a-
vonoids exhibiting antioxidant activity include avonols, avones, isoavone, and antho-
cyanidin and are found mainly in citrus fruits, tea, onion, berries, broccoli and soybean
[86].
Stilbenes are a major sub-class of polyphenols present in the plants which also show
antioxidant activity [90]. Stilbenes such as resveratrol help in preventing the oxidative
stress to proteins and lipids and it also increases the activity of antioxidant enzymes such
as GPx and SOD [91]. Phenolic acids such as salicylic acid, vanillic acid, caeic acid also
show signicant antioxidant activity [85].
2.5. Polysterols
Polysterols are a subclass of sterols, which are a type of lipid characterized by a spe-
cic chemical structure containing a steroid nucleus [92]. These compounds naturally oc-
cur in plants and have gained recognition for their potential health benets, particularly
due to their antioxidant properties [93]. Polysterols possess the ability to scavenge free
radicals and reduce oxidative stress within the body, thereby contributing to overall
health and wellbeing [82]. One example of a polysterol compound with potent antioxidant
activity is beta-sitosterol, which has been studied for its potential role in promoting cardi-
ovascular health and supporting the immune system [94]. Another example is campes-
terol, which also exhibits antioxidant eects and may contribute to the prevention of
chronic diseases associated with oxidative damage [95].
A comprehensive list of phytochemical classes and their representative antioxidant
molecules, along with their high-altitude plant sources and their associated health benets
is shown in Table 1.
Pharmaceuticals 2024, 17, 975 12 of 61
Tab l e 1. List of phytochemical classes, along with representative molecules within each class having antioxidant property, their sources from high-altitude plants
and their therapeutic properties against various oxidative stress associated diseases.
Phytochemical
Class Sub-Class Representative Compounds
Chemical Formu-
lae PubChem ID High Altitude Plant
Source
Preventive Activity
Against Reference
Carotenoids
Carotenes
Alpha-carotene C40H56 6419725
Gentiana algida Pall.,
Rhododendron ferrugineum
L.,
Ranunculus glacialis L., Sax-
ifraga oppositifolia L.,
Primula hirsuta All.
Cardiovascular diseases,
type 2 diabetes, cancer,
skin and eye diseases, age-
ing, inflammation
[96,97]
Beta-carotene C40H56 5280489
Lycopene C40H56 446925
Phytoene C40H64 5280784
Phytofluene C40H62 6436722
Xanthophylls
Lutein C40H56O2 5281243
Canthaxanthin C40H52O2 5281227
Antheraxanthin C40H56O3 5281223
Zeaxanthin C40H56O2 5280899
β-cryptoxanthin C40H56O 5281235
Astaxanthin C40H52O4 5281224
Fucoxanthin C42H58O6 5281239
Rubixanthin C40H56O 5281252
Violaxanthin C40H56O4 448438
Vitamins
Ascorbic Acid C6H8O6 54670067
Vaccinium macrocarpon Ai-
ton. (Mountain cranberry),
Sorbus aucuparia Poir., Sor-
bus scopulina Greene, Juni-
p
erus recurva Buch. -Ham.
ex D. Don.
Age-related muscular de-
generation, cataract, cardi-
ovascular diseases, immu-
nosuppression
[98,99]
Tocopherols
Alpha-tocopherol C29H50O2 14985
Cardiovascular diseases,
cancer, obesity, diabetes
Beta-tocopherol C28H48O2 6857447
Gama-tocopherol C28H48O2 92729
Delta-tocopherol C27H46O2 92094
Tocotrienols Alpha-tocotrienol C29H44O2 5282347
Polyphenols Flavonoids
Quercetin C15H10O7 5280343
Rhodiola rosea L.,
Vaccinium vitis-idaea L.,
Dipsacus fullonum L.,
Dipsacus sylvestris Huds.,
Obesity, neurodegenera-
tive diseases, type 2 diabe-
tes, and cardiovascular dis-
eases
[100,101]
Kaempferol C15H10O6 5280863
Fisetin C15H10O6 5281614
Isorhamnetin C16H12O7 5281654
Pharmaceuticals 2024, 17, 975 13 of 61
Myricetin C15H10O8 5281672
J
uniperus recurva Buch. -
Ham. ex D. Don.
Luteolin C15H10O6 5280445
Apigenin C15H10O5 5280443
Sinensetin C20H20O7 145659
Isosinensetin C20H20O7 632135
Nobiletin C21H22O8 72344
Tangeretin C20H20O7 68077
Galangin C15H10O5 5281616
Chrysin C15H10O4 5281607
Baicalin C21H18O11 64982
Catechin C15H14O6 9064
Epicatechin C15H14O6 72276
Epicatechin gallate C22H18O10 107905
Gallocatechin C15H14O7 65084
Epigallocatechin C15H14O7 72277
Epigallocatechin gallate C22H18O11 65064
Daidzein C15H10O4 5281708
Genistein C15H10O5 5280961
Daidzin C21H20O9 107971
Naringenin C15H12O5 439246
Naringin C27H32O14 442428
Hesperidin C28H34O15 10621
Hesperetin C16H14O6 72281
Eriodicytol C15H12O6 11095
Pelargonidin C15H11O5 440832
Cyanidin C15H11O6 128861
Delphinidin C15H11ClO7 68245
Peonidin C16H13O6 441773
Petunidin C16H13O7 441774
Malvidin C17H15O7 159287
Stilbenes Resveratrol C14H12O3 445154
Pinosylvin C14H12O2 5280457
Pharmaceuticals 2024, 17, 975 14 of 61
Piceatannol C14H12O4 667639
Pterostilbene C16H16O3 5281727
Rhapontigenin C15H14O4 5320954
Isorhapontigenin C15H14O4 5318650
Phenolic acids
Salicylic acid C7H6O3 338
Hydroxybenzoic acid C7H6O3 135
Protocatechuic acid C7H6O4 72
Gallic acid C7H6O5 370
Syringic acid C9H10O5 10742
Vanillic acid C8H8O4 8468
Gentisic acid C7H6O4 3469
Coumaric acid C9H6O2 323
Phytosterols
Campesterol C28H48O 173183
Rhodiola spp.,
Dipsacus spp.,
J
uniperus spp.
Elevated cholesterol level,
inflammation, oxidative
stress, immunosuppres-
sion.
[102,103]
Sitosterol C29H50O 222284
Stigmasterol C29H48O 5280794
Campestanol C28H50O 119394
Stigmastanol C29H52O 241572
Pharmaceuticals 2024, 17, 975 15 of 61
3. Role of Phytochemical Antioxidants in Mitigating Major Lifestyle-Associated
Oxidative Stress-Induced Health Disorders
3.1. Cardiovascular Diseases
Cardiovascular disease (CVD), the leading cause of global mortality, is intricately
linked to oxidative damage, with ROS orchestrating various deleterious eects [104]. As
discussed in the section regarding cardiovascular diseases, elevated ROS levels diminish
nitric oxide availability, inducing vasoconstriction and hypertension, while also disrupt-
ing myocardial calcium handling, leading to arrhythmias and cardiac remodelling via hy-
pertrophic signalling and apoptosis [105,106] (Figure 4). Chronic oxidative stress in heart
failure triggers cardio myocyte apoptosis, brosis, and mitochondrial dysfunction, per-
petuating myocardial damage and dysfunction through pro-inammatory cytokine acti-
vation, brotic growth factor release, and impaired calcium homeostasis. Atrial brillation
(AF) is the most common cardiac arrhythmia, fuelled by oxidative stress-induced atrial
remodelling and inammation, promoting structural changes and brosis, which create a
substrate for atrial brillation [107].
Figure 4. Oxidative stress-induced cardiovascular diseases and modulation via phytochemical an-
tioxidants (the illustration was created using BioRender at www.biorender.com). [MAPK: mitogen-
activated protein kinase; ROS: reactive oxygen species; JNK: c-Jun N-terminal kinase; p38: p38 mi-
togen-activated protein kinase; Akt: protein kinase B (PKB); NF-κB: nuclear factor kappa-light-
chain-enhancer of activated B cells; AP-1: activator protein 1; oxLDL: oxidized low-density lipopro-
tein; TBF-α: tumour necrosis factor alpha; PGF2-α: prostaglandin F2 alpha; IL-6: interleukin 6; MDA:
malondialdehyde; PARP-1: poly (ADP-ribose) polymerase 1].
In the relentless pursuit to mitigate oxidative damage in cardiovascular tissue, there
has arisen a growing interest in the utilization of medicinal plants as natural antioxidants
[108]. The bioactive components derived from these botanical sources, encompassing pol-
yphenols and polysaccharides commonly found in traditional herbal medicine, hold
promise in combaing oxidative stress and its associated cardiovascular disorders [109].
Table 2 delineates the myriad plant bioactive compounds targeting oxidative stress path-
ways and related cardiovascular diseases. As free radicals instigate a chain reaction of
oxidative damage within cardiovascular tissues [19], the active constituents found in
Pharmaceuticals 2024, 17, 975 16 of 61
medicinal plants serve as potent scavengers, blocking this detrimental process through
both direct and indirect mechanisms [110].
One important example is curcumin, which is derived from the turmeric plant and is
renowned for its anti-inammatory and antioxidant properties. Curcumin exerts antioxi-
dant eects by directly scavenging free radicals and upregulating endogenous antioxidant
enzymes [111]. It also inhibits inammatory pathways, such as NF-κB pathway, thereby
mitigating inammation and oxidative stress in cardiovascular tissues [111]. Epigallocat-
echin gallate (EGCG), found in tea, is renowned for its potent antioxidant and cardiopro-
tective eects. EGCG modulates signalling pathways involved in oxidative stress and in-
ammation, such as the MAPK and PI3K/Akt pathways, thereby protecting against car-
diovascular diseases [112]. Quercetin, abundant in various fruits, vegetables, and teas,
functions as a free radical scavenger, inhibits lipid peroxidation, and enhances the activity
of antioxidant enzymes like SOD and CAT. Furthermore, it modulates inammatory path-
ways, including NF-κB and COX, thereby mitigating oxidative stress and inammation in
cardiovascular tissues [113].
Given their favourable safety prole and multifaceted antioxidative properties, the
exploration and integration of plant-derived phytochemical antioxidants into clinical
practice hold tremendous potential for ameliorating oxidative stress in the management
of cardiovascular disorders [114].
Tab l e 2. Phytochemicals, along with their high-altitude plant sources, are reported to mitigate oxi-
dative stress-induced cardiovascular diseases [108].
Phytochemical Plant Chemical Structure Treatment Mechanism of Action Reference
Allicin
A
llium humile
Kunth Hypertension Inhibits the formation of
LPO and MDA
[108,115]
Berberine Berberis aristata
DC.
Hypertension Reduces O
2
and H
2
O
2
lev-
els
[116]
Delphinidin-3-
glucoside
Vaccinium myr-
tillus L.
Coronary heart disease,
ischemia-reperfusion
injury
Inhibits caspase-3, bax,
and ap-JNK expression
[117,118]
Gastrodin Gastrodia elata
Blume.
Heart failure Regulates AMPK, Akt,
mTOR, and Bcl-2
[119]
Gypenoside
Gynostemma
p
entaphyllum
Thunb.
Acute myocardial in-
farction
Regulates the
PI3K/Akt/mTOR signal-
ling pathway
[120,121]
Matrine Sophora
f
lavescens Aiton.
Arrhythmia Increases production of
SOD
[122–124]
Pharmaceuticals 2024, 17, 975 17 of 61
Orientin
illettia nitida
Benth.
Coronary heart disease,
atherosclerosis Reduces ROS
[125–127]
Paeonol
Paeonia
suffruticosa An-
drews
Arrhythmia, coronary
heart disease
Inhibits free radical reac-
tion
[122,128]
Polysaccharides
A
stragalus pro-
p
inquus
Schischk.
Coronary heart disease,
acute myocardial in-
farction
Inhibits the expression of
NOX
[129]
Quercetin Dendrobium no-
bile Lindl.
Acute myocardial in-
farction, ischemia
Reperfusion
Reduce ROS
[130]
Tanshinone II-A
Salvia
miltiorrhiza
Bunge.
Coronary heart disease,
acute myocardial in-
farction
Regulates Nrf2/ARE/HO-
1 and TGF-beta1/signal
transduction
[131,132]
Tetramethylpy-
razine
Ligusticum
chuanxiong
Heart failure,
coronary heart disease
Increases the activity of
SOD, CAT and GSH-Px
[133,134]
[LPO: lipid peroxidation; MDA: malondialdehyde; O
2
: oxygen; H
2
O
2
: hydrogen peroxide; bax: Bcl-
2-associated X protein; ap-JNK: activator protein-1 c-Jun N-terminal kinase; AMPK: AMP-activated
protein kinase; Akt: protein kinase B; mTOR: mechanistic target of rapamycin; Bcl-2: B-cell lym-
phoma 2; Bad: Bcl-2-associated death promoter; PI3K: phosphoinositide 3-kinase; SOD: superoxide
dismutase; ROS: reactive oxygen species; NOX: NADPH oxidase; Nrf2: nuclear factor erythroid 2-
related factor 2; ARE: antioxidant response element; HO-1: heme oxygenase 1; TGF-beta1: trans-
forming growth factor beta 1; CAT: catalase; GSH-Px: glutathione peroxidase].
3.2. Neurodegenerative Disorders
Neurodegenerative disorders involve the loss of functional capacity and eventual
dysfunction or death of neuronal cells in the brain [135]. Diseases like Parkinson’s and
Alzheimer’s are characterized by neurodegeneration, and oxidative stress plays a major
role in their pathogenesis [136]. The high level of ROS generation and low antioxidant
levels in brain cells make them susceptible to oxidative damage, which alters the function
of lipids, DNA and proteins, contributing to neurodegeneration (Figure 5) [137,138].
In Alzheimer’s disease, ROS stimulate the cleavage of amyloid precursor protein
(APP), enhancing the production of Aβ peptides which aggregates to form toxic Aβ
plaques. [139]. During oxidative stress, ROS induces activation of kinases and inhibition
of phosphatases leading dysregulate tau phosphorylation dynamics which destabilizes
microtubules and leads to their aggregation into neurobrillary tangles [140]. ROS over-
whelm the endogenous antioxidant defence system, which amplies oxidative damage
and potentiates neuronal vulnerability. The activation of microglia initiates an inamma-
tory cascade, which starts a pro-inammatory cytokine release and causes exacerbate neu-
roinammation, contributing to neuronal dysfunction and degeneration [32]. Sequential
lipid peroxidation generates breakdown products like 4-hydroxy-2,3-nonenal (HNE), el-
evated levels of which, in brain tissues, is indicative of Alzheimer’s disease [141,142].
Pharmaceuticals 2024, 17, 975 18 of 61
Figure 5. Oxidative stress-induced neurodegenerative disease pathology and modulation by anti-
oxidant phytochemicals. (the illustration was created using BioRender at www.biorender.com).
[TNFα: tumour necrosis factor alpha, iNOS: inducible nitric oxide synthase, IL-1β: interleukin-1
beta, IL-6: interleukin-6, IL-12: interleukin-12, IL-23: interleukin-23, NMDA: N-methyl-D-aspartate,
p65: RelA (a subunit of the NF-κB transcription factor), p53: tumour protein p53].
Parkinson’s disease, the second most common neurodegenerative disorder in elderly
individuals, on the other hand, primarily aects the motor functions of the body, leading
to noticeable movement disorders. OS promotes the misfolding of α-synuclein protein,
which aggregates to form Lewy bodies. PD is linked with increased levels of HNE in brain
tissues. Increased levels of 8-hydroxyguanine and 8-hydroxy-2-deoxyguanosine, resulting
from oxidative damage to DNA base pairs, are also indicative of Parkinson’s disease
[33,139].
Several potent phytochemicals have shown potential in combating neurodegenera-
tive diseases, oering avenues for novel therapeutic interventions [143] (Table 3). For Alz-
heimer’s disease, compounds like curcumin, found in turmeric, exhibit anti-inammatory
and antioxidant properties, inhibiting the formation of beta-amyloid plaques and reduc-
ing neuroinammation [144].
Resveratrol, abundant in red grapes and berries, demonstrates neuroprotective ef-
fects by modulating signalling pathways involved in neuronal survival and reducing ox-
idative stress [145]. Similarly, avonoids, such as EGCG found in green tea, and quercetin,
which is abundant in onions and apples, possess neuroprotective properties by scaveng-
ing free radicals and inhibiting neuroinammation [146].
In Parkinson’s disease, phytochemicals, like polyphenols, particularly found in ber-
ries, cocoa, and grapes, exhibit neuroprotective eects by enhancing mitochondrial func-
tion, reducing oxidative stress, and inhibiting alpha-synuclein aggregation [147]. Addi-
tionally, compounds, like sulforaphane, present in cruciferous vegetables, activate cellular
defence mechanisms against oxidative stress and inammation, potentially mitigating
neuronal damage in Parkinson’s disease [148].
Phytochemical compounds have also been found to decrease the risk of 4-hydroxy-
2,3-nonenal (HNE) aggregation, a reactive aldehyde produced during oxidative stress and
implicated in various neurodegenerative diseases. For instance, polyphenolic compounds,
such as curcumin, found in turmeric, and resveratrol, abundant in red grapes and berries,
Pharmaceuticals 2024, 17, 975 19 of 61
have been shown to inhibit HNE-induced protein aggregation and lipid peroxidation
[149]. Additionally, avonoids, like EGCG from tea and quercetin from onions and apples,
have demonstrated protective eects against HNE-induced toxicity by modulating cellu-
lar signalling pathways and enhancing antioxidant defences. These compounds possess
strong antioxidant properties, scavenging free radicals and mitigating oxidative damage
and thereby reducing the formation of HNE adducts and subsequent aggregation [150].
Tab le 3. Phytochemicals, along with their high-altitude plant sources, reported to mitigate oxidative
stress-induced neurodegenerative disorders [151].
Phytochemicals Plant Structure Mode of Action Refer-
ence
1,8-Cineole
Salvia officinalis
L.
Selectively suppresses NF- κB and activation of
pro-inflammatory gene expression and cytokine
production, enhances neurogenesis
[152]
Asiatic acid Centella asiatica
(L.) urban
Inhibits pro-inflammatory cytokines and inflam-
matory pathway and promotes neurogenesis
[153,154]
Asiaticoside Centella asiatica
(L.) urban
Inhibits pro-inflammatory cytokines
[155,156]
Bacoside A Bacopa monniera
(L.) Pennel
Reduces oxidative stress-induced neuronal dam-
age, enhances cholinergic neurotransmission, im-
proves cognitive function, inhibits pro-inflamma-
tory cytokines, inhibits amyloid-beta (Aβ) peptide
aggregation, and promotes synaptic remodelling
[157,158]
Baohuoside I Centella asiatica
(L.) urban
Promotes the antioxidant activity of essential en-
zyme such as SOD, CAT and GSH-Px.
[159]
Betulic acid Centella asiatica
(L.) urban
Inhibiting pro-inflammatory cytokines and signal-
ling pathways and promotes neurotrophic factor
BDNF expression contributing to overall brain
health
[160]
Borneol
Salvia officinalis
L.
Exhibits antioxidant properties and suppresses
pro-inflammatory cytokine production
[161]
Pharmaceuticals 2024, 17, 975 20 of 61
Brahmic acid Centella asiatica
(L.) urban
Promotes neurogenesis; modulates neurotransmit-
ter levels, including acetylcholine, serotonin, and
dopamine; and reduces the production of pro-in-
flammatory cytokines
[155]
Camphor
Salvia officinalis
L.
Exhibits antioxidant properties and suppresses
NF-κB activation and pro-inflammatory cytokine
production
[162]
Caryophyllene
Salvia officinalis
L.
Demonstrates anti-inflammatory activity, modu-
lates neurotransmitter systems and enhances neu-
rogenesis
[163]
Herpestine Bacopa monniera
(L.) Pennel
Enhances neuronal synthesis, increases kinase ac-
tivity, and restores synaptic activity and nerve im-
pulse transmission
[164]
Linalool
Salvia officinalis
L.
Scavenges free radicals, suppresses NF-κB activa-
tion and pro-inflammatory cytokine production,
modulates neurotransmitter systems and enhances
neurogenesis
[152]
Luteolin
Picrorhiza scroph-
ulariiflora Pen-
nell.
Reduces neuroinflammation, promotes expression
of brain-derived neurotrophic factor (BNDF) and
modulates neurotransmitter systems, such as do-
pamine and serotonin
[165]
Madecassic acid Centella asiatica
(L.) urban
Inhibits pro-inflammatory cytokines and signal-
ling pathways and promotes neurotrophic factors’
BDNF expression
[160,166]
Picroside II
Picrorhiza scroph-
ulariiflora Pen-
nell.
Inhibits neuronal apoptosis
[167]
[NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; SOD: superoxide dismutase;
CAT: catalase; GSH-Px: glutathione peroxidase; BDNF: brain-derived neurotrophic factor].
3.3. Metabolic Disorders: Diabetes and Obesity
Metabolic disorders, including obesity and diabetes, are closely linked with the gen-
eration of ROS in the body [8]. Studies have shown a positive correlation between de-
creased levels of high-density lipoproteins (HDLs) and increased levels of low-density
lipoproteins (LDLs) with oxidative stress. Lower levels of HDLs result in dysfunctional
Pharmaceuticals 2024, 17, 975 21 of 61
antioxidant defence mechanisms, leading to elevated oxidative stress (Figure 6) [168,169].
OS is also implicated in obesity as excessive ROS production acts as a trigger for abnormal
amplication and enlargement of pre-adipocytes and adipocytes. This abnormal adipose
cell growth leads to adipogenesis, a fundamental factor in obesity [37]. Improper dietary
paerns, including high carbohydrate and high-fat diets, can increase oxidative stress in
the body, contributing to obesity [170].
Figure 6. Antioxidant phytochemicals and modulation of oxidative stress-induced metabolic disor-
ders (obesity and diabetes) (the illustration was created using BioRender at www.biorender.com).
[AMPK: AMP-activated protein kinase; SIRT1: sirtuin 1; Nrf2: nuclear factor erythroid 2-related fac-
tor; 2NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK: mitogen-acti-
vated protein kinase; IRS: insulin receptor substrate; UPR: unfolded protein response; PKC: protein
kinase C].
Diabetes, on the other hand, characterized by high glucose levels and decreased in-
sulin sensitivity, is another metabolic disorder linked to oxidative stress [36]. Mitochon-
drial dysfunction resulting from oxidative stress contributes signicantly to insulin re-
sistance, impairing insulin responses and leading to abnormal glucose levels [171]. Oxi-
dative radicals also promote apoptosis in pancreatic beta-cells, modifying cell cycle regu-
lators and contributing to the diabetes development [12]. In type 2 diabetes, islet inam-
mation causing pancreatic β cell dysfunction underscores inammation’s signicance
[172]. Concurrently, oxidative stress in people with diabetes and obesity plays a major role
in causing cardiovascular associated complications as well [173].
Plant products have been gaining aention for the potential mitigation of metabolic
disorders by modulating proinammatory cytokines and ROS. Methanolic extracts from
Capparis spinosa L. leaves show in vitro anti-inammatory eects, inhibiting membrane
destabilization, and exerting anti-inammatory eects in murine models [174]. Plant sec-
ondary metabolites like carotenoids and alkaloids induce an anti-inammatory response
by suppressing IL-17 and inducing IL-4 gene expression [175]. With concerns about syn-
thetic antioxidants’ long-term safety, there is rising demand for natural antioxidants to
mitigate oxidative stress-related diseases [176]. Recognized as rich in essential antioxi-
dants, plants are increasingly viewed as functional ingredients promoting health. Plant-
derived products, including phytochemicals, emerge as a valuable natural source of anti-
inammatory agents with potential therapeutic implications for metabolic disorders
Pharmaceuticals 2024, 17, 975 22 of 61
(Table 4). For instance, curcumin, resveratrol, quercetin, epigallocatechin gallate, berber-
ine, and alpha-lipoic acid have garnered signicant aention for their potential in mitigat-
ing oxidative stress-related metabolic dysregulations [177]. Curcumin exerts its eects
through NF-κB pathway inhibition, activation of the Nrf2 pathway, and modulation of
insulin signalling, thereby oering therapeutic benets in diabetes, obesity, and cardio-
vascular diseases [178]. Similarly, resveratrol activates sirtuin 1 (SIRT1), possesses antiox-
idant activity, and activates AMP-activated protein kinase (AMPK), contributing to its me-
dicinal properties against metabolic disorders [179]. Quercetin scavenges free radicals,
modulates inammatory pathways, and enhances mitochondrial function, making it ben-
ecial for metabolic health. EGCG exhibits antioxidant activity, regulates insulin signal-
ling, and modulates adipocyte function, thereby improving metabolic parameters in var-
ious disorders [180]. Berberine activates AMPK, modulates gut microbiota, and inhibits
inammatory pathways, oering therapeutic potential in metabolic disorders [181]. Al-
pha-lipoic acid exerts antioxidant eects, regulates mitochondrial function, and modu-
lates insulin signalling, contributing to its ecacy against metabolic dysregulations [182].
Overall, understanding the mechanistic insights into these plant bioactive compounds is
crucial for developing targeted strategies to combat oxidative stress-related metabolic dis-
orders and improve public health outcomes.
Tab l e 4. Phytochemicals, along with their high-altitude plant sources, as treatment options against
metabolic disorders [183].
Phytochemical Plant Chemical Structure Mode of Action Reference
Anthocyanin
A
ristotelia
chilensis (Mo-
lina) Stuntz
Inhibits synthesis of the pro-inflammatory
cytokines, TNF-α and IL-6, further reducing
inflammation associated with diabetes and
obesity, and modulates the NF-κB signalling
pathway, leading to decreased expression of
inflammatory mediators
[184]
Ascorbic acid
Rosehips pro-
duced by Rosa
p
endulina L.
Enhances insulin sensitivity, facilitating the
uptake of glucose into cells; reduces risk of
hyperglycaemia; and modulates lipid metab-
olism by reducing lipid peroxidation and in-
hibiting fatty acid synthesis, which prevents
dyslipidemia
[185,186]
Caffeine Ilex guayusa
Loes.
Stimulates lipolysis and thermogenesis, caf-
feine may help reduce circulating levels of
LDL cholesterol and triglycerides, thereby
preventing the development of atheroscle-
rotic plaques
[187]
Niazirin
M
oringa oleifera
Lam.
Helps regulate lipid metabolism, reducing
the level of triglyceride and LDL cholesterol
while increasing the production of HDL cho-
lesterol; modulates lipid metabolism and
helps prevent the formation of atherosclerotic
plaques; and maintains vascular health in di-
abetic individuals.
[188,189]
Proanthocyanidins Vitis vinifera L.
Promotes endothelial NO production, lead-
ing to vasodilation and improved blood flow;
inhibits endothelial cell apoptosis and pre-
serve vascular homeostasis; prevents for-
mation of atherosclerotic plaques; and main-
tains cardiovascular health
[190]
Pharmaceuticals 2024, 17, 975 23 of 61
Phenolic acids (Pro-
tocatechuic acid)
and saponins
A
ndrosace um-
bellata (Lour.)
Merr.
Promotes the production of serum antioxi-
dant enzymes, upregulates the expression of
hepatic antioxidant genes, and inhibits the
NF-κB signalling pathway, leading to the de-
creased expression of inflammatory media-
tors
[191,192]
[TNF-α: tumour necrosis factor alpha; IL-6: interleukin 6; NF-κB: nuclear factor kappa-light-chain-
enhancer of activated B cells; NO: nitric oxide; LDL: low-density lipoprotein; HDL: high-density
lipoprotein].
4. High-Altitude Medicinal Plants: Bulk Producers of Antioxidants
Plants that thrive in high-altitude environments face numerous challenges due to ex-
treme environmental conditions, such as low carbon dioxide and oxygen levels, intense
mutagenic radiation, and drastic temperature uctuations. These factors create a harsh
survival environment for plants. ROS production is heightened in these plants, leading to
cellular damage and impairing photosynthesis. In response to these conditions, plants
have developed adaptive mechanisms to counteract the negative eects of oxidative stress
caused by ROS [193].
High-altitude plants have evolved the ability to synthesize secondary metabolites in
large quantities. These metabolites, including avonoids, phenols, tannins, and other
compounds, serve as antioxidants within the plants [47]. By accumulating these secondary
metabolites, plants can adapt to the extreme environmental conditions and mitigate the
harmful eects of ROS-induced oxidative damage. This defence mechanism helps these
plants maintain their cellular integrity and sustain their growth and survival in such harsh
environments [194].
4.1. Environmental Factors Inuencing Antioxidant Production in High-Altitude Medicinal
Plants
High-altitude regions, characterized by unique environmental conditions, present
challenges as well as opportunities for plant life. The synthesis of antioxidant phytochem-
icals in high-altitude medicinal plants is inuenced by several environmental factors:
4.1.1. Solar Radiation Intensity and Ultraviolet (UV) Exposure
High-altitude regions often experience increased solar radiation due to reduced at-
mospheric ltration. Elevated UV radiation levels can lead to oxidative stress in plant tis-
sues by generating ROS. Plants respond by activating antioxidant defence mechanisms
modulated by avonoids such as the production of quercetin, kaempferol, catechins and
others to scavenge ROS and protect cellular components [195].
4.1.2. Temperature Fluctuations
High-altitude environments exhibit signicant diurnal temperature variations, in-
cluding cold nights and warm days. Temperature uctuations can disrupt cellular home-
ostasis and induce oxidative stress. High-altitude plants adapt by synthesizing antioxi-
dant compounds such as chlorogenic acid, a phenolic compound, to mitigate temperature-
induced oxidative damage and maintain cellular integrity [96].
Pharmaceuticals 2024, 17, 975 24 of 61
4.1.3. Low Oxygen Levels (Hypoxia)
Reduced atmospheric pressure at higher elevations results in lower oxygen levels,
leading to hypoxic conditions. Hypoxia-induced oxidative stress can occur due to im-
paired mitochondrial function and increased ROS production. High-altitude plants en-
hance the production of alkaloid antioxidants such as berberine to counteract hypoxia-
induced oxidative damage [96].
4.1.4. Water Scarcity and Drought Stress
Water availability in high-altitude regions can be limited, particularly in arid or semi-
arid environments. Drought stress disrupts cellular hydration and photosynthetic pro-
cesses, triggering oxidative stress. High-altitude plants accumulate osmo-protectants,
such as proline and antioxidants, such as avonoids to mitigate water stress-induced ox-
idative damage and maintain cellular hydration [196].
4.1.5. Soil Composition and Nutrient Availability
High-altitude soils often exhibit low nutrient availability, high acidity, and metal-rich
compositions. Adverse soil conditions can exacerbate oxidative stress in plants by limiting
nutrient uptake and promoting metal-induced ROS generation. High-altitude plants pro-
duce metal chelators that bind and detoxify heavy metals present in the soil, reducing
metal-induced oxidative stress. Polyphenols scavenge ROS and regulate nutrient uptake,
contributing to antioxidant defence and nutrient homeostasis [197].
4.1.6. Altitude-Dependent Factors
Altitude-specic variables, including atmospheric pressure, humidity, and air pollu-
tion, inuence antioxidant production in high-altitude plants. Changes in atmospheric
pressure and humidity modulate plant metabolism and ROS production, while air pollu-
tants like ozone and nitrogen oxides contribute to oxidative stress. High-altitude plants
adjust their antioxidant defences, such as the production of terpenoids, which exhibit
adaptogenic properties, enhancing plant resilience to altitude-dependent stressors like
changes in atmospheric pressure and humidity. Anthocyanins act as antioxidants and UV
protectants, shielding plant tissues from oxidative damage and UV radiation at high alti-
tudes [96].
4.2. High-Altitude Plants and Their Antioxidant Potential
Plants have held a signicant role in the eld of medicine since ancient times [198].
Various plant species, such as Tulsi and Neem, have been recognized for their benecial
eects on human health, functioning as antibacterial, anti-inammatory, and antioxidant
agents [199]. In particular, certain plants found in the high-altitude regions possess unique
properties and produce phytochemicals and essential oils, rich in phenolic compounds
and avonoids etc. These phytochemicals have the ability to scavenge free radicals
through various mechanisms, such as electron donation, hydrogen atom donation, acting
as reducing agents, or chelation of metal ions [82]. By employing these strategies, they
eectively neutralize harmful free radicals, thereby providing antioxidant protection.
These natural compounds hold great promise in the eld of drug discovery, as they serve
as botanical leads for the development of novel therapeutic agents. The following section
describes selected high-altitude medicinal plants along with their antioxidant potential.
4.2.1. Saussurea lappa (Decne.) C. B. Clarke
Saussurea lappa (Decne.) C. B. Clarke is a medicinal plant that belongs to the Aster-
aceae family and is predominantly found at high altitudes, ranging from 2500 to 3500 m
above mean sea level, primarily in the Himalayan region [200]. It is commonly referred to
as ‘Costus’ and has garnered signicant aention due to its extensive medicinal
Pharmaceuticals 2024, 17, 975 25 of 61
applications. Notably, this plant is enriched with essential vitamins, including vitamin
B12, vitamin B2, vitamin A, as well as vital minerals such as calcium, iron, and zinc [201].
A distinctive feature of Costus is the presence of a phytochemical called costunolide,
which is primarily found in its roots [201]. Costunolide exhibits remarkable antioxidant
activity, which has been aributed to its ability to counteract the development of cancer
[202]. The compound contains N-acetylcysteine, which plays a pivotal role in neutralizing
ROS by facilitating the production of key enzymes like SOD and CAT [203]. These aid in
the detoxication of harmful free radicals, thereby contributing to the plant’s antioxidant
defence system. Through its antioxidant properties, Costus holds potential as a therapeutic
agent in the prevention and management of various diseases [204].
4.2.2. Arnebia benthamii (Wall. ex G. Don) I. M. Johnst.
Arnebia, scientically known as Arnebia benthamii (Wall. ex G. Don) I. M. Johnst., is a
highly valued medicinal plant belonging to the Boraginaceae family. It thrives in high-
altitude Himalayan regions, specically ranging from 3000 to 3900 m above mean sea level
[205]. However, it is important to note that this plant has been classied as a critically
endangered species in the Northwestern Himalayas by the International Union for Con-
servation of Nature (IUCN) [206]. Himalayan Arnebia possess various phytochemicals, in-
cluding a prominent compound called shikonin [207]. Shikonin plays a vital role in pre-
venting oxidative DNA damage through its free radical scavenging mechanism. As a qui-
none derivative, shikonin acts as a potent antioxidant, eectively thwarting lipid peroxi-
dation and DNA damage by neutralizing free radicals and reducing ferrous ions [82].
The antioxidative properties of shikonin contribute to the overall preservation of cel-
lular integrity, providing a protective shield against oxidative stress. The presence of shi-
konin in Himalayan Arnebia underscores its medicinal signicance and potential thera-
peutic applications [208]. Studies have highlighted the antioxidant capabilities of this
plant, shedding light on its role in preventing oxidative damage and maintaining cellular
health [209,210].
4.2.3. Pinus nigra Aiton, Hort. Kew. [W. Aiton]
Belonging to the Pinaceae family, this particular plant species thrives in the high-
altitude regions (2000 m above mean sea level) of the Toros mountains and holds a great
signicance in combaing oxidative stress-induced damage [211]. This plant abundantly
produces phenols and avonoids, which are extremely ecient in neutralizing several
free radical species, including hydrogen peroxides and superoxide free radical species,
including superoxide radicals and hydrogen peroxide. This antioxidant activity is facili-
tated through multiple mechanisms, such as chelation of metal ions, free radical scaveng-
ing and the reduction of ferrous ions [212].
The presence of phenols and avonoids in this plant demonstrates its adaptation to
cope with the challenging environmental conditions it encounters. By eectively neutral-
izing free radicals, these compounds help protect the plant’s cellular components from
oxidative damage and maintain their functionality. Studies have highlighted the antioxi-
dative properties of this plant, shedding light on its potential role in preventing oxidative
stress-related disorders [213].
4.2.4. Cedrus deodara (Roxb. ex D. Don) G. Don
Cedrus deodara, also known as the Deodar cedar, is a signicant plant that has been
used in Ayurveda for its medicinal benets [214]. It is an evergreen plant found at high
altitudes, specically around 3000–3300 m above mean sea level [214]. Belonging to the
family Pinaceae, this plant contains phytochemicals, such as ‘Metairesinol,’ which exhibit
antioxidant activity [215]. These phytochemicals help in inhibiting oxidative stress by che-
lating metal ions or transferring hydrogen atoms to free radical species [212].
Pharmaceuticals 2024, 17, 975 26 of 61
4.2.5. Podophyllum hexandrum Royle
Podophyllum hexandrum, also known as Himalayan May apple, is found at an altitude
of around 3000–3500 m above mean sea level [216]. It belongs to the Berberidaceae family
and exhibits high antioxidant activity due to phytochemicals, such as podophyllotoxin,
present in its rhizome, leaves, and other parts [216]. The extracts of this plant are capable
of neutralizing hydrogen peroxide and superoxide radicals, thus preventing lipid peroxi-
dation, and also stimulate the activity of antioxidant enzymes [217].
4.2.6. Valeriana jatamansi D. Don
Valeriana jatamansi, known as Mushkibala in Hindi, is a high-altitude medicinal plant
found at an altitude of around 3000 m above mean sea level [218]. It belongs to the Vale-
rianaceae family and possesses antiseptic and antioxidant properties [218]. It contains a
class of terpenoids called valepotriates, which are responsible for its medicinal applica-
tions [219]. The rhizome of Valeriana jatamansi contains phenols and avonoids, which ex-
hibit antioxidant activity by donating hydrogen atoms or quenching singlet oxygen spe-
cies. It can also chelate certain metal ions, thereby inhibiting the generation of ROS [220].
4.2.7. Berberis aristata DC.
Berberis aristata, also known as Daru Haldhi, is a Himalayan shrub found at an alti-
tude of around 2000–3000 m above sea level. It is primarily found in the areas of Himachal
Pradesh, Nepal, and Sri Lanka [221]. Berberis aristata possesses antioxidant potential at-
tributed to certain protoberberines present in its root and shoot extracts. These com-
pounds contribute to the neutralization of ROS, reducing the risk of oxidative stress-re-
lated issues such as hepatic damage [222].
4.2.8. Pedicularis longiora Rudolph
Pedicularis longiora is a plant widely found in the Himalayan regions of Ladakh,
Jammu and Kashmir, at an altitude of approximately 2700 m above mean sea level [223].
This plant is valued for its medicinal properties, particularly its antioxidant and anti-in-
ammatory eects [224]. It contains phytochemicals such as avonoids and phenols,
which reduce lipid peroxidation by scavenging superoxide radicals. Moreover, Pedicularis
longiora enhances the activity of CAT and SOD, further contributing to its antioxidant
activity [224].
4.2.9. Aconitum heterophyllum Wall. ex Royle
Aconitum heterophyllum, also known as Indian aconite or Atees, is an Ayurvedic me-
dicinal plant native to the Himalayan region, including Jammu and Kashmir, Nepal, Sik-
kim, and Uarakhand, at altitudes ranging from 2500 to 4000 m above mean sea level
[225]. It belongs to the Ranunculaceae family. The roots, stems, and leaves of this plant
contain alkaloids and avonoids, which play a crucial role in detoxifying ROS within the
body [226]. These compounds contribute to the prevention of gastrointestinal problems
such as liver inammation [227].
4.3. Underutilization of High-Altitude Medicinal Plants
High-altitude regions, dened as areas above 1500 m (4900 feet) elevation, encompass
diverse ecosystems ranging from alpine meadows to snow-capped peaks. These regions
are home to a rich array of medicinal plants that have been traditionally used by indige-
nous communities for centuries to treat various ailments [228]. The harsh environmental
conditions of high-altitude environments, including intense solar radiation, extreme tem-
peratures, and oxidative stress, have driven the evolution of plants towards unique bio-
chemical compositions and pharmacological properties. For instance, one example of a
high-altitude medicinal plant with potent antioxidant properties is Rhodiola rosea, also
known as golden root or arctic root. Indigenous to mountainous regions of Europe and
Pharmaceuticals 2024, 17, 975 27 of 61
Asia, Rhodiola rosea has been traditionally used to increase resistance to physical and en-
vironmental stress, enhance mental performance, and promote longevity. Studies have
aributed its adaptogenic and antioxidant eects to bioactive compounds, including sali-
droside, rosavin, and avonoids, which scavenge free radicals, reduce oxidative damage,
and modulate stress-responsive pathways [14]. Similarly, Berberis aristata, a high-altitude
plant native to the Himalayas, is valued for its medicinal properties, including its antiox-
idant, anti-inammatory, and hepatoprotective eects. Berberis aristata contains bioactive
alkaloids, such as berberine, palmatine, and berbamine, which exhibit potent antioxidant
activity by neutralizing ROS, inhibiting lipid peroxidation, and enhancing cellular antiox-
idant enzymes [229].
However, despite their immense potential therapeutic benets, a large variety of
these plants, and the products they produce, remain largely underutilized in modern
medicine. Several factors contribute to this underutilization [9]. Firstly, there is a lack of
comprehensive scientic research exploring the antioxidant potential of high-altitude me-
dicinal plants. Limited funding and resources are allocated to studying plants in remote
mountainous regions, making it dicult to gather robust scientic evidence to support
their medicinal properties. As a result, many of these plants remain overlooked in phar-
maceutical and nutraceutical industries. Additionally, challenges in accessing high-alti-
tude environments pose logistical diculties for researchers. Harsh terrain, extreme
weather conditions, and limited infrastructure make it challenging to conduct eld studies
and collect plant samples. This impedes eorts to characterize the bioactive compounds
and pharmacological activities of high-altitude medicinal plants [230].
Furthermore, traditional knowledge of these plants is at risk of being lost as the
young population inhabiting mountainous regions tends to migrate to urban areas and
adopt modern lifestyles. The decline of indigenous knowledge and traditional healing
practices contributes to the under appreciation of high-altitude medicinal plants in main-
stream healthcare systems [231]. This necessitates the compilation of knowledge of im-
portant medicinal plants thriving in high-altitude regions, along with their reported bio-
active compounds and their reported medicinal applications. Table 5 provides a compre-
hensive compilation of 168 such plants of medicinal value, which are able to survive in
high-altitude regions, along with their ethnopharmacological applications. A large major-
ity of these plants are unexplored and have not been utilized to their full potential. The
comprehensive detailed analysis of their phytochemicals could act as starting point for
the exploration of their potential to mitigate oxidative stress-related disorders.
Pharmaceuticals 2024, 17, 975 39 of 61
Tab l e 5. List of high-altitude medicinal plants, along with their reported bioactive compounds and their pharmacological properties.
S. No. Plant Name Plant Family Altitude (m above
m.s.l.) Parts Used Principle Bioactive Com-
pound Pharmacological Activity Refer-
ence
1.
A
llium humile Kunth
Amaryllidaceae
3200–4500 Whole plant Allicin Antioxidant [232]
2.
A
llium semenovii Regel. 2000–3000 Whole plant Alliin Antioxidant
[233]
3.
A
llium stoliczki Regel 3200–3700 Bulbs S-Allyl-L-cysteine sulfox-
ide
Antioxidant, Cardiovascular
health benefits [234]
4. Pistacia integerrima L. Anacardiaceae 800–2200 Fruits Gallic acid, Quercetin Antioxidant,
Anti-inflammatory [235]
5.
A
ngelica glauca Edgew.
Apiaceae
2000–3800 Roots Angelicin,
Umbelliferone
Antioxidant,
Hepatoprotective [236]
6. Bupleurum falcatum L 2130–3500 Roots Saikosaponins Anti-inflammatory,
Hepatoprotective [237]
7. Chaerophyllum aromaticum L. 2800–3200 Roots Coumarin,
Umbelliferone
Antioxidant,
Anti-inflammatory [238]
8. Ferula jaeschkeana Vatke 2600–3000 Rhizomes Ferutinin, Ferulenol Antioxidant [239]
9. Heracleum candicans L. 1800–4000 Leaves, Stem
Roots Bergapten, Psoralen Antioxidant,
Anti-inflammatory [240]
10. Pleurospermum brunonis Benth. ex
C.B Clarke 3000–4000 Leaves Psoralen, Isopsoralen Antioxidant,
Anti-inflammatory [241]
11. Selinum vaginatum C.B. Clarke 2700–3800 Roots Bhutkeshi Selinidin, Selinidiol Antioxidant,
Anti-inflammatory [242]
12.
A
risaema flavum (Forsk.) Schott. Araceae 2000–3400 Rhizome Arisarumol Antioxidant,
Anti-inflammatory [243]
13. Hedera nepalensis C. Koch Araliaceae 1500–3000 Leaves, Stems Hederacoside C, Heder-
agenin
Antioxidant,
Anti-inflammatory [244]
14.
A
chillea millefolium L.
Asteraceae
3200–3700 Leaves,
Flowers Apigenin, Luteolin Antioxidant,
Anti-inflammatory [245]
15.
A
rtemisia absinthium L. 2000–3660 Whole plant Absinthin,
Anabsinthin Antioxidant [246]
16.
A
rtemisia macrocephala Jacq. ex
Bess 3400–5500 Aerial parts Artemisinin,
Dihydroartemisinin Antioxidant, Anticancer [247]
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17. Carduus nutans L. 2600–3000 Leaves, Roots Silymarin Hepatoprotective,
Antioxidant [248]
18. Cichorium intybus L. 2600–3000 Leaves, Roots Inulin, Lactucin Hepatoprotective,
Hypoglycemic [249]
19. Erigeron acris L. 2600–3400 Roots Quercetin, Kaempferol Anti-inflammatory,
Antioxidant [250]
20. Inula cappa DC. 2600–3500 Roots Alantolactone,
Isoalantolactone
Antioxidant,
Anti-inflammatory [251]
21. Inula racemosa Hook. f. 2000–3100 Roots Alantolactone,
Isoalantolactone
Antioxidant,
Anti-inflammatory [252]
22.
J
urinea dolomiaea Boiss. 3000–4000 Roots
J
urineol,
J
urineol acetate
Antioxidant,
Anti-inflammatory [253]
23.
J
urinea macrocephala DC. 3000–4000 Roots Leaves
J
urineol,
J
urineol acetate
Antioxidant,
Anti-inflammatory [254]
24. Saussurea albescens Hook. f. et.
Thomson 2000–3600 Leaves Costunolide, Eupatilin Antioxidant,
Anti-inflammatory [255]
25. Saussurea costus (Falc.)
Lipsch. 2600–4000 Roots Costunolide, Dehydro-
costus lactone
Antioxidant,
Anti-inflammatory [256]
26. Saussurea gossypiphora D. Don 4500–5300 Flowers Saussureamine Antioxidant,
Anti-inflammatory [257]
27. Scorzonera virgata DC. 2700–4200 Leaves Inulin,
Scorzodioside B
Hepatoprotective,
Hypoglycemic [258]
28. Waldhemia glabra (Decne.) Regel. 4000–5000 Aerial parts
Waldhemiol,
Waldhemidin
Antioxidant,
Anti-inflammatory [259]
29. Waldhemia tomentosa (Decne.) Re-
gel. 3800–4500 Whole plant
Waldhemiol,
Waldhemidin
Antioxidant,
Anti-inflammatory [260]
30. Impatiens sulcata Wall. Balsaminaceae 2000–3900 Whole plant Lawsone Antioxidant,
Anti-inflammatory [261]
31. Berberis lycium Royle Berberidaceae 1200–3000 Roots, stems Berberine, Palmatine Antioxidant, Antidiabetic [262]
32. Betula utilis D. Don Betulaceae 2900–4000 Bark Betulin, Betulinic acid Antioxidant,
Anti-inflammatory [263]
33. Biebersteinia odora Steph. ex Fish Biebersteiniaceae 4200–5030 Rootstocks Coumarin, Antioxidant, [264]
Pharmaceuticals 2024, 17, 975 41 of 61
Umbelliferone Anti-inflammatory
34.
A
rnebia benthamii (Wall. ex G.
Don.) Johnston
Boraginaceae
3000–3900 Roots Alkannin, Shikonin Antioxidant,
Anti-inflammatory [265]
35. Cynoglossum wallichii G. Don 2600–3700 Leaves Shikonin,
Deoxyshikonin
Antioxidant,
Anti-inflammatory [266]
36. Cynoglossum zeylanicum Thunb. ex
Lehm. Brand. 2600–3350 Roots Shikonin,
Deoxyshikonin
Antioxidant,
Anti-inflammatory [266]
37. Myosotis silvatica Ehrh. ex Hoffm. 3200–4200 Whole plant Tannins, Flavonoids Antioxidant,
Anti-inflammatory [267]
38. Onosma hispida Wall. ex G. Don 2000–3400 Roots, Leaves Alkannin, Shikonin Antioxidant,
Anti-inflammatory [268]
39.
A
rabidopsis mollissma (C. May.) N.
Busch
Brassicaceae
3800–4300 Leaves Sinapine, Sinapic acid Antioxidant,
Anti-inflammatory [269]
40.
A
rabis nova Vill. 3500–3900 Fruits Glucosinolates Antioxidant, Anticancer
[270]
41. Brassica rapa L. ssp. 3200–4500 Whole plant Glucosinolates Antioxidant, Anticancer
[271]
42. Descurainia sophia (L.) Webb. ex
Prantl 2600–3500 Whole plant Linalool,
Thymoquinone
Antioxidant,
Anti-inflammatory [272]
43. Lepidium latifolium L. 2500–4300 Aerial parts Glucosinolates Antioxidant [273]
44. Nasturtium officinale W.T. Ait. Hort. 2600–3500 Whole plant Glucosinolates Antioxidant [274]
45. Sisymbrium orientale L. 2600–3600 Seeds Glucosinolates Antioxidant [275]
46. Sarcococca saligna (D. Don)
Muell.-Arg. Buxaceae 1500–2300 Leaves, Stem Sarcococcin Antioxidant,
Anti-inflammatory [276]
47. Codonopsis clematidea (Schrenk)
C.B. Clarke
Campanulaceae
3000–3800 Flowers Codonopsin,
Codonopsidic acid
Antioxidant,
Immunomodulatory [277]
48. Codonopsis ovata Benth. 2700–3200 Whole plant Codonopsin,
Codonopsidic acid
Antioxidant,
Immunomodulatory [278]
49. Cyananthus lobatus Wall. ex Benth 3000–4000 Leaves, flowers Cyanolobatolide Antioxidant,
Anti-inflammatory [279]
50. Capparis himalayensis Jafri Capparaceae 2800–3300 Leaves Flavonoids,
Glucosinolates Antioxidant [280]
51. Lonicera hypoleuca Decne. Caprifoliaceae 2900–3100 Stem Chlorogenic acid,
Luteolin
Antioxidant,
Anti-inflammatory [281]
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52. Lonicera quinquelocularis Hardw. 2600–3500 Stems, Leaves,
Fruit
Chlorogenic acid,
Luteolin
Antioxidant,
Anti-inflammatory [282]
53. Viburnum cotinifolium D. Don 2300–2600 Fruits Iridoids, Flavonoids Antioxidant,
Anti-inflammatory [283]
54. Viburnum
g
randiflorum Buch-
Ham. ex D. Don 2800–4300 Fruits, seeds Iridoids, Flavonoids Antioxidant,
Anti-inflammatory [283]
55. Cerastium cerastoides (L.) Britt.
Caryophyllaceae
2000–4000 Whole plant Tannins, Flavonoids Antioxidant,
Anti-inflammatory [86]
56.
M
yosoton aquaticum (L.) Moench 2000–2800 Leaves, Stem Tannins, Flavonoids Antioxidant,
Anti-inflammatory [284]
57. Silene vulgaris (Moench) Garcke 2740–3450 Leaves, Twigs Tannins, Flavonoids Antioxidant,
Anti-inflammatory [285]
58. Stellaria media (L.) Vill. 2600–3000 Leaves Tannins, Flavonoids Antioxidant,
Anti-inflammatory [286]
59. Chenopodium album L.
Chenopodiaceae
350–4300 Leaves, Seeds Saponins, Flavonoids Antioxidant,
Anti-inflammatory [287]
60. Chenopodium foliosum Wall. 2000–4000 Fruits Saponins, Flavonoids Antioxidant,
Anti-inflammatory [288]
61. Convolvulus arvensis L. Convolvulaceae 3000–4000 Flower buds Alkaloids, Flavonoids Antioxidant,
Neuroprotective [289]
62. Corylus jacquemontii Decne. Corylaceae 2000–3300 Seeds Catechins, Quercetin Antioxidant,
Anti-inflammatory [290]
63. Rosularia alpestris (Kar. and Kir.)
Boriss. Crassulaceae 3000–4300 Whole plant
Phenolic compounds, Fla-
vonoids
Antioxidant,
Anti-inflammatory [102]
64.
J
uniperus communis L.
Cupressaceae
3000–4200 Needles Monoterpenes,
Flavonoids Antioxidant [291]
65. Juniperus indica Bertol. 3500–4500 Wood Monoterpenes,
Flavonoids Antioxidant [292]
66. Cuscuta reflexa Roxb. Cuscutaceae 800–2500 Whole plant Flavonoids, Alkaloids Antioxidant,
Hepatoprotective [293]
67. Datisca cannabina L. Datiscaceae 2800–3200 Leaves, Roots Tannins, Flavonoids Antioxidant,
Anti-inflammatory [294]
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68. Dioscorea deltoidea Wall. ex Kunth Dioscoreaceae 2000–2800 Tuber Diosgenin, Dioscin Antioxidant,
Anti-inflammatory [15]
69. Elaeagnus conferta Roxb.
Elaeagnaceae
1500–2200 Fruits Triterpenoids,
Flavonoids
Antioxidant,
Anti-inflammatory [295]
70. Hippophae rhamnoides L. 2600–3500 Fruits, Stem Flavonoids, Vitamin C Antioxidant,
Immunomodulatory [296]
71. Hippophae salicifolia D. Don 2800–3500 Fruits Flavonoids, Vitamin C Antioxidant,
Immunomodulatory [297]
72. Cassiope fastigiata (Wall.) D. Don
Ericaceae
3800–4600 Leaves Polyphenols,
Flavonoids
Antioxidant,
Anti-inflammatory [298]
73. Rhododendron anthopogon D. Don 3200–4500 Leaves, Flowers Rhododendrin,
Ursolic acid
Antioxidant,
Anti-inflammatory [299]
74. Rhododendron arboretum Sm. 2000–4000 Leaves, Flowers Arbutin, Quercetin Antioxidant,
Anti-inflammatory [300]
75. Rhododendron campanulatum D.
Don 3000–4300 Leaves Arbutin, Quercetin Antioxidant,
Anti-inflammatory [301]
76. Gentiana kurroo Royle
Gentianaceae
1800–4200 Roots Gentisin,
Swertiamarin
Antioxidant,
Hepatoprotective [302]
77. Gentiana leucomelaena Maxim. ex
Kusn. 2500–5000 Whole plant Gentisin,
Swertiamarin
Antioxidant,
Hepatoprotective [303]
78. Gentiana moorcroftiana 2700–5000 Leaves Gentisin,
Swertiamarin
Antioxidant,
Hepatoprotective [304]
79. Gentiana tianshanica Rupr. 3900–3900 Whole plant Gentisin,
Swertiamarin
Antioxidant,
Hepatoprotective [305]
80. Gentiana tubiflora (G. Don)
Grirseb. 4000–5300 Whole plant Gentisin,
Swertiamarin
Antioxidant,
Hepatoprotective [306]
81. Gentianopsis detonsa (Rottb.) Ma 2700–4200 Whole plant Gentisin,
Swertiamarin
Antioxidant,
Hepatoprotective [303]
82. Gentianopsis paludosa (Hook.) Ma 3000–4000 Whole plant Gentisin,
Swertiamarin
Antioxidant,
Hepatoprotective [307]
83. Swertia chirayita (Roxb. ex
Fleming) Karst. 1500–3000 Whole plant Amarogentin,
Swertiamarin
Antioxidant,
Hepatoprotective [308]
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84. Geranium pratense L.
Geraniaceae
2680–3900 Whole plant Geraniin, Tannins Antioxidant,
Anti-inflammatory [309]
85. Geranium wallichianum D. Don ex
Sweet 2600–3980 Whole plant Geraniin, Tannins Antioxidant,
Anti-inflammatory [310]
86.
J
uglans regia L.
J
uglandaceae 1000–3300 Leaves, seeds
J
uglone, Quercetin Antioxidant,
Anti-inflammatory [311]
87. Lamium album L.
Lamiaceae
1500–2400 Roots,
Rhizomes
Rosmarinic acid,
Flavonoids
Antioxidant,
Anti-inflammatory [312]
88. Origanum vulgare L 1800–3600 Leaves, Stems Carvacrol, Thymol Antioxidant [313]
89. Phlomis bracteosa Royle ex Benth. 3200–4400 Whole plant Ursolic acid Antioxidant,
Anti-inflammatory [314]
90. Salvia nubicola Wall. ex Sweet 2000–2700 Roots, Leaves
Salvianolic acid,
Rosmarinic acid
Antioxidant,
Anti-inflammatory [315]
91.
A
stragalus bicuspis Fischer
Leguminosae
3100–3500 Whole plant Astragaloside IV Antioxidant,
Immunomodulatory [316]
92.
A
stragalus candolleanus Royle 3000–4000 Roots Astragaloside IV Antioxidant,
Immunomodulatory [317]
93.
A
stragalus grahamianus Royle ex
Benth. 3000–3500 Whole plant Astragaloside IV Antioxidant,
Immunomodulatory [318]
94.
A
stragalus himalayanus Klotzsch 3200–4400 Flowers Seeds Astragaloside IV Antioxidant,
Immunomodulatory [319]
95.
A
stragalus strobiliferus Royle 3000–4000 Roots Astragaloside IV Antioxidant,
Immunomodulatory [320]
96.
A
stragalus zanskarensis Benth. ex
Bunge 3200–4600 Roots Astragaloside IV Antioxidant,
Immunomodulatory [321]
97. Cicer microphyllum Benth. 3200–4600 Aerial parts, Flavonoids, Saponins Antioxidant,
Anti-inflammatory [322]
98. Desmodium elegans DC. 2000–4000 Leaves Flavonoids, Alkaloids Anti-inflammatory [323]
99. Lotus corniculatus L. 2500–3400 Whole plant Rutin, Quercetin Antioxidant,
Anti-inflammatory [324]
100.
M
edicago falcata L. 2700–3500 Aerial parts Isoflavones, Saponins Antioxidant,
Anti-inflammatory [325]
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101. Trifolium pratense L. 2600–3800 Whole plant Formononetin,
Biochanin A Antioxidant [326]
102. Trifolium repens L. 2600–3200 Whole plant Trifoside, Genistein Antioxidant,
Anti-inflammatory [327]
103. Trigonella emodi Benth. 2600–3800 Whole plant Trigonelline,
Diosgenin
Antioxidant, Antidiabetic, Hy-
polipidemic [328]
104. Vicia sativa L. 2600–3000 Whole plant Vicine, Convicine Antioxidant, Antidiabetic [329]
105. Eremurus himalaicus Baker Liliaceae 3200–4500 Fruits Steroidal saponins Anti-inflammatory,
Immunomodulatory [330]
106. Viscum album L. Loranthaceae 2000–3000 Bark Viscotoxins, Lectins Antioxidant,
Immunomodulatory [331]
107.
M
alva neglecta Wallr.
Malvaceae
2600–4500 Whole plant Mucilage Antioxidant,
Anti-inflammatory [332]
108.
M
alva verticillata L. 2500–3800 Seeds Mucilage Antioxidant,
Anti-inflammatory [333]
109.
M
orus serrata Roxb. Moraceae 2000–2300 Leaves, Fruits Morin, Resveratrol Antioxidant,
Anti-inflammatory [334]
110.
M
orina coulteriana Royle
Morinaceae
3000–3700 Flowers Morin Antioxidant,
Anti-inflammatory [335]
111.
M
orina longifolia Wall. ex DC. 3000–4300 Roots, Flowers Morin Antioxidant,
Anti-inflammatory [336]
112.
J
asminum officinale L. Oleaceae 1800–4000 Leaves Stems
J
asmonic acid,
Quercetin
Antioxidant,
Anti-inflammatory [337]
113. Epilobium angustifolium L.
Onagraceae
3000–4700 Roots Oenothein B,
Quercetin
Antioxidant,
Anti-inflammatory [338]
114. Oenothera glazioviana Micheli 2000–2700 Whole plant Linoleic acid,
Gamma-linolenic acid
Antioxidant,
Anti-inflammatory [339]
115. Dactylorhiza hatagirea D. Don Orchidaceae 3000–3800 Rhizome Phenanthrenes Antioxidant,
Anti-inflammatory [340]
116.
M
econopsis aculeata Royle Papaveraceae 2400–4200 Whole plant Alkaloids, Flavonoids Antioxidant,
Anti-inflammatory [341]
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117. Parnassia nubicola Hook. f. Parnassiaceae 1900–3400 Roots Parnassiol Antioxidant, Hepatoprotective,
Anti-inflammatory [342]
118. Cedrus deodara (Royle ex D. Don)
Pinaceae
1600–3000 Wood Deodarone, Cedrol Antioxidant [343]
119. Pinus gerardiana Wall. ex Lambert. 2500–3000 Fruits/Kernels Pinene, Pinenes Antioxidant,
Anti-inflammatory [344]
120. Pinus nigra Aiton, Hort. Kew. [W.
Aiton] 1300–2200 Fruits/Kernels Pinene, limonene borneol Antioxidant,
Anti-inflammatory [345]
121. Plantago depressa Willd.
Plantaginaceae
2000–4500 Whole plant Glycosides,
Flavonoids
Antioxidant,
Anti-inflammatory [346]
122. Plantago major L. 2000–2800 Leaves, Roots, Aucubin, Ursolic acid Antioxidant,
Anti-inflammatory [347]
123. Bistorta vaccinifolia (Wall. ex
Meisn.) Greene
Polygonaceae
3000–4600 Whole plant Tannins, Flavonoids Antioxidant,
Anti-inflammatory [348]
124. Koenigia delicatula (Meisn.) H. Hara 3000–4500 Stems Tannins, Flavonoids Antioxidant,
Anti-inflammatory [349]
125. Oxyria digyna Hill 2600–5300 Whole plant Oxycoumarins Antioxidant,
Anti-inflammatory [350]
126. Polygonum alpinum Allioni. 1500–2400 Stems, Leaves Rutin, Quercetin Antioxidant,
Anti-inflammatory [351]
127. Polygonum aviculare L. 2000–4200 Flower buds Polyphenols,
Flavonoids
Antioxidant,
Anti-inflammatory [352]
128. Polygonum plebejum R.Br. 1000–4000 Whole plant Polyphenols,
Flavonoids
Antioxidant,
Anti-inflammatory [353]
129. Polygonum pubescens Blume 1500–3700 Roots Polyphenols,
Flavonoids
Antioxidant,
Anti-inflammatory [354]
130. Polygonum tortuosum D. Don 3600–4900 Young peduncle Polyphenols,
Flavonoids
Antioxidant,
Anti-inflammatory [352]
131.