AJTCCM VOL. 30 NO. 2 2024 59
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Pulmonary hypertension (PH) is defined as a mean pulmonary
artery pressure ≥20 mmHg when diagnosed with right heart
catheterisation,[1] or a right ventricular systolic pressure ≥40 mmHg
(in the absence of pulmonary stenosis and acute right heart failure)
as measured with transthoracic echocardiography.[2] Approximately
75 million people suer from PH globally,[3] and it occurs mainly in
women.[4] It is associated with several conditions, such as HIV, le
heart disease, schistosomiasis, chronic obstructive pulmonary disease
and tuberculosis sequelae.[5-7] ese conditions increase pulmonary
vascular remodelling that results in increased pulmonary vasculature
resistance and therefore PH. e current PH treatment regimens have
made a signicant clinical impact, as they improve clinical outcomes
and quality of life to a certain degree.[1] However, they do not cure
PH, suggesting that its pathophysiology is not fully understood,[8] and
this limited impact of the current drugs on PH highlights a need for
better treatment regimens. During the past 5 years, and particularly
in the post-COVID-19 period, drug repurposing has been proposed
as a novel way to augment the health benets aorded by current PH
drugs.[9] e articles on this topic are too many to list in full, but these
three show the importance of the idea.[10-12]
A brief overview of the pathophysiology
and treatment of PH
PH has a complex pathophysiology that includes an array of molecular
factors and proteins that trigger myriad molecular pathways[13] such
as increased proliferation of pulmonary artery smooth-muscle cells
(PASMCs) and a cancer-like phenotype characterised by PASMC
resistance to apoptosis and excessive proliferation of pulmonary artery
Pulmonary hypertension and the potential of ‘drug’ repurposing:
Acase for African medicinal plants
S Jacobs, MB ChB, MSc; C Payne, MSc; S Shaboodien, BSc Hons; T Kgatla, BSc Hons;
A Pretorius, BSc Hons; C Jumaar, BSc Hons; G Maarman, MSc, PhD ; O Sanni, MSc, PhD
Centre for Cardiometabolic Research in Africa (CARMA), Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health
Sciences, Stellenbosch University, Cape Town, South Africa
Corresponding author: G J Maarman (gmaarma[email protected])
Pulmonary hypertension (PH) is a haemodynamic disorder in which elevated blood pressure in the pulmonary circulation is caused
by abnormal vascular tone. Despite advances in treatment, PH mortality remains high, and drug repurposing has been proposed as
a mitigating approach. is article reviews the studies that have investigated drug repurposing as a viable option for PH. We provide
an overview of PH and highlight pharmaceutical drugs with repurposing potential, based on limited evidence of their mechanisms of
action. Moreover, studies have demonstrated the benets of medicinal plants in PH, most of which are of Indian or Asian origin. Africa
is a rich source of many medicinal plants that have been scientically proven to counteract myriad pathologies. When perusing these
studies, one will notice that some African medicinal plants can counteract the molecular pathways (e.g. proliferation, vasoconstriction,
inammation, oxidative stress and mitochondrial dysfunction) that are also involved in the pathogenesis of PH. We review the actions
of these plants with actions applicable to PH and highlight that they could be repurposed as adjunct PH therapies. However, these plants
have either never been tested in PH, or there is little evidence of their actions against PH. We therefore encourage caution, as more
research is needed to study these plants further in experimental models of PH while acknowledging that the outcomes of such proof-
of-concept studies may not always yield promising ndings. Regardless, this article aims to stimulate future research that could make
timely contributions to the eld.
Keywords. Pulmonary hypertension, novel therapeutics, drug repurposing, African medicinal plants, adjunct therapies.
Afr J Thoracic Crit Care Med 2024;30(2):e1352. https://doi.org/10.7196/AJTCCM.2024.v30i2.1352
Synopsis
What the study adds. Pulmonary hypertension (PH) remains a fatal disease, and 80% of the patients live in developing countries where
resources are scarce and specialised therapies are oen unavailable. Drug repurposing is a viable option to try to improve treatment
outcomes.
Implications of the ndings. We propose that another form of ‘drug’ repurposing is the use of medicinal plants, many of which have
demonstrated benets against pathological processes that are also key in PH, e.g. apoptosis, tumour-like growth of cells, proliferation,
oxidative stress and mitochondrial dysfunction.
60 AJTCCM VOL. 30 NO. 2 2024
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endothelial cells (PAECs).[14] Other pathways include pulmonary
inflammation, elevated oxidative stress, lung mitochondrial
dysfunction, lung brosis and pulmonary vasoconstriction.[14] ese
pathways ultimately result in obliterative changes to the pulmonary
arterioles, including thickening of the intima and medial layers[13] and
plexogenic arteriopathy.[15]
Treatment options for PH improve PH-related symptoms by
targeting these molecular pathways. Drugs include endothelin-1-
receptor antagonists, phosphodiesterase type 5 inhibitors, soluble
guanylate cyclase stimulators, prostacyclin analogues and prostacyclin-
receptor agonists.[16] PH survival without treatment used to average
2.8 years, with survival rates of 68%, 48% and 34% at 1, 3 and 5 years
aer diagnosis, respectively.[17] However, with treatment, survival rates
have improved to 97.2%, 91.5%, 84.2%, 80.2% and 75.9% at 1, 2, 3, 4
and 5 years, respectively.[18] Great strides have therefore been made
with regard to PH treatment, but there is room for improvement, as
despite these drugs, patients still die from PH. is situation suggests
that there is a need for better treatment strategies.[19]
Drug repurposing in PH
e aim of drug repurposing[20] in PH is to reutilise drugs that were
traditionally used for other diseases in the hope that they may provide
health benets for PH patients too. Accumulating literature suggests
that there is indeed an instrumental role for drug repurposing in PH.
For instance, imatinib, a tyrosine kinase inhibitor used in patients
with chronic myelogenous leukaemia,[21] has been shown to have
vasodilatory properties by blocking the platelet-derived growth
factor-activated pathway of vascular remodelling.[22] It can therefore
be linked to PH, which develops through a similar mechanism.[23]
As a result, imatinib was repurposed for PH and has been shown to
improve haemodynamics and pulmonary vascular resistance in PH
patients.[24] Other examples are summarised in Table1.
Repurposing from an African perspective
Most Africans rely on medicinal plants as a source of healthcare.[42]
The World Health Organization reports that ~80% of developing
countries depend largely on medicinal plants for the treatment of
ailments and diseases.[43] Over the years, African traditional plants
have received attention for their health benefits, a characteristic
that is attributed to their high polyphenol content.[44] There has
been a close to 60% increase in the number of research outputs
based on the potential health benefits of African medicinal plants
in the past decade.[45]
Many of these African medicinal plants have benecial eects
against diseases such as cancer,[46] diabetes,[47] inflammation[48]
and bacterial respiratory diseases.[49] However, there is a paucity of
studies investigating the potential of African medicinal plants in
counteracting PH, and this is a pity, as these plants oer a niche for
the discovery of novel therapeutic targets or adjunct therapies for
PH. Such discoveries could equate to aorable therapies to assist PH
patients in resource-limited developing-world settings. PH drugs are
expensive and therefore inaccessible to many patients in developing
countries, where most public health healthcare systems cannot aord
to foot the high costs of pharmaceutical drugs. ere is therefore
a continued search for adjunct PH therapies that are eective and
aordable.[50] For this purpose, few studies have investigated natural
products or traditional herbs as an adjunct therapeutic approach
in PH.[51-53] Some medicinal plants from India and Asia show
considerable benet against key aspects of PH pathophysiology,[51-53]
but there is a paucity of such studies on African medicinal plants
and PH. is is strange, as Africa boasts rich biodiversity and a wide
range of plant species that have medicinal properties. We perused
the literature for studies that have demonstrated the underlying
mechanisms of these African medicinal plants, and we review
whether they counteract molecular pathways in other diseases that
are also involved in the pathogenesis of PH. We propose that these
African medicinal plants could be used against PH and that this may
also be observed as a form of ‘drug’ repurposing. Needless to say,
more research is warranted.
Anti-inammatory eects of African
medicinal plants
Inammation is usually triggered by damage to living tissues resulting
from microbial infections, physical damage or defective immune
responses.[54] Various mechanisms of action have been proposed to
explain the anti-inammatory activity of medicinal plants. ese
mechanisms include inhibition of 15-lipoxygenases,[55] elevation of
nitric oxide (NO) production,[57] inhibition of phospholipase A2,[56] and
modulation of proinammatory gene expression.[57] African medicinal
plants have become synonymous with anti-inammatory eects;[48]
in fact, Aspalathus linearis (also known as rooibos) is a unique South
African species that is considered a potent anti-inammatory agent.
Studies have shown that it achieves this action by limiting the cellular
release of proinammatory cytokines (tumour necrosis factor alpha
(TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6)) in
lipopolysaccharide-induced inammation.[58,59] Similar eects have
been shown with the African potato in a rat model of diclofenac-
induced inammation[60] (Table2).
Antioxidant properties of African
medicinal plants
African medicinal plants are well known for their ability to scavenge
free radicals and activate cell antioxidant defence systems.[64] eir
mechanism of action is complex, but reactive oxygen species (ROS)
stimulate the translocation of nuclear respiratory factor 2 (Nrf-
2) to the nucleus, where it binds to antioxidant response element
motifs to enhance redox defence[65] and the elevation of intracellular
antioxidant gene and protein expression, as well as the increase of
antioxidant enzyme activities.[66] Several African medicinal plants
can counteract the deleterious eects of elevated oxidative damage to
cell structures, including lipids, proteins and DNA. Aloe claviora is
a plant that can scavenge ROS and limit lipid peroxidation,[67] while
Aloe vera and Aspalathus linearis induce antioxidant eects via the
Nrf-2 pathway (Table3).
Close to 90% of cellular ROS is produced by mitochondria,[68]
while the same organelles are key role players in the optimal
function of cellular antioxidant systems.[69] In the absence of
proper mitochondrial regulation, antioxidant capacity is reduced,
which leads to the excessive production of ROS that further impair
mitochondrial function.[70] A. vera has been shown to improve
mitochondrial function by reducing ROS production, while
Moringa oleifera can do the same via an Nrf2/haem oxygenase 1
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Table1. A list of pharmaceutical drugs used for other diseases that could be repurposed for PH (some have recently been tested in
a PH context)
Drug Approved for Eects in models of PH References
Imatinib Chronic myeloid leukaemia Improves haemodynamics and exercise capacity Frost etal.[24]
Tacrolimus Solid-organ transplantation Improves BMPR2 expression in peripheral blood
mononuclear cells of human subjects
Spiekerkoetter etal.[25]
Anastrozole Breast cancer Improves 6-minute walk distance and reduces
17β-oestradiol levels
Kawut etal.[26]
Paclitaxel Ovarian cancer Inhibits pulmonary vascular remodelling by FoxO1-
mediated autophagy suppression
Feng etal.,[27]
Zhaoetal.[28]
Etanercept Rheumatoid arthritis Prevents and reverses monocrotaline-induced PH by
reducing inammatory cell inltration
Zhang etal.[29]
Carvedilol Congestive heart failure Reduces right ventricular systolic pressures in patients Cheong etal.[30]
Melatonin Jet lag Improves cardiac function, reduces oxidative stress,
enhances antioxidant systems, and inhibits pulmonary
vascular remodelling
Hung etal.,[31]
Maarman etal.,[32]
Wang etal.[33]
Hydroxychloroquine Malaria Attenuates PH by decreasing proliferation and increases
apoptosis of pulmonary artery smooth-muscle cells in
pulmonary hypertensive arteries.
Ryan[34]
Anakinra Rheumatoid arthritis Reduces inammation and right ventricular dysfunction
in PH via interleukin signalling
Trankle etal.[35]
Rituximab Non-Hodgkin’s lymphoma Improves 6-minute walk distance Zamanian etal.[36]
Sotatercept Chemotherapy-induced
anaemia, multiple
myeloma, beta-
thalassaemia, and end-
stage kidney disease
Improves pulmonary vascular resistance in patients, and
reduced N-terminal pro-B-type natriuretic peptide levels
Humbert etal.[37]
Dimethyl fumarate Multiple sclerosis Improves PH by blocking proinammatory pathways and
reducing the inltration of immune cells in lung tissue.
Grzegorzewska etal.[38]
Fasudil Angina and cerebral
vasospasm
Reduces pulmonary vascular resistance in PH patients Fujita etal.,[39]
Fukumoto etal.[40]
Nesiritide Acute decompensated
heart failure
Ameliorates pulmonary capillary wedge pressure Michaels etal.[41]
PH = pulmonary hypertension; FoxO1 = forkhead box protein O1.
Table2. African medicinal plants (tested in non-PH models) with anti-inammatory activity that could be repurposed for PH
Plant Common name Experimental model Mechanism References
Hypoxis
hemerocallidea
African potato Diclofenac-induced
inammation animal model
of rats
Inhibition of iNOS and NF-κB Ojewole[60]
In vitro model Zulqar etal.[61]
Aspalathus linearis Rooibos tea Lipopolysaccharide-induced
inammation animal model
of mice
Inhibition of proinammatory
cytokines (TNF-α, IL-1β and IL-6)
Ajuwon etal.,[58]
LeeandBae[59]
In vitro model Lee and Bae[59]
Ximenia cara Large sourplum In vitro model Inhibits the messenger RNA
expression of proinammatory
genes (IL-6, iNOS and TNF-α)
Zhen etal.[62]
Asparagus africanus Wild asparagus Carrageenan-induced rat paw
oedema and inammation in
Swiss albino and Wistar rats
Inhibition of inammation by
limiting proinammatory cytokines
Ojewole[60]
Aloe ferox Aloe Carrageenan-induced rat paw
oedema and inammation
Inhibition of inammation due to a
high content of malic acid acylated
carbohydrates
Mwale and Masika[63]
PH = pulmonary hypertension; iNOS = inducible nitric oxide synthase; NF-κB = nuclear factor kappa B; TNF-α = tumour necrosis factor alpha; IL-1β = interleukin 1beta; IL-6 = interleukin 6.
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(HO-1) signalling pathway (Table3). Mitochondrial dysfunction
is considered a key component of PH that occurs specically in
PASMCs and PAECs.[71] Potent antioxidants[32,72] that could improve
mitochondrial function and mitochondrial regulation have
previously been highlighted as therapeutic targets for PH by our
group.[13,73] It therefore follows that African medicinal plants may
be able to show benet in PH models by reducing ROS production,
limiting oxidative stress and improving mitochondrial function.
Antiprolic eects of African medicinal
plants
African medicinal plants have potent antiprolic eects in a wide
range of experimental models.[78] A root bark extract of Zanthoxylum
paracanthum was tested in human breast cancer (HCC1395)
and human prostate cancer (DU145) cell lines, where it showed
antiprolic activity,[79] but the mechanisms remain poorly understood.
e African cherry has demonstrated antiprolic activity in human
prostate cancer cells, which is believed to be mediated via reduced
apoptosis.[80] Other plants that have similar eects include Zingiber
ocianale and Sutherlandia frutescens in human cancer cell lines[81,82]
(Table4).
In PH, proliferation is a key feature that leads to pulmonary
arteriolar remodelling,[83] and because PASMCs and PAECs become
resistant to apoptosis, PH has been deemed to have a cancer-like
phenotype.[84] Furthermore, impaired apoptosis regulation in
these cells is also a major determinant of PASMC proliferation in
remodelling.[85] ere are myriad mechanisms outside the scope of
this review, but impaired apoptosis regulation and cell metabolism
are instrumental. Given the evidence that African medicinal plants
can induce antiprolic eects, it is therefore likely that that they
may also provide benet against the cancer-like phenotype observed
inPH.
African medicinal plants that have been
tested in models expressing features
ofPH
Some African medicinal plants have been reported to induce therapeutic
eects either in PH models or in experimental models that express
certain key features of PH, including right ventricular hypertrophy, lung
brosis, pulmonary inammation, pulmonary artery vasoconstriction
and endothelial cell proliferation (Table5). ese plants can reduce
inammation in PH models by decreasing inammation factors such
as nuclear factor kappa B (NF-κB), TNF-α, and type 1 and type 2
T-helper (1 and 2) cytokines.[88] African medicinal plants have
polyphenols that give these plants the ability to counteract the features
listed here, through potent antioxidant actions. Some of these plants can
increase antioxidant enzyme activities of superoxide dismutase, catalase
and glutathione peroxidase, while others can regulate mitochondrial
function as a means to limiting ROS production.[89,90] Other plants
induce vascular relaxation by increasing NO and endothelial NO
synthase expression (Table5). Extracts of these plants have also been
reported to counteract vascular remodelling in PH models, doing
so by suppressing epithelial-mesenchymal transition through the
transforming growth factor beta1 (TGF-β1)/Smad pathway,[91] which
decreases the expression of p38 mitogen-activated protein[92] and causes
reduction of endothelin1.[93]
Challenges and recommendations
Several challenges exist concerning the use of medicinal plants
for the treatment of human diseases. It must be acknowledged
that African medicinal plants often have pleiotropic effects,[102]
and establishing a single mechanism is dicult. Other challenges
include poor bioavailability,[103] nonspecific or pleiotropic
actions,[42] mitohormesis,[104] drug interactions,[105] and poor
pharmacokinetics[106] and lack of accurate/effective dosage and
Table3. African medicinal plants could be repurposed for PH owing to their highly relatable mechanisms of actions against
pathways that are key to PH pathogenesis
Plant Common name Experimental model Mechanism References
Dacryodes edulis Safou plum Fructose-STZ diabetes induced
rat model
Suppresses the expression of Nrf-2
to induce antioxidant activity
Erukainure etal.[74]
Moringa oleifera Drumstick tree
or moringa
In vitro model Suppresses H2O2-induced
mitochondrial depolarisation and
apoptosis through suppression
of the mitochondrial-mediated
apoptosis pathway, while it activates
the Nrf-2/HO-1 signalling pathway
Kirindage etal.[75]
Lipopolysaccharide-induced
inammation model in mice
Decreased mitochondrial
superoxide content, and restoration
of the mitochondrial membrane
potential in the LPS-induced
macrophages
Sailaja etal.[76]
Aloe vera Aloe In vitro model Attenuates oxidative stress, initiates
antioxidant defences, regulates
mitochondrial dysfunction and
suppresses apoptosis
Xu etal.[77]
Aloe claviora Aloe In vitro model Inhibits lipid peroxidation and has
ROS scavenging eects
Lindsey etal.[67]
PH = pulmonary hypertension; Nrf-2 = nuclear respiratory factor 2; H2O2 = hydrogen peroxide; HO-1 = haem oxygenase 1; LPS = lipopolysaccharide; ROS = reactive oxygen species.
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Table4. African medicinal plants (tested in non-PH models) with antiprolic and apoptosis activity for smooth-muscle cell
remodelling that could be repurposed for PH
Plant Common name Experimental model Mechanism References
Curculigo orchioides
Gaertn
Golden eye
grass or black
musli
In a human breast cancer cell
line (MCF-7)
Induced anti-cancer eects
by increasing cell death of
cancercells
Singh[86]
Sutherlandia
frutescens
Cancer bush LS180 colorectal cancer
mini-tumours
Induced anti-cancer eects by
limiting cancer cell metabolism
Gouws etal.[81]
Fagaropsis angolensis Murumu or dale roat and colon cancer cell
lines (Hep2 and CT-26.CL-25)
Induced antiprolic eects via
the actions of polyphenols
Gaobotse etal.[87]
Zanthoxylum
paracanthum
Kokwaro
(Rutaceae)
Cancer cell lines (HCC1395,
DU145, Vero E6)
Induced antiprolic activity Kaigongi etal.[79]
Prunus africana African cherry Human prostate cancer cells
(PC3)
Induced antiprolic activity
possibly mediated via an
increase in apoptosis
Komakech etal.[80]
PH = pulmonary hypertension.
Table5. A list of African medicinal plants that have demonstrated to have therapeutic actions in models that express features of PH
Plant Experimental model of PH Mechanism References
Terminalia arjuna Monocrotaline-induced
PHrat model
Reduces right ventricle hypertrophy and medial wall
thickness of pulmonary arteries through the decrease
of lipid peroxidation, and NADPH oxidases protein
expression in the lung and increases superoxide
dismutase and catalase activity
Kapoor etal.,[94]
Pawar and Bhutani[95]
Moringa oleifera Lam. Monocrotaline-induced
PHrat model
Increases superoxide dismutase levels Chen etal.[96]
Securigera securidaca L. Broiler chicken reared at
high altitude
Prevents the inactivation of NO through scavenging of
superoxide ions
Ahmadipour[97]
Allium sativium (garlic) Acute hypoxic pulmonary
vasoconstriction
Increases the action of endothelial NO synthase,
thereby relaxing the vascular smooth muscles
Fallon etal.[98]
Allium macrostemon
Bunge
Isolated pulmonary artery Initiates Ca2+/protein kinase A and endothelial NO
synthase signalling pathway in endothelial cells
Han etal.[99]
Trifolium pratense L. Broiler chicken reared at
high altitude
Increases NO synthase secretion Jiang and Yang[93]
Mimosa pigra L. Hypoxia-induced PH in rats Elevates NO production and decreases pulmonary
artery pressure in hypoxia-induced PH
Rakotomalala etal.[92]
Centella asiatica Hypoxia-induced PH in rats Activates the NO-mediated signals by enhancing the
phosphorylation of serine/threonine-specic protein
kinase/eNOS, thus promoting NO production and
protecting endothelial cells from hypoxia-induced
apoptosis
Wang etal.[100]
Acacia senegal Waterpipe smoke exposure Prevents pulmonary inammation and DNA damage,
and restores the impairment of lung function via
prevention of expression of NF-κB that induced an
overexpression of Nrf2 in mice
Nemmar etal.[101]
Artemisia herba-alba
Asso.
Broiler chicken Down-regulates and up-regulates 1 and 2
cytokines, respectively, in chronic multisystemic
inammation in Algerian patients
Messaoudene etal.[88]
Trifolium pratense L. Broiler chicken Reduces endothelin 1 in lung tissues Jiang and Yang[93]
Mimosa pigra L. Hypoxia-induced PH in rats Decreases the expression of p38 mitogen-activated
protein, thus ameliorating the proliferative endothelial
cells of the lung tissue in rats
Rakotomalala etal.[92]
Aloe ferox Paraquat-induced
pulmonary brosis in mice
Attenuates pulmonary brosis by suppressing the EMT
process through the TGF-β1/Smads/p38 pathway
Zhang etal.[91]
PH = pulmonary hypertension; NADPH = nicotinamide adenine dinucleotide phosphate; NO = nitric oxide; Ca2+ = calcium ions; eNOS = endothelial nitric oxide synthase; NF-κB = nuclear factor kappa
B; Nrf2 = nuclear respiratory factor 2; 1 = type 1 T-helper; 2 = type 2 T-helper; EMT = epithelial-mesenchymal transition; TGF-β1 = transforming growth factor beta 1.
64 AJTCCM VOL. 30 NO. 2 2024
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dose conversion from experimental studies to human trials.[107,108]
However, great advances have been made in trying to overcome these
challenges in experimental studies or clinical trials, such as the use of
inductively coupled plasma-optical emission spectrophotometry[103]
and nanoparticles[109] to improve, for example, bioavailability. e
latter has had considerable success in previous studies. A point of
caution is needed here, as conventional methods of nanoparticle
production use polyvinyl alcohol, polyethylene glycol, and D-alpha-
tocopheryl polyethylene glycol 1000 succinate as stabilisers during
synthesis. However, these are toxic, and researchers have been
searching for stabilisers that are non-toxic. Studies have shown that
plant extracts can also be used as stabilisers for the fabrication of
stable poly (lactide-co-glycolide) nanoparticles.[110] We recommend
that future studies test poly (lactide-co-glycolide) nanoparticles
that have been enriched with a medicinal plant extract to enhance
cellular uptake and increase bioactivity.[111] Most medicinal plants or
herbs contain several bioactive compounds,[112] making it dicult
to know which compounds in an extract have been loaded onto
the nanoparticle, so it may be challenging to ensure consistent
experimental outcomes across studies. We are of the opinion that
where all or most of the individual compounds in an extract have
been successfully captured onto nanoparticles, it may still provide
signicant health benets or remarkably improve the actions of
nanoparticles.[113,114]
Conclusion
Drug repurposing oers a relatively novel approach to achieving
better treatment outcomes in PH. Drugs that could be repurposed for
PH include melatonin, anakinra, rituximab and nesiritide. African
medicinal plants also have potential as adjuvant therapies for PH,
as they have been reported to have few to no side-eects and the
ability to counteract instrumental pathways or vascular remodelling,
which makes them attractive therapeutic targets for PH. ey may
improve the quality of life of patients suering from PH and could
oer an aordable adjuvant in resource-limited settings. Viable
options include A. linearis, Allium sativium, Trifolium pratense L.,
Mimosa pigra L. and Aloe ferox. However, the majority of these
plants have never been tested in an experimental PH model, so our
proposition is hypothetical at best. Regardless, we believe that future
studies should investigate these and other African medicinal plants
in appropriate models of PH, to test their ecacy and eectiveness.
Perhaps one day we will be able to put Africa’s diverse ora to good
use in PH research.
Declaration. None.
Acknowledgements. None.
Author contributions. All authors meet the criteria to qualify as authors,
have contributed signicantly and equally to the manuscript, and have
seen/approved the nal version of the manuscript.
Funding. Special thanks and appreciation to the Faculty of Medicine
and Health Sciences at Stellenbosch University, the National Research
Foundation of South Africa, the South African Medical Research Council,
the South African Rooibos Council, and the Harry Crossley Foundation
of South Africa.
Conicts of interest.None.
1. Simonneau G, Montani D, Celermajer DS, etal. Haemodynamic definitions
and updated clinical classification of pulmonary hypertension. Eur Respir J
2019;53(1):1801913. https://doi.org/10.1183/13993003.01913-2018
2. ienemann F, Dzudie A, Mocumbi AO, etal. e causes, treatment, and outcome
of pulmonary hypertension in Africa: Insights from the Pan African Pulmonary
Hypertension Cohort (PAPUCO) Registry. Int J Cardiol 2016;221:205-211. https://
doi.org/10.1016/j.ijcard.2016.06.242
3. Hui-i G. e management of acute pulmonary arterial hypertension. Cardiovasc
er 2011;29(3):153-175. https://doi.org/10.1111/j.1755-5922.2009.00095.x
4. Simonneau G. Updated clinical classication of pulmonary hypertension. J Am Coll
Cardiol 2013;62(25 Suppl):D34-D41. https://doi.org/10.1016/j.jacc.2013.10.029
5. Hoeper MM, Humbert M, Souza R, etal. A global view of pulmonary hypertension.
Lancet Respir Med 2016;4(4):306-322. https://doi.org/10.1016/S2213-2600(15)00543-3
6. Mocumbi AO, ienemann F, Sliwa K. A global perspective on the epidemiology
of pulmonary hypertension. Can J Cardiol 2015;31(4):375-381. https://doi.
org/10.1016/j.cjca.2015.01.030
7. Idrees M, Butrous G, Mocumbi A, etal. Pulmonary hypertension in the developing
world: Local registries, challenges, and ways to move forward. Glob Cardiol Sci
Pract 2020;2020(1):e202014. https://doi.org/10.21542/gcsp.2020.14
8. Rosenkranz S, Howard LS, Gomberg-Maitland M, Hoeper MM. Systemic
consequences of pulmonary hypertension and right-sided heart failure. Circulation
2020;141(8):678-693. https://doi.org/10.1161/CIRCULATIONAHA.116.022362
9. Toshner M, Spiekerkoetter E, Bogaard H, Hansmann G, Nikkho S, Prins KW.
Repurposing of medications for pulmonary arterial hypertension. Pulm Circ
2020;10(4):2045894020941494. https://doi.org/10.1177/2045894020941494
10. Gessler T. Inhalation of repurposed drugs to treat pulmonary hypertension. Adv
Drug Deliv Rev 2018;133:34-44. https://doi.org/10.1016/j.addr.2018.06.003
11. Prins KW, enappan T, Weir EK, Kalra R, Pritzker M, Archer SL. Repurposing
medications for treatment of pulmonary arterial hypertension: What’s old
is new again. J Am Heart Assoc 2019;8(1):e011343. https://doi.org/10.1161/
JAHA.118.011343
12. eilmann AL, Ormiston ML. Repurposing benzbromarone for pulmonary arterial
hypertension: Can channelling the past deliver the therapy of the future? Eur Respir
J 2019;53(6):1900583. https://doi.org/10.1183/13993003.00583-2019
13. Maarman GJ. Pulmonary arterial hypertension and the potential roles of
metallothioneins: A focused review. Life Sci 2018;214:77-83. https://doi.
org/10.1016/j.lfs.2018.10.039
14. Teichert-Kuliszewska K, Kutryk MJB, Kuliszewski MA, etal. Bone morphogenetic
protein receptor-2 signaling promotes pulmonary arterial endothelial cell
survival: Implications for loss-of-function mutations in the pathogenesis of
pulmonary hypertension. Circ Res 2006;98(2):209-217. https://doi.org/10.1161/01.
RES.0000200180.01710.e6
15. Stacher E, Graham BB, Hunt JM, etal. Modern age pathology of pulmonary
arterial hypertension. Am J Respir Crit Care Med 2012;186(3):261-272. https://doi.
org/10.1164/rccm.201201-0164OC
16. Gale S. e evolving treatment landscape of pulmonary arterial hypertension. Am
J Manag Care 2021;27(3 Suppl):S42-S52. https://doi.org/10.37765/ajmc.2021.88610
17. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary
hypertension. Circulation 2002;106(12):1477-1482. https://doi.org/10.1161/01.
cir.0000029100.82385.58
18. Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial
hypertension: Prediction by the 2015 European pulmonary hypertension
guidelines risk stratication model. Eur Respir J 2017;50(2):1700740. https://doi.
org/10.1183/13993003.00740-2017
19. Swisher JW, Weaver E. e evolving management and treatment options for patients
with pulmonary hypertension: Current evidence and challenges. Vasc Health Risk
Manag 2023;19:103-126. https://doi.org/10.2147/VHRM.S321025
20. Cha Y, Erez T, Reynolds IJ, etal. Drug repurposing from the perspective of
pharmaceutical companies. Br J Pharmacol 2018;175(2):168-180. https://doi.
org/10.1111/bph.13798
21. Kantarjian HM, Cortes JE, Kim D-W, etal. Bosutinib safety and management of
toxicity in leukemia patients with resistance or intolerance to imatinib and other
tyrosine kinase inhibitors. Blood 2014;123(9):1309-1318. https://doi.org/10.1182/
blood-2013-07-513937
22. Ahmed AA, Khaleel KJ, Fadhel AA. Potential effect of imatinib on some sex
hormones for male patients of chronic myelogenous leukemia in Baghdad province.
Bionatura 2021;6(4):2193-2195. https://doi.org/10.21931/RB/2021.06.04.9
23. Solinc J, Ribot J, Soubrier F, Pavoine C, Dierick F, Nadaud S. e platelet-derived
growth factor pathway in pulmonary arterial hypertension: Still an interesting
target? Life (Basel) 2022;12(5):658. https://doi.org/10.3390/life12050658
24. Frost AE, Barst RJ, Hoeper MM, etal. Long-term safety and ecacy of imatinib in
pulmonary arterial hypertension. J Heart Lung Transplant 2015;34(11):1366-1375.
https://doi.org/10.1016/j.healun.2015.05.025
AJTCCM VOL. 30 NO. 2 2024 65
REVIEW
25. Spiekerkoetter E, Sung YK, Sudheendra D, etal. Randomised placebo-controlled
safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension.
Eur Respir J 2017;50(3):1602449. https://doi.org/10.1183/13993003.02449-2016
26. Kawut SM, Archer-Chicko CL, DeMichele A, etal. Anastrozole in pulmonary
arterial hypertension: A randomised, double-blind, placebo-controlled trial. Am J
Respir Crit Care Med 2017;195(3):360-368. https://doi.org/10.1164/rccm.201605-
1024OC
27. Feng W, Wang J, Yan X, etal. Paclitaxel alleviates monocrotaline-induced pulmonary
arterial hypertension via inhibition of FoxO1-mediated autophagy. Naunyn
Schmiedebergs Arch Pharmacol 2019;392(5):605-613. https://doi.org/10.1007/
s00210-019-01615-4
28. Zhao J, Yang M, Wu X, etal. Eects of paclitaxel intervention on pulmonary vascular
remodeling in rats with pulmonary hypertension. Exp er Med 2019;17(2):1163-
1170. https://doi.org/10.3892/etm.2018.7045
29. Zhang LL, Lu J, Li MT, Wang Q, Zeng XF. Preventive and remedial application of
etanercept attenuate monocrotaline-induced pulmonary arterial hypertension. Int J
Rheum Dis 2016;19(2):192-198. https://doi.org/10.1111/1756-185X.12304
30. Cheong HI, Farha S, Park MM, etal. Endothelial phenotype evoked by low dose
carvedilol in pulmonary hypertension. Front Cardiovasc Med 2018;5:180. https://
doi.org/10.3389/fcvm.2018.00180
31. Hung MW, Yeung HM, Lau CF, Poon AMS, Tipoe GL, Fung ML. Melatonin
attenuates pulmonary hypertension in chronically hypoxic rats. Int J Mol Sci
2017;18(6):1125. https://doi.org/10.3390/ijms18061125
32. Maarman G, Blackhurst D, ienemann F, etal. Melatonin as a preventive and
curative therapy against pulmonary hypertension. J Pineal Res 2015;59(3):343-353.
https://doi.org/10.1111/jpi.12263
33. Wang R, Pan J, Han J, etal. Melatonin attenuates dasatinib-aggravated hypoxic
pulmonary hypertension via inhibiting pulmonary vascular remodeling. Front
Cardiovasc Med 2022;9:790921. https://doi.org/10.3389/fcvm.2022.790921
34. Ryan JJ. Chloroquine in pulmonary arterial hypertension: A new role for an
old drug? Circ Cardiovasc Genet 2013;6:310-311. https://doi.org/10.1161/
CIRCGENETICS.113.000214
35. Trankle CR, Canada JM, Kadariya D, etal. IL-1 blockade reduces inammation in
pulmonary arterial hypertension and right ventricular failure: A single-arm, open-
label, phase IB/II pilot study. Am J Respir Crit Care Med 2019;199(3):381-384.
https://doi.org/10.1164/rccm.201809-1631LE
36. Zamanian RT, Badesch D, Chung L, etal. Safety and ecacy of B-cell depletion
with rituximab for the treatment of systemic sclerosis-associated pulmonary
arterial hypertension: A multicenter, double-blind, randomised, placebo-controlled
trial. Am J Respir Crit Care Med 2021;204(2):209-221. https://doi.org/10.1164/
rccm.202009-3481OC
37. Humbert M, McLaughlin V, Gibbs JSR, etal. Sotatercept for the treatment of
pulmonary arterial hypertension. N Engl J Med 2021;384(13):1204-1215. https://
doi.org/10.1056/NEJMoa2024277
38. Grzegorzewska AP, Seta F, Han R, etal. Dimethyl fumarate ameliorates pulmonary
arterial hypertension and lung brosis by targeting multiple pathways. Sci Rep
2017;7:41605. https://doi.org/10.1038/srep41605
39. Fujita H, Fukumoto Y, Saji K, etal. Acute vasodilator eects of inhaled fasudil, a
specic Rho-kinase inhibitor, in patients with pulmonary arterial hypertension.
Heart Vessels 2010;25(2):144-149. https://doi.org/10.1007/s00380-009-1176-8
40. Fukumoto Y, Matoba T, Ito A, etal. Acute vasodilator eects of a Rho-kinase
inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart
2005;91(3):391-392. https://doi.org/10.1136/hrt.2003.029470
41. Michaels AD, Chatterjee K, de Marco T. Effects of intravenous nesiritide on
pulmonary vascular hemodynamics in pulmonary hypertension. J Card Fail
2005;11(6):425-431. https://doi.org/10.1016/j.cardfail.2005.01.009
42. Mahomoodally MF. Traditional medicines in Africa: An appraisal of ten potent
African medicinal plants. Evid Based Complement Alternat Med 2013;2013:617459.
https://doi.org/10.1155/2013/617459
43. Verma S, Singh SP. Current and future status of herbal medicines. Vet World
2008;1(11):347-350. https://doi.org/10.5455/vetworld.2008.347-350
44. Unuofin JO, Otunola GA, Afolayan AJ. Polyphenolic content, antioxidant
and antimicrobial activities of Vernonia mespilifolia Less. Used in folk
medicine in the Eastern Cape Province, South Africa. J Evid Based Integr Med
2018;23:2515690x18773990. https://doi.org/10.1177/2515690X18773990
45. Van Wyk B-E. A review of commercially important African medicinal plants. J
Ethnopharmacol 2015;176:118-134. https://doi.org/10.1016/j.jep.2015.10.031
46. Brown AC, Reitzenstein JE, Liu J, Jadus MR. e anti-cancer eects of poi (Colocasia
esculenta) on colonic adenocarcinoma cells in vitro. Phytother Res 2005;19(9):767-
771. https://doi.org/10.1002/ptr.1712
47. Mohammed A. Hypoglycemic potential of African medicinal plants in diabetic
and non-diabetic human subjects: A review. Clin Complement Med Pharmacol
2023;3(2):100081. https://doi.org/10.1016/j.ccmp.2023.100081
48. Khumalo GP, van Wyk BE, Feng Y, Cock IE. A review of the traditional use of
southern African medicinal plants for the treatment of inflammation and
inammatory pain. J Ethnopharmacol 2022;283:114436. https://doi.org/10.1016/j.
jep.2021.114436
49. Cock IE, van Vuuren SF. e traditional use of southern African medicinal plants
for the treatment of bacterial respiratory diseases: A review of the ethnobotany
and scientific evaluations. J Ethnopharmacol 2020;263:113204. https://doi.
org/10.1016/j.jep.2020.113204
50. De Wet CJ, Aeck DG, Jacobsohn E, etal. Inhaled prostacyclin is safe, eective,
and aordable in patients with pulmonary hypertension, right heart dysfunction,
and refractory hypoxemia aer cardiothoracic surgery. J orac Cardiovasc Surg
2004;127(4):1058-1067. https://doi.org/10.1016/j.jtcvs.2003.11.035
51. Xiang L, Li Y, Deng X, Kosanovic D, Schermuly RT, Li X. Natural plant
products in treatment of pulmonary arterial hypertension. Pulm Circ
2018;8(3):2045894018784033. https://doi.org/10.1177/2045894018784033
52. Xue Z, Li Y, Zhou M, et al. Traditional herbal medicine discovery for the
treatment and prevention of pulmonary arterial hypertension. Front Pharmacol
2021;12:720873. https://doi.org/10.3389/fphar.2021.720873
53. Zeng Z, Wang X, Cui L, Wang H, Guo J, Chen Y. Natural products for the treatment
of pulmonary hypertension: Mechanism, progress, and future opportunities. Curr
Issues Mol Biol 2023;45(3):2351-2371. https://doi.org/10.3390/cimb45030152
54. Humbert M, Morrell NW, Archer SL, etal. Cellular and molecular pathobiology of
pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12S):S13-S24. https://
doi.org/10.1016/j.jacc.2004.02.029
55. Chedea VS, Jisaka M. Inhibition of soybean lipoxygenases – structural and activity
models for the lipoxygenase isoenzymes family. In: Krezhova D, ed. Recent Trends
for Enhancing the Diversity and Quality of Soybean Products. IntechOpen,
2011:109-130. https://doi.org/10.5772/17976
56. Nworu CS, Akah PA. Anti-inflammatory medicinal plants and the molecular
mechanisms underlying their activities. Afr J Tradit Complement Altern Med
2015;12(Suppl):52-61. https://doi.org/10.4314/ajtcam.v12i6.3S
57. Kim HP, Son KH, Chang HW, Kang SS. Anti-inammatory plant avonoids and
cellular action mechanisms. J Pharmacol Sci 2004:96(3):229-245. https://doi.
org/10.1254/jphs.crj04003x
58. Ajuwon OR, Oguntibeju OO, Marnewick JL. Amelioration of lipopolysaccharide-
induced liver injury by aqueous rooibos (Aspalathus linearis) extract via inhibition
of pro-inammatory cytokines and oxidative stress. BMC Complement Altern Med
2014;14:392. https://doi.org/10.1186/1472-6882-14-392
59. Lee W, Bae J-S. Anti-inammatory eects of aspalathin and nothofagin from
rooibos (Aspalathus linearis) in vitro and in vivo. Inammation 2015;38(4):1502-
1516. https://doi.org/10.1007/s10753-015-0125-1
60. Ojewole JA. Antinociceptive, anti-inammatory and antidiabetic properties of
Hypoxis hemerocallidea Fisch. & C.A. Mey. (Hypoxidaceae) corm [‘African Potato’]
aqueous extract in mice and rats. J Ethnopharmacol 2006;103(1):126-134. https://
doi.org/10.1016/j.jep.2005.07.012
61. Zulqar F, Khan SI, Ali Z, etal. Norlignan glucosides from Hypoxis hemerocallidea
and their potential in vitro anti-inflammatory activity via inhibition of iNOS
and NF-κB. Phytochemistry 2020;172:112273. https://doi.org/10.1016/j.
phytochem.2020.112273
62. Zhen J, Guo Y, Villani T, etal. Phytochemical analysis and anti-inammatory activity
of the extracts of the African medicinal plant Ximenia cara. J Anal Methods Chem
2015;2015:948262. https://doi.org/10.1155/2015/948262
63. Mwale M, Masika PJ. Analgesic and anti-inammatory activities of Aloe ferox Mill.
aqueous extract. Afr J Pharm Pharmacol 2010;4(6):291-297.
64. Nau MO, Salawu MO, Kazeem MI. 21-Antioxidant activity of African medicinal
plants. In: Kuete V, ed. Medicinal Plant Research in Africa. Oxford: Elsevier,
2013:787-803. https://doi.org/10.1016/B978-0-12-405927-6.00021-7
65. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol
2013;53:401-426. https://doi.org/10.1146/annurev-pharmtox-011112-140320
66. Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid
Redox Signal 2018;29(17):1727-1745. https://doi.org/10.1089/ars.2017.7342
67. Lindsey KL, Viljoen AM, Jäger AK. Screening of Aloe species for antioxidant activity.
S Afr J Botany 2003;69(4):599-602. https://doi.org/10.1016/S0254-6299(15)30302-1
68. Tirichen H, Yaigoub H, Xu W, Wu C, Li R, Li Y. Mitochondrial reactive oxygen
species and their contribution in chronic kidney disease progression through
oxidative stress. Front Physiol 2021;12:627837. https://doi.org/10.3389/
fphys.2021.627837
69. Mailloux RJ. Mitochondrial antioxidants and the maintenance of cellular
hydrogen peroxide levels. Oxid Med Cell Longev 2018;2018:7857251. https://doi.
org/10.1155/2018/7857251
70. Dan Dunn J, Alvarez LAJ, Zhang X, Soldati T. Reactive oxygen species and
mitochondria: A nexus of cellular homeostasis. Redox Biol 2015;6:472-485. https://
doi.org/10.1016/j.redox.2015.09.005
71. Suliman HB, Nozik-Grayck E. Mitochondrial dysfunction: Metabolic drivers of
pulmonary hypertension. Antioxid Redox Signal 2019;31(12):843-857. https://doi.
org/10.1089/ars.2018.7705
72. Maarman GJ, Lecour S. Melatonin against pulmonary arterial hypertension: Is
it ready for testing in patients? Cardiovasc J Afr 2021;32(2):111-112. https://doi.
org/10.5830/CVJA-2021-008
66 AJTCCM VOL. 30 NO. 2 2024
REVIEW
73. Maarman GJ. Making a case for metallothioneins conferring cardioprotection
in pulmonary hypertension. Med Hypotheses 2020;137:109572. https://doi.
org/10.1016/j.mehy.2020.109572
74. Erukainure OL, Ijomone OM, Chukwuma CI, Xiao X, Salau VF, Islam MS.
Dacryodes edulis (G. Don) H.J. Lam modulates glucose metabolism, cholinergic
activities and Nrf2 expression, while suppressing oxidative stress and dyslipidemia
in diabetic rats. J Ethnopharmacol 2020;255:112744. https://doi.org/10.1016/j.
jep.2020.112744
75. Kirindage KGIS, Fernando IPS, Jayasinghe AMK, etal. Moringa oleifera hot water
extract protects vero cells from hydrogen peroxide-induced oxidative stress by
regulating mitochondria-mediated apoptotic pathway and Nrf2/HO-1 signaling.
Foods 2022;11(3):420. https://doi.org/10.3390/foods11030420
76. Sailaja BS, Aita R, Maledatu S, Ribnicky D, Verzi MP, Raskin I. Moringa
isothiocyanate-1 regulates Nrf2 and NF-κB pathway in response to LPS-driven
sepsis and inammation. PLoS ONE 2021;16(4):e0248691. https://doi.org/10.1371/
journal.pone.0248691
77. Xu C, Ding C, Zhou N, Ruan X-M, Guo B-X. A polysaccharide from Aloe vera L. var.
chinensis (Haw.) Berger prevents damage to human gastric epithelial cells in vitro
and to rat gastric mucosa in vivo. J Functional Foods 2016;24:501-512. https://doi.
org/10.1016/j.j.2016.04.035
78. Osafo N, Boakye YD, Agyare C, Obeng S, Foli JE, Minkah PAB. African plants
with antiproliferative properties. In: Farid AB, ed. Natural Products and Cancer
Drug Discovery. IntechOpen, 2017: ch. 1. https://doi.org/10.5772/intechopen.68568
79. Kaigongi MM, Lukhoba CW, Yaouba S, Makunga NP, Githiomi J, Yenesew A. In
vitro antimicrobial and antiproliferative activities of the root bark extract and
isolated chemical constituents of Zanthoxylum paracanthum Kokwaro (Rutaceae).
Plants (Basel) 2020;9(7):920. https://doi.org/10.3390/plants9070920
80. Komakech R, Yim NH, Shim KS, etal. Root extract of a micropropagated Prunus
africana medicinal plant induced apoptosis in human prostate cancer cells (PC-3)
via caspase-3 activation. Evid Based Complement Alternat Med 2022;2022:8232851.
https://doi.org/10.1155/2022/8232851
81. Gouws C, Smit T, Willers C, Svitina H, Calitz C, Wrzesinski K. Anticancer
potential of Sutherlandia frutescens and Xysmalobium undulatum in LS180
colorectal cancer mini-tumors. Molecules 2021;26(3):605. https://doi.org/10.3390/
molecules26030605
82. Kim MO, Lee M-H, Oi N, etal. [6]-Shogaol inhibits growth and induces apoptosis
of non-small cell lung cancer cells by directly regulating Akt1/2. Carcinogenesis
2014;35(3):683-691. https://doi.org/10.1093/carcin/bgt365
83. Shi Y, Pieniek M, Fard A, O’Brien J, Mannion JD, Zalewski A. Adventitial
remodeling aer coronary arterial injury. Circulation 1996;93(2):340-348. https://
doi.org/10.1161/01.cir.93.2.340
84. Frump AL, Lai YC, Lahm T. Assessing the cancer hypothesis of pulmonary arterial
hypertension: The devil is in the detail. Am J Physiol Lung Cell Mol Physiol
2020;318(6):L1140-L1141. https://doi.org/10.1152/ajplung.00084.2020
85. Cho A, Mitchell L, Koopmans D, Langille BL. Eects of changes in blood ow rate
on cell death and cell proliferation in carotid arteries of immature rabbits. Circ Res
1997;81(3):328-337. https://doi.org/10.1161/01.res.81.3.328
86. Singh R, Gupta GA. Antimicrobial and antitumor activity of the fractionated
extracts of Kalimusli (Curculigo orchioides). Int J Green Pharmacy 2008;2(1).
https://doi.org/10.22377/ijgp.v2i1.393
87. Gaobotse G, Venkataraman S, Brown PD, etal. e use of African medicinal plants
in cancer management. Front Pharmacol 2023;14:1122388. https://doi.org/10.3389/
fphar.2023.1122388
88. Messaoudene D, Belguendouz H, Ahmedi ML, etal. Ex vivo eects of avonoïds
extracted from Artemisia herba alba on cytokines and nitric oxide production in
Algerian patients with Adamantiades-Behçet’s disease. J Inamm (Lond) 2011;8:35.
https://doi.org/10.1186/1476-9255-8-35
89. Yunusa S, Kura AU, Magaji SY, Ladan AA. Phytoconstituents and in-vivo antioxidant
activity of ethanol leaf extract of Moringa oleifera Lam (Moringacea) in mice. Acta
Sci Pharm Sci 2019;3(3):43-47.
90. Mahmoud KB, Wasli H, Mansour RB, Jemai N. Antidiabetic, antioxidant and
chemical functionalities of Ziziphus jujuba (Mill.) and Moringa oleifera (Lam.)
plants using multivariate data treatment. S Afr J Botany 2022;144(5):219-228.
https://doi.org/10.1016/j.sajb.2021.08.017
91. Zhang G, Bai R, Huang J, Gao Y, Yun X, Haji AA. Barbaloin attenuates pulmonary
brosis through TGF-β1/Smads/p38 pathway. J Pharm Pharmacol 2022;74(8):1160-
1169. https://doi.org/10.1093/jpp/rgac023
92. Rakotomalala G, Agard C, Tonnerre P, etal. Extract from Mimosa pigra attenuates
chronic experimental pulmonary hypertension. J Ethnopharmacol 2013;148(1):106-
116. https://doi.org/10.1016/j.jep.2013.03.075
93. Jiang Y, Yang Y. Trifolium pratense isoflavones improve pulmonary vascular
remodelling in broiler chickens. J Anim Physiol Anim Nutr (Berl) 2016;100(6):1159-
1168. https://doi.org/10.1111/jpn.12424
94. Kapoor D, Vijayvergiya R, Dhawan V. Terminalia arjuna in coronary artery disease:
Ethnopharmacology, pre-clinical, clinical & safety evaluation. J Ethnopharmacol
2014;155(2):1029-1045. https://doi.org/10.1016/j.jep.2014.06.056
95. Pawar R, Bhutani K. Eect of oleanane triterpenoids from Terminalia arjuna –
a cardioprotective drug on the process of respiratory oxyburst. Phytomedicine
2005;12(5):391-393. https://doi.org/10.1016/j.phymed.2003.11.007
96. Chen K-H, Chen Y-J, Yang C-H, etal. Attenuation of the extract from Moringa
oleifera on monocrotaline-induced pulmonary hypertension in rats. Chin J Physiol
2012;55(1):22-30. https://doi.org/10.4077/CJP.2012.AMM104
97. Ahmadipour B. Securigera securidaca seed medicinal herb supplementation of
diets improves pulmonary hypertensive response in broiler chickens reared at high
altitude. J Anim Physiol Anim Nutr (Berl) 2018;102(6):1601-1607. https://doi.
org/10.1111/jpn.12981
98. Fallon MB, Abrams GA, Abdel-Razek TT, etal. Garlic prevents hypoxic pulmonary
hypertension in rats. Am J Physiol 1998;275(2):L283-L287. https://doi.org/10.1152/
ajplung.1998.275.2.L283
99. Han C, Qi J, Gao S, etal. Vasodilation eect of volatile oil from Allium macrostemon
Bunge are mediated by PKA/NO pathway and its constituent dimethyl disulde
in isolated rat pulmonary arterials. Fitoterapia 2017;120:52-57. https://doi.
org/10.1016/j.tote.2017.05.007
100. Wang X, Cai X, Wang W, et al. Effect of asiaticoside on endothelial cells in
hypoxia‑induced pulmonary hypertension. Mol Med Rep 2018;17(2):2893-2900.
https://doi.org/10.3892/mmr.2017.8254
101. Nemmar A, Al-Salam S, Beegam S, Yuvaraju P, Ali BH. Waterpipe smoke exposure
triggers lung injury and functional decline in mice: Protective eect of gum Arabic.
Oxid Med Cell Longev 2019;2019:8526083. https://doi.org/10.1155/2019/8526083
102. Iwu MM. Pharmacognostical prole of selected medicinal plants. In: Iwu MM, ed.
Handbook of African Medicinal Plants. Boca Raton, Fla: CRC Press, 2014: ch. 3.
https://doi.org/10.1201/b16292-4
103. Okem A, Southway C, Ndhlala AR, van Staden J. Determination of total and
bioavailable heavy and trace metals in South African commercial herbal
concoctions using ICP-OES. S Afr J Botany 2012;82:75-82. https://doi.org/10.1016/j.
sajb.2012.07.005
104. Yun J, Finkel T. Mitohormesis. Cell Metab 2014;19(5):757-766. https://doi.
org/10.1016/j.cmet.2014.01.011
105. Cordier W, Steenkamp V. Drug interactions in African herbal remedies. Drug
Metabol Drug Interact 2011;26(2):53-63. https://doi.org/10.1515/DMDI.2011.011
106. Alolga RN, Fan Y, Zhang G, etal. Pharmacokinetics of a multicomponent herbal
preparation in healthy Chinese and African volunteers. Sci Rep 2015;5(1):12961.
https://doi.org/10.1038/srep12961
107. Nair AB, Jacob S. A simple practice guide for dose conversion between animals
and human. J Basic Clin Pharm 2016;7(2):27-31. https://doi.org/10.4103/0976-
0105.177703
108. Otieno JN, Hosea KM, Lyaruu HV, Mahunnah RL. Multi-plant or single-plant
extracts, which is the most eective for local healing in Tanzania? Afr J Tradit
Complement Altern Med 2008;5(2):165-172. https://doi.org/10.4314/ajtcam.
v5i2.31269
109. Armendáriz-Barragán B, Zafar N, Badri W, etal. Plant extracts: From encapsulation
to application. Expert Opin Drug Deliv 2016;13(8):1165-1175. https://doi.org/10.1
080/17425247.2016.1182487
110. Böke N, Kapiamba KF, Kimpiab E, Otor HO, Petrik L. Synthesis of bimetallic
FeMn nanoparticles using rooibos tea extract: Characterisation and application.
Int J Environ Sci Technol 2023;20:12741-12752. https://doi.org/10.1007/s13762-
023-04792-1
111. De Alcantara Lemos J, Oliveira AEMFM, Araujo RS, Townsend DM, Ferreira
LAM, de Barros ALB. Recent progress in micro and nano-encapsulation of
bioactive derivatives of the Brazilian genus Pterodon. Biomed Pharmacother
2021;143:112137. https://doi.org/10.1016/j.biopha.2021.112137
112. Ivanišová E, Kačániová M, Savitskaya TA, Grinshpan DD. Medicinal herbs:
Important source of bioactive compounds for food industry. In: Ahmad RS, ed.
Herbs and Spices: New Processing Technologies. IntechOpen, 2021: ch. 2. https://
doi.org/10.5772/intechopen.98819
113. Mazibuko-Mbeje SE, Dludla PV, Johnson R, etal. Aspalathin, a natural product
with the potential to reverse hepatic insulin resistance by improving energy
metabolism and mitochondrial respiration. PLoS ONE 2019;14(5):e0216172.
https://doi.org/10.1371/journal.pone.0216172
114. Patel O, Muller CJF, Joubert E, Rosenkranz B, Louw J, Awortwe C. erapeutic
eects of an aspalathin-rich green rooibos extract, pioglitazone and atorvastatin
combination therapy in diabetic db/db mice. PLoS ONE 2021;16(5):e0251069.
https://doi.org/10.1371/journal.pone.0251069
Received 4 August 2023. Accepted 25 March 2024. Published 4 July.
