Edible mushrooms as potential functional foods in amelioration of hypertension

Abstract

Edible mushrooms are popular functional foods attributed to their rich nutritional bioactive constituent profile influencing cardiovascular function. Edible mushrooms are omnipresent in various prescribed Dietary Approaches to Stop Hypertension, Mediterranean diet, and fortified meal plans as they are rich in amino acids, dietary fiber, proteins, sterols, vitamins, and minerals. However, without an understanding of the influence of mushroom bioactive constituents, mechanism of action on heart and allergenicity, it is difficult to fully comprehend the role of mushrooms as dietary interventions in alleviating hypertension and other cardiovascular malfunctions. To accomplish this endeavor, we chose to review edible mushrooms and their bioactive constituents in ameliorating hypertension. Hypertension and cardiovascular diseases are interrelated and if the former is managed by dietary changes, it is postulated that overall heart health could also be improved. With a concise note on different edible varieties of mushrooms, a particular focus is presented on the antihypertensive potential of mushroom bioactive constituents, mode of action, absorption kinetics and bioavailability. Ergosterol, lovastatin, cordycepin, tocopherols, chitosan, ergothioneine, γ‐aminobutyric acid, quercetin, and eritadenine are described as essential bioactives with hypotensive effects. Finally, safety concerns on allergens and limitations of consuming edible mushrooms with special reference to chemical toxins and their postulated metabolites are highlighted. It is opined that the present review will redirect toxicologists to further investigate mushroom bioactives and allergens, thereby influencing dietary interventions for heart health.

Full text

REVIEW
Edible mushrooms as potential functional foods in amelioration
of hypertension
Abdur Rauf
1,2
| Payal B. Joshi
3
| Zubair Ahmad
1
| Hassan A. Hemeg
4
|
Ahmed Olatunde
5
| Saima Naz
6
| Nabia Hafeez
7
| Jesus Simal-Gandara
8
1
Department of Chemistry, University of
Swabi, Swabi, Pakistan
2
Department of Chemistry, College of Science,
Princess Nourah bint Abdulrahman University,
Riyadh, Saudi Arabia
3
Operations and Method Development,
Shefali Research Laboratories, Ambernath,
India
4
Department of Medical Laboratory
Technology, College of Applied Medical
Sciences, Taibah University, Al Madinah Al
Munawwarah, Saudi Arabia
5
Department of Medical Biochemistry,
Abubakar Tafawa Balewa University, Bauchi,
Nigeria
6
Department of Biotechnology, Bacha Khan
University, Khyber Pakhtunkhwa, Pakistan
7
Center of Biotechnology and Microbiology,
University of Peshawar, Peshawar, Pakistan
8
Nutrition and Bromatology Group, Analytical
Chemistry and Food Science Department,
Faculty of Science, Universidade de Vigo,
Ourense, Spain
Correspondence
Jesus Simal-Gandara, Nutrition and
Bromatology Group, Analytical Chemistry and
Food Science Department, Faculty of Science,
Universidade de Vigo, E-32004 Ourense,
Spain.
Email: jsimal@uvigo.es
Funding information
Universidade de Vigo, Grant/Award Number:
CRUE/CSIC
Abstract
Edible mushrooms are popular functional foods attributed to their rich nutritional
bioactive constituent profile influencing cardiovascular function. Edible mushrooms
are omnipresent in various prescribed Dietary Approaches to Stop Hypertension,
Mediterranean diet, and fortified meal plans as they are rich in amino acids, dietary
fiber, proteins, sterols, vitamins, and minerals. However, without an understanding of
the influence of mushroom bioactive constituents, mechanism of action on heart and
allergenicity, it is difficult to fully comprehend the role of mushrooms as dietary inter-
ventions in alleviating hypertension and other cardiovascular malfunctions. To
accomplish this endeavor, we chose to review edible mushrooms and their bioactive
constituents in ameliorating hypertension. Hypertension and cardiovascular diseases
are interrelated and if the former is managed by dietary changes, it is postulated that
overall heart health could also be improved. With a concise note on different edible
varieties of mushrooms, a particular focus is presented on the antihypertensive
potential of mushroom bioactive constituents, mode of action, absorption kinetics
and bioavailability. Ergosterol, lovastatin, cordycepin, tocopherols, chitosan, ergothio-
neine, γ-aminobutyric acid, quercetin, and eritadenine are described as essential bio-
actives with hypotensive effects. Finally, safety concerns on allergens and limitations
of consuming edible mushrooms with special reference to chemical toxins and their
postulated metabolites are highlighted. It is opined that the present review will redi-
rect toxicologists to further investigate mushroom bioactives and allergens, thereby
influencing dietary interventions for heart health.
KEYWORDS
absorption kinetics, bioactive constituents, cardiovascular, edible mushrooms, functional foods,
hypertension
Abbreviations: AHA, American Heart Association; AMPKα, activated protein kinase α; CVDs, cardiovascular diseases; CytochromeP450scc, cytochrome P450 side-chain cleavage enzyme;
CYP7A1, cytochrome P450 7A1; DASH, Dietary Approaches to Stop Hypertension; DGAT1, diacylglycerol O-acyltransferase-1; FAOSTAT, Food and Agriculture Organization Corporate
Statistical Database; FFs, functional foods; GABA, γ-amino butyric acid; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IC
50
, half-maximal inhibitory concentration; LDLR, low-density
lipoprotein receptor; MedDiet, Mediterranean diet; PKC, protein kinase C; PWE, pressurized water extraction; SAHH, S-adenosylhomocysteine hydrolyze; SQS mRNA, squalene synthase
messenger RNA.
Received: 28 December 2022 Revised: 7 April 2023 Accepted: 24 April 2023
DOI: 10.1002/ptr.7865
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.
2644 Phytotherapy Research. 2023;37:2644–2660.
wileyonlinelibrary.com/journal/ptr

1|INTRODUCTION
Hypertension is one of the major risk factors for heart diseases and an
indicator of global health exigency. It is regarded as a chronic, non-
communicable, modifiable, and a multifactorial pathophysiological
condition associated with increased arterial blood pressure. A normal
blood pressure is sustained at an average diastolic blood pressure
(80 mmHg) and average systolic blood pressure (120 mmHg). Accord-
ing to National Health and Nutrition Examination Surveys, hyperten-
sion is defined as “systolic blood pressure greater than or equal to
140 mmHg and/or diastolic blood pressure greater than or equal to
90 mmHg”(Egan & Zhao, 2013). Hypertension, or systemic arterial
hypertension if unchecked, leads to serious pathological conditions
namely, stroke, CVDs, heart failure, aortic syndromes, aortic valve ste-
nosis, atrial fibrillation and hypertensive cardiomyopathy
(Fuchs, 2018). According to Noncommunicable Diseases Risk Factor
Collaboration report, hypertension is asymptomatic and caused a
global burden of hypertensive patients (Nguyen & Chow, 2021).
In 2015, an estimated 4.5 million deaths in men and 4.0 million
deaths in women were attributed to higher systolic pressure
(>115 mmHg), of which 88% were in low-income and middle-income
regions (Zhou et al., 2021). Efforts are directed toward either by pre-
scribing antihypertensive drugs or dietary changes that includes func-
tional foods. Functional foods (FFs) have gained considerable
attention for managing various chronic ailments including hyperten-
sion. In this review, we have focused on edible mushrooms and their
role in ameliorating hypertension.
The genesis to review edible mushrooms as functional food ingre-
dient relies on that fact that it has numerous bioactive constituents
and its promissory inclusion as healthier meat products (Pérez-Montes
et al., 2021). Table 1depicts the production of edible mushrooms in
2021. Venkatakrishnan et al. (2020) performed meta-analysis describ-
ing influence of FFs and nutraceuticals and their pathophysiological
impact on hypertension. Sporadic reports claim variety of food stuffs
or dietary changes to determine the efficacy for various pathological
conditions of the heart. Recently, growing interest on edible mush-
rooms for its functional ingredients in food industries and as dietary
supplements is palpable (You et al., 2022). With abundance of bioac-
tive constituents, mushrooms are explored for novel compounds that
could potentially act as therapeutics. Edible mushrooms have demon-
strated their efficacy as therapeutics in ailments such as diabetes,
obesity, cancer, and CVDs leading to human wellness (Singh
et al., 2022). Since long, mushrooms are explored for novel com-
pounds that may have pharmacological relevance. At times, it can be
posed that mushrooms are rich with numerous bioactives that it may
seem rather indistinguishable as edible or medicinal by terminology.
The expanse of edible mushrooms is so vast that it was realized to
reexamine the classification system of the fungus (Li et al., 2021).
Herein, we ventured to describe various edible mushrooms with
potency toward ameliorating hypertension.
The present review is structured as: first, we describe the litera-
ture review on edible mushrooms focusing on heart health. Next, we
discuss functional foods as substitutes for synthetic drugs with mush-
rooms under purview. Different types of edible mushrooms and their
bioactive constituents are discussed in detail along with some patent
literature. An insight on correlating structure of bioactive constituents
and their hypotensive effects are postulated with a concise note on
mushroom toxins. Furthermore, discussion on absorption kinetics and
bioavailability of mushroom bioactives is provided. Of all the functional
foods (FFs), it is argued that edible mushrooms exert hypocholesterole-
mia, yet with certain limitations. Taking cues from the review by Izzo
et al. (2016), we explored current efforts undertaken to determine food
(mushroom)-function (hypotension) relationship that is not a straight-
forward endeavor. A concise note on the limitations of edible mush-
rooms as a dietary functional food is presented to avoid overclaiming
its benefits per se. It is advised that health practitioners must suggest
edible mushrooms in diet with caution as it is also a potential allergen.
1.1 |Literature review
In the quest to unravel the relationship of food (mushroom)-disease
(hypertension), a literature search was performed using PubMed, Sci-
ence Direct, and Google Scholar. We also included articles that were
cross-referenced from bibliographic references from the collected
papers. Due to the premise of the review, selected patents and perti-
nent books on hypertension and edible mushrooms are cited, wher-
ever necessary, to provide an expanse to the readers.
Francia et al. (1999) reviewed on fungal macromycetes that
exerted decreased hypertension, hyperchloresterolemia and dyslipo-
protenemia. Guillam
on et al. (2010) reported the influence of consum-
ing mushrooms on CVD biomarkers and identified bioactive
constituents exerting hypotensive effects. Choi et al. (2012) described
the therapeutic potential of edible mushrooms on cardiac diseases.
This was followed by literature reports on edible mushrooms as health
promoting foods (Roupas et al., 2012; Ahmad et al., 2013; Roncero-
Ramos & Delgado-Andrade, 2017). A concise review by Mohamed
TABLE 1 Production of edible mushrooms (FAOSTAT, 2021).
Country Production (in tons)
China, Mainland 41,117,736.71
Japan 469,046.11
Poland 378,800
United States of America 343,820
Netherlands 260,000
India 243,000
Spain 163,800
Canada 137,796
Russian Federation 110,976.96
France 99,110
Indonesia 90,420.22
United Kingdom 85,754.04
Germany 83,800
Italy 67,770
Australia 42,526
RAUF ET AL.2645

Yahaya et al. (2014) discussed on correlating edible mushroom con-
sumption for preventing hypertensive symptoms. Tung et al. (2020)
reported link between cardiovascular syndrome and consuming mush-
rooms. However, the review listed various bioactive constituents of
mushrooms to heart health with no correlation to structure–activity
relationships (SAR). González et al. (2020) reviewed on edible mush-
rooms fortified in different food products. Wouk et al. (2021)
described the carbohydrate chemistry of β-glucans and their role as
polysaccharide-protein complex exerting antihypertension. Individual
studies on mushrooms are also reported such as Volvariella volvacea
(Chiu et al., 1995), Ganoderma lucidum (Ahmad et al., 2021; Rahman
et al., 2018), Pleurotus sp. (dos Reis et al., 2022). With growing interest
of edible mushrooms, this review attempts to explore relation of
mushroom bioactives with anticholesterolemic effects.
2|METHODS TO MANAGE
HYPERTENSION
An increase in the intra-arterial pressure is referred to as hyperten-
sion. Often categorized as essential and secondary hypertension, the
former one is fairly common and managed by dietary changes and
prescription drugs. Secondary hypertension is less predominant type
of metabolic disorder caused due to endocrine malfunction. The two
common methods of managing hypertension are first, prescribing
“antihypertensives”and second, including dietary changes with func-
tional foods. Nevertheless, the chosen method for controlling hyper-
tension is based on age, severity, gender and race of the patient.
2.1 |Antihypertensive drugs
Antihypertensives are synthetic drugs prescribed as a therapeutic
intervention for alleviating, preventing, or treating hypertension.
These drugs are categorized based on the site or mechanism of action.
Some of the most popular classes used as first-line therapy include,
targeting renin–angiotensin system, calcium channel blockers, adreno-
ceptor antagonists and diuretics (Jackson & Bellamy, 2015). Calcium
channel blockers act by preventing calcium to enter heart and blood
vessel muscle cells. Diltiazem, nifedipine and amlodipine tend to
enlarge the arteries thereby lowering blood pressure (Savage
et al., 2020). Enalapril, lisinopril, and perindopril are examples of angio-
tensin-converting enzyme (ACE) inhibitors that lower blood pressure by
relaxing blood vessels. Drugs such as azilsartan, candesartan, eprosar-
tan, irbesartan, losartan, olmesartan, valsartan block the renin-
angiotensin system. These drugs reduce blood pressure by dislodging
angiotensin II from the angiotensin I receptors (P. Zhang et al., 2020).
Amiloride, chlorthalidone, frusemide, and indapamide are common
diuretics, also referred to as “water pills,”which act by excreting extra
water and salts from the body via urine (Shah, 2004).
Hypercalcemia, excess fluid loss, heart palpitations, dizziness,
fatigue, and swelling are common side effects of antihypertensives.
These drugs potentially cross blood–brain barrier and blood cerebro-
spinal fluid barrier, thereby exerting psychotropic effects (Carnovale
et al., 2022; Hollis et al., 2019). There are rising incidences of
pregnancy-related hypertension called, gestational hypertension and
preeclampsia (Ford et al., 2022). Antihypertensives have adverse
impact on either the mother or fetus, or both. Dietary interventions
must be prescribed in such cases based on age, patient history and
allergenicity (Fogacci et al., 2020; Sun & Niu, 2020).
2.2 |Functional foods as alternative to
antihypertensive drugs
Functional foods (FFs) are those that are consumed as a regular diet
and offer various bioactive constituents providing nutrition and posi-
tive health impacts. Strict adherence to medication is difficult and
thus, changes in diet for intervening chronic illness without
compromising taste and flavors is plausible. Gebreyohannes et al.
(2019) discussed correlation of nonadherence to antihypertensives
and poor heart conditions. Thus, FFs are employed to achieve sustain-
able management of chronic ailments. Most of the literature features
terminologies, “functional foods”and “nutraceuticals”interchange-
ably. These terms have separate definitions. Readers are encouraged
to refer (Egbuna & Dable-Tupas, 2020; Cheung, 2009; Pandita &
Pandita, 2023) for definitions. Mushrooms are one of the popular FFs
and its consumption correlates to incorporating numerous health-
promoting compounds. They occupy special place in different cultures
as medicine and culinary delicacies. Today, food industries fortify
most of their products with edible mushrooms in ready-to-eat noo-
dles, milk powders, breads, biscuits and puddings. Edible and medici-
nal mushrooms are no different, and the former terminology is used
throughout the article for brevity.
3|EDIBLE MUSHROOMS AS POTENT
FUNCTIONAL FOODS
Mushroom are “macrofungus with distinctive fruiting body that can
be either epigeous or hypogeous and large enough to be seen with
naked eye and to be picked by hand”(Chang & Miles, 1992). Mush-
rooms are abundantly loaded with essential bioactives such as ergos-
terol, polyphenols, terpene and terpenoids, polysaccharides and
proteins (Gupta et al., 2019). All these fungal bioactives tend to exert
positive effects on reducing hypertension (Figure 1). Mushrooms pos-
sess a typical “meaty”texture making them an ideal plant-based meat
substitute. With varying degrees of success, mushrooms are included
in diet plans and fortified in meat-based food stuffs.
3.1 |DASH diet and Mediterranean foods
Enormous studies revealed that nutraceuticals (Borghi et al., 2022),
Dietary Approaches to Stop Hypertension (DASH) (Cicero et al., 2021;
Farhadnejad et al., 2019; Strilchuk et al., 2020) and Mediterranean
diets (Cowell et al., 2021; De Pergola & D'Alessandro, 2018) have a
marked influence on hypertensive patients.
2646 RAUF ET AL.

DASH or Mediterranean foods are typical culinary diet regime
that incorporates fruits, vegetables, nuts, legumes, fish, lean meat,
mushrooms, low-fat diary products and reduced saturated fats,
sodium content/salts, sugars and cholesterol. One key feature is its
exclusion of red meats. DASH diet was formulated by AHA that rec-
ommends 55% carbohydrates, 18% proteins, 27% fats with minerals
and vitamins (Appel et al., 2006). Mushroom-based diet has lower
sodium content (about 100 and 400 ppm) and hence, particularly use-
ful for hypertensive patients (Vetter, 2003). Edible mushrooms are
considered as a part of this dietary plan.
Such dietary plan is postulated to lower hypertension among
patients, though meta-analysis and systematic reviews are inconclu-
sive on this claim (Siervo et al., 2015). Mediterranean diet
(or MedDiet) is a typical meal plan for hypertensive patients and
mushrooms is considered as a vegetable on USDA's MyPyramid and
MedDiet Pyramid. Agarwal and Fulgoni III (2020) assessed the nutri-
tional influence of mushrooms prescribed by USDA's guidelines. They
examined mushroom composite (made of white, crimini and porta-
bello) and raw oyster mushrooms. It was revealed that 1 serving of
84 g (one serving 2000 kcal) raw edible mushrooms increased mac-
ronutrients (5%), dietary fiber (2%–6%), riboflavin (15%), potassium
(11%), niacin (13%–26%), Cu (13%–22%), vitamin D (9%–11%) and
choline levels (14%) post-inclusion of oyster mushrooms. The corre-
lation on edible mushrooms in MedDiet and CVDs is currently trialed
by Purdue University and Mushroom council (Campbell, 2022). Today,
most meat- or muscle-based foods are fortified with edible mush-
rooms to take advantage of its bioactive properties (Das et al., 2021).
3.2 |Different types of edible mushrooms
Portobello, oyster, shiitake, maitake, reishi, shimeji, yellow-cap, cauli-
flower and enoki mushrooms are described. Edibility of mushrooms
also comes across as being region-specific, as most wild mushrooms
that are poisonous for one particular country may be medicinal for
another region or country. Table 2lists selected patents pertaining to
novel mushroom extraction processes for hypotensive compounds.
The presence of characteristic bioactive compounds especially, high
amount of selenium further adds to lower the chances of chronic dis-
eases (Falandysz, 2008). It is loaded with vitamins (riboflavin, thia-
mine, cobalamin, ascorbic acid and vitamin D) and minerals (Mn, Ca,
Cu, Fe, P, K, Na, Mg, and Se) (Mattila et al., 2001).
3.2.1 | Portobello mushrooms
Agaricus bisporus (or portobello mushroom) is widely consumed mush-
room and has a mild taste. It contains glutathione, selenium, β-glucan,
and ergothioneine known to exert hypoglycemic and hypolipidemic
effects synergistically (Jeong et al., 2010). β-Glucan is a soluble fiber
that has the ability to form gel-like substance on digestion. This gel-
like substance traps cholesterol and triglycerides to prevent their
absorption in GI tract that eventually lowers the blood cholesterol
levels (Sima et al., 2018). Ergothioneine reduces triglyceride levels and
prevents the formation of arterial plaque—one of the causative factors
of heart failure (Martin, 2010).
3.2.2 | Oyster mushrooms
Pleurotus ostreatus (or oyster mushrooms) are widely popular, possess
mild anise-type flavors and are either served as raw or cooked forms.
Certain bioactive peptides are obtained after digestion of P. ostreatus
mushrooms inhibit ACE-I that plays a crucial role in reducing blood
pressure and glucose levels (Agunloye & Oboh, 2022; Baeva
et al., 2019).
FIGURE 1 Nutritional profile of edible mushrooms.
RAUF ET AL.2647

3.2.3 | Shiitake mushrooms
Lentinula edodes (or shiitake mushrooms) are a staple edible mush-
room characterized as large, brown mushrooms with umami flavors.
On cooking, shiitake develops a velvety texture. Bioactive compounds
such as ergosterol, eritadenine and lentinan exert hypotensive effects
(Agunloye & Oboh, 2022). Preclinical studies illustrated that shiitake
extracts stimulate removal of excess sodium renally and reduces fluid
retention. It also contains calcium and magnesium that play a key role
in lowering hypertension (Khatun et al., 2007).
3.2.4 | Maitake mushrooms
Grifola frondosa (or maitake mushrooms) are indispensable to Asian
cooking. Their name is derived from Japanese language; meaning
dancing mushrooms due to their characteristic ribbon-like appearance.
It has deep earthy flavor that makes it an ideal choice for meals with
complex flavors. In vivo studies on rat models revealed that maitake
mushrooms have potency to enhance insulin sensitivity, reduce
inflammation and triglyceride levels especially in age-related hyper-
tensive cases (Preuss et al., 2010).
3.2.5 | Reishi mushrooms
Ganoderma lingzhi (or reishi mushrooms) are characterized by their
deep-red colors and bitter taste. It is mostly consumed as as a supple-
ment in powder form and is also used in cooking. Fungal bioactives
found in reishi mushrooms play an important role in regulation of
ACE; an enzyme responsible for cardiovascular functioning and
decreased serum cholesterol levels (El Sheikha, 2022).
3.2.6 | Shimeji/brown mushrooms
Hypsizus marmoreus (or shimeji mushrooms) occur in a variety of
shapes and is bitter to taste, when consumed raw. On cooking, shimeji
mushrooms elicit a nutty umami flavor. It contains angiotensin ACE
inhibitors (oligopeptides) that reduces blood pressure. Several poly-
saccharides, flavonoids, cytokines and other phenolic content in
shimeji mushrooms prevent oxidative stress and inflammation,
thereby improving blood pressure dynamics (Chien et al., 2016).
3.2.7 | Yellow cap mushrooms
Cantharellus cibarius (or yellow cap mushrooms) are golden-yellow col-
ored wild edible chanterelle mushrooms with unique fruity-peppery fla-
vors. Niacin, pantothenic acid, vitamin D, copper, phenols and flavanoids
helps to lower blood pressure, and is safer for consumption in pregnancy-
induced hypertension and preeclampsia (Kozarski et al., 2015).
3.2.8 | Cauliflower mushrooms
As the name suggests, Sparasis crispa (or cauliflower mushrooms)
resembles to cauliflower in shape and are combined with red meat,
soups and noodle broths. Sparassol (methyl-2-hydroxy-4-methoxy-
6-methylbenzoate) is an antimicrobial agent (Sharma et al., 2022).
S. crispa was determined as an antihypertensive food and prevented
stroke on experimentation in spontaneously hypertensive rats. An
increase in NO production served as the main mechanism behind
decreased blood pressure dynamics. It improved endothelial dysfunc-
tion by activating Akt/eNOS pathway on the cerebral cortex in hyper-
tensive rats (Yoshitomi et al., 2011).
3.2.9 | Enoki (Golden needle) mushrooms
Flammulina velutipes (or enoki/enokitake mushrooms) are lighter in
color with log stems while the wild variety tends to be darker with
shorter stems. Mycosterol is a major bioactive constituent found in
enoki mushrooms that is postulated to lower blood pressure dynamics
and decrease the concentration of total cholesterol levels in blood
and liver (Yeh et al., 2014).
4|MECHANISM OF ACTION
The consumption of mushrooms is related to various biomarkers to
determine their influence on heart health and blood pressure
TABLE 2 Patents on selected edible mushrooms or their products and their pharmacological claims related to cardiovascular conditions.
Mushroom products/bioactive extraction process Pharmacological claim References
Milk powder supplement obtained from Pleurotus ostreatus Hypocholesterolemic Motte and Wyvekens
(2015)
Novel ACE inhibitor from Lentinula edodes and Creolophus cirrhatus using
proteases
Hypotensive action Ito et al. (2006)
Food supplements prepared from G. frondosa,P. eryngii and H. erinaceus Antihypertensive, lowers blood lipid
levels
Zhiqiang et al. (2008)
Method of eritadenine production in liquid phase fermentation of Lentinus
edodes
Hypocholesterolemic agent Berglund et al. (2008)
Novel method to prepare heteroglycans from Ganoderma lucidum Anti-obesity, antihypertensive Ko et al. (2017)
2648 RAUF ET AL.

dynamics. Biomarkers which are used to determine the causal food-
hypertension link are cholesterol, total LDL, HDL, fasting triacylgly-
cerol, homocysteine, homeostasis, antiplatelet aggregation, and
inflammation.
Cholesterol is an essential sterol found in all mammalian cells and
is a vital component that influences phospholipid layers, cell mem-
brane functionalities, cell cycles, protein regulation and most impor-
tantly, initiates production of steroidal hormones and bile acids
(Rozman & Gebhardt, 2020).
As seen in Figure 2, cholesterol biosynthesis is an enzymatic bio-
chemical pathway called mevalonate pathway occurring through
hepatic system and involves 20 reactions cascading through various
enzymes. The transformation of HGA-CoA to mevalonic acid is a rate-
limiting step. Any changes in HGA-CoA enzyme activity will immedi-
ately influence changes in cholesterol biosynthesis. Hence, this trans-
formation step is a therapeutic target for alleviating hypertension
especially using statins.
Statins found in mushrooms can inhibit the activity of a key
enzyme in cholesterol synthesis, called the HMG-CoA reductase.
Other modes of action are vasorelaxation by flavanols and reduced
platelet aggregation due to fibrinolytic enzymes (Figure 2b,c) that
plays similar role of plasmin in fibrinolytic system. Both flavanols, par-
ticularly quercetin and fibrinolytic enzymes are found abundantly in
mushrooms and are known to exert vasorelaxation and inhibit vascu-
lar plaque within the arteries.
Efforts to unravel the mode of action of different bioactive con-
stituents are reported (see Table 3). It is postulated that the synergis-
tic effects of mediating cholesterol biosynthesis, fibrinolytic systems
and vasorelaxation via Ca-channels prevents hypertension. A detailed
account on effect of mushroom bioactives on cholesterol homeostasis
and gut absorption is described in Section 5.1. It was recently postu-
lated that severity of COVID-19 infection and underlying hyperten-
sion is due to ACE-II enzyme activity and immunocompromised or
disordered renin-angiotensin-aldosterone system (Peng et al., 2021).
However, this claim is beyond the scope of our present discussion.
Proceeding with the next section, discussion on structural moieties of
bioactives and their influence on hypertension is presented.
5|MUSHROOM BIOACTIVES AND
CARDIOVASCULAR FUNCTION
Natural products obtained from mushrooms are well-established as
lead compounds for developing novel medicines. Lovastatin, ergos-
terol, cordycepin, polysaccharides such as mannitols, chitosan, erita-
denine, indoles, tocopherols, β-glucans, GABA, ergothioneine are
chosen bioactive constituents (Scheme 1) that exert positive effects
on heart function.
An attempt is made to examine the structural features and corre-
late them to their effects on lowering hypertension or other cardio-
vascular conditions. Chemical structures are redrawn using
ACD/ChemSketch version 2020.1.2 (Advanced Chemistry Develop-
ment Inc., Canada, http://www.acdlabs.com).
Ergosterol, a fungal phytosterol is structurally similar to choles-
terol. If ergosterol assimilates in the alimentary tract, it gets accumu-
lated in the adrenal glands. It metabolizes in vivo to generate a
bioactive constituent, 17α,24-dihydroxyergosterol (Slominski
et al., 2005) (see Scheme 2).
Ergosterol undergoes photolysis to generate various metabolites
of vitamin D that has the potential to regulate calcium levels in the
FIGURE 2 Possible mechanism of action of mushrooms on hypertension. cGMP, cyclic guanosine monophosphate; HDL, high-density
lipoprotein; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; MTTP, microsomal triglyceride transfer protein; SR-B1,
Scavenger Receptor Class B type 1; VLDL, very low-density lipoprotein.
RAUF ET AL.2649

TABLE 3 Mechanism of action to alleviate hypertension and mushroom bioactive constituents (Mohamed Yahaya et al., 2014).
Mushroom species Bioactive constituents Mechanism of action
Ganoderma lucidum Ganoderol A, B; Ganoderal A, Ganoderic acid Y ACE activity inhibition (Kabir et al., 1988)
Polyporus sclerotium Ergosta-4-6-8(14), 22-tetraen-3-one Antialdosteronic, diuretic (Yuan et al., 2004)
Lentinula edodes Potassium (K
+
form) Hyperpolarization of smooth muscle cells, stimulating Na–K pumps,
dose dependent (Haddy et al., 2006)
Lentinan, eritadenine Vasodilation (Bisen et al., 2010)
Sarcodona spratus L-Piperidine-2-carboxylic acid Competitive ACE inhibition attributed to stereochemical orientation
of COOH group (Kiyoto et al., 2008)
Marasmius androsaceus Tripeptide 3,3,5,5-tetramethyl-4-piperidone Ganglionic blocker (L. Zhang et al., 2009)
Pleurotus cystidiosus and
Agaricus bisporus
Oligo peptides and proteins ACE activity inhibition (Lau et al., 2012)
Antrodia camphorata Maleic/succinic acid derivatives, triterpenoids,
benzenoid, benzoquinone derivatives
Reduces aggregation and phosphorylation of PKC in phorbol-
12,13-dibutyrate-activated platelets (Lu et al., 2014)
Cordyceps militaris Cordycepin Alleviates cardiac hypertrophy via AMPKαsignaling and reduces
oxidative stresses (Wang et al., 2019)
SCHEME 1 Selected bioactive constituents in edible mushrooms in ameliorating hypertension.
SCHEME 2 Metabolism of ergosterol.
2650 RAUF ET AL.

body. It was predicted by Pilz et al. (2008) that lower levels of vitamin
D is associated with increased risk of hypertension and mortality.
Cordycepin is a bioactive constituent obtained from Cordyceps
militaris and exerts lowering of lipid levels in blood, alleviates accumu-
lation of total cholesterol, LDLs and triglycerides (Gao et al., 2011).
The causal link of cordycepin and antihypertensive effects could be
attributed to its structural similarity with adenosine moiety.
Lovastatin is a typical bioactive compound found in fruiting por-
tion of A. bisporus,C. cibarius and L. edodes. It comprises of a lactone
ring and conjugated decene ring connected by an ester linkage to
2-methylbutyryl group. Lovastatin can enzymatically transform to
hydroxy acid that inhibits transformation of HMG-CoA to mevalonic
acid and finally to cholesterol (Kała et al., 2020).
Tocopherols obtained from Craterellus cornucopioides is known to
exert positive effect on heart function. A systematic review by Rych-
ter et al. (2022) found the correlation of vitamin E and its role in allevi-
ating risk factors of CVDs inconclusive.
Chitosan is a polysaccharide found in Imerlia badia that could alle-
viate LDLs in blood and liver and triglyceride levels in the blood
(Ylitalo et al., 2002). The efficacy of chitosan on heart function was
explored through an in vivo study (Gallaher et al., 2000) and meta-
analysis using murine models (Ahn et al., 2021). Both these studies
were inconclusive, but meta-analysis study revealed that gut absorp-
tion results in chitosan efficacy on the heart's functionality.
Ergothioneine is a sulfur-containing amino acid with an imidazole
moiety postulated to protect heart against myoglobin oxidation to fer-
ryl myoglobin catalyzed by reactive oxygen or nitrogen species. Due
to ergothioneine's existence as a tautomer (i.e., between thiol and
thione form), its thione form tends to exist as a predominant antioxi-
dant. Smith et al. (2020) reported a direct correlation of five different
metabolites, one of which was ergothioneine obtained through diet to
enhance cardiovascular function.
γ-Aminobutyric acid (GABA) is a bioactive compound and various
in vivo and in vitro studies revealed that systemically-injected GABA-
agonists caused lowering of blood pressure and bradycardia by acti-
vating GABA-receptors in cardiovascular tissues (Kimura et al., 2002;
Ma et al., 2015).
Quercetin is a naturally occurring flavanol exerting hypotensive,
vasodilator, anti-ischemic, and antiatherosclerosis effects. Hydroxy
groups on quercetin donate their hydrogen atoms and quench singlet
oxygen or nitrogen species and are potent antioxidants. Similar role is
observed for catechin; an antioxidant and vasorelaxant rendering
them as potential bioactives for ameliorating hypertension (Serban
et al., 2016).
Eritadenine is an alkaloid that is structurally analogous to adeno-
sine moiety. It is an efficient inhibitor of cholesterol absorption within
the GI tract thereby maintaining synergistic equilibria between plasma
and tissue cholesterol levels (Bisen et al., 2010). Eritadenine exerts
faster elimination of blood cholesterol either by stimulated tissue
uptake or inhibited tissue release. However, eritadenine's direct effect
on cholesterol biosynthesis is unclear. It is postulated that eritadenine
can suppress metabolic conversion of linoleic acid to arachidonic acid
(Yamada et al., 2002) and slow down homocysteine production—an
amino acid that reduces HDL levels in plasma via a mechanism of inhi-
biting hepatic biosynthesis of main HDL apolipoprotein (Liao
et al., 2006). Eritadenine also exerts an inhibitory effect on a key
enzyme called S-adenosylhomocysteine hydrolyze (SAHH). SAHH
enzyme plays an important role in hepatic phospholipid metabolism
and hence its inhibition by eritadenine could lower cholesterol levels
in the blood serum. Furthermore, it was observed that derivative of
eritadenine called 3-deaza eritadenine and its analog compounds also
exert hypocholesterolemic activities (Yamada et al., 2007).
Edible mushrooms comprise of higher linoleic/linolenic ratio that
also influences cardiac functionalities. PUFAs are ‘essential’FAs that
get converted to tissue hormones thereby preventing arterial blood
clots and hypertension (Sande et al., 2019). Table 4depicts the
amount of important hypotensive bioactives found in selected edible
mushrooms. An efficient method to prevent CVDs and thrombosis is
antiplatelet therapy (Jennings, 2009; Kiernan et al., 2009). Yoon et al.
(2003) isolated acidic polysaccharides from Auricularia auricula that
exhibited antiplatelet aggregation. Furthermore, nonsulphated poly-
saccharide catalyzed thrombin inhibition by antithrombin. They
observed in ex vivo tests where rats were orally fed with polysaccha-
ride showed an inhibitory effect on platelet aggregation similar to
aspirin's antiplatelet activity. Hericenone B is a phenolic bioactive con-
stituent isolated from Hericinum erinaceus mushrooms which demon-
strated antiplatelet activity in collagen-induced rat and human
platelets at IC50 3μm concentration (Mori et al., 2010). D-Mannitol
is another bioactive; structurally a sugar alcohol from P. cornucopiae
that exerted hypotensive action in hypertensive rats (Hagiwara
et al., 2005). Other plethora of compounds with hypotensive effects
are, gallic acid (Jin et al., 2017), formononetin (Nestel et al., 2007; Xing
et al., 2010), chlorogenic acid (Suzuki et al., 2006) (Akila et al., 2017),
biochanin A (Jalaludeen et al., 2015), fomiroid A (Chiba et al., 2014)
and hispidin (Kim et al., 2014).
5.1 |Absorption kinetics and metabolic role of
mushroom bioactive constituents
The role of mushroom bioactives and their influence on cholesterol
biosynthesis have been extensively studied in vitro and in vivo
models. In an in vitro digestion model study, Gil-Ramírez et al. (2014)
observed that ergosterol-enriched fractions from supercritical fluid
extraction technique were superior than β-sitosterol in displacing cho-
lesterol. Moreover, sterol-enriched mushroom extracts inhibited
HMG-CoA reductase in vitro, and ergosterol was postulated to act as
a competitive inhibitor of C24-reductase due to its double bond at C-
22 position of its side chain. Polysaccharide fractions obtained using
pressurized water extraction (PWE) technique from three mushroom
varieties viz, A. bisporus,L. edodes, and P. ostreatus was postulated to
impair cholesterol absorption thereby rendering hypercholesterolemia
(Palanisamy et al., 2014). Selenium-enriched mushrooms are postu-
lated to enhance the inhibitory activity of statins. In an in vitro study,
A. bisporus extracts were obtained via PWE technique and applied to
HepG2 (hepatoma) cells for 24 h to evaluate genes responsible for
RAUF ET AL.2651

cholesterol homeostasis. They observed downregulation of squalene
synthase messenger RNA attributed to lowered cholesterol levels (Gil-
Ramirez et al., 2015). Even with the presence of bioactives in edible
mushrooms, not much benefit can be derived if they are not assimi-
lated well in the body. A seminal study was reported by Kała et al.
(2017) which demonstrated the bioavailability of bioactive constitu-
ents from 12 varieties of mushrooms in artificial digestive juices. Arti-
ficial digestive juices were prepared that mimicked typical human
digestive system (artificial saliva, gastric and intestinal juices). They
reported highest extraction of serotonin from oyster mushrooms and
phenolic compounds namely protocatechuic acid, p-hydroxybenzoic,
syringic and gallic acid (Kała et al., 2017). It was realized that zinc
(Ozyildirim & Baltaci, 2023) and indole compounds (Tan et al., 2022)
present in mushrooms have antihypertensive effects. Kała et al.
(2019) reported a seminal study on mushroom bioavailability that
revealed zinc and indole compounds could regulate hypertension.
Kała et al. (2020) reported extracting lovastatin that possesses
cholesterol-lowering effects using in vitro models. Muszy
nska et al.
(2020) reported bioavailability of copper, zinc, and selenium from shii-
take mushrooms by investigating its extraction in artificial stomach
juices. All these studies reported good bioavailability of mushroom
bioactives into the human body. Next, vitamin D deficiency is a
known phenomenon among the global populace. Amrein et al. (2020)
reported vitamin D deficiency and the general need for providing it as
a synthetic supplement. Over the years, there are collated evidences
that vitamin D and heart health are correlated. A population-based
cohort study was conducted using Mendelian randomization analyses
to evaluate dose–response relationship between vitamin D and heart
health (Sofianopoulou et al., 2021). Keegan et al. (2013) examined
in vivo study for bioavailability of vitamin D extracted from white but-
ton mushrooms. Their team reported that ingesting UV-irradiated
mushrooms loaded with D
2
had the potency to maintain or cause
increased total D levels in blood serum levels. Similar studies on bioac-
tive hypotensive constituents are also reported for ergothioneine
(Weigand-Heller et al., 2012), eritadenine (Morales et al., 2018), cor-
dycepin (J. B. Lee, Radhi, et al., 2019), quercetin (Almeida et al., 2018)
and ergosterol along with β-glucans (Morales et al., 2019).
Pertinent in vivo studies are performed that illustrate the specific
action of mushroom bioactives on genes that modulate cholesterol
biosynthesis. P. ostreatus fiber extracts were postulated to modulate
transcription of specific genes that played role in cholesterol biosyn-
thesis. On obtaining transcriptomic profiles from C57BL/6J mice fed
with hypercholesterolemic diets followed by mushroom supplemen-
ted fiber diet, demonstrated reduced triglyceride levels due to DGAT1
TABLE 4 Content of important bioactive constituents in selected edible mushrooms.
Species
Bioactive constituents
ReferencesName Content
Agaricus bisporus Ergothioneine (mg 100 g1dry weight) 45.0 Dubost et al. (2007)
Fatty acids (LA:LLA:OA) % 67.3:1.5:6.1 Öztürk et al. (2011)
β-Carotene (μg/100 g) 368.01–423.48 (cap)
281.94–754.30 (stalk)
Agboola et al. (2023)
Lovastatin (mg/kg) 565.4 Chen et al. (2012)
Lentinula edodes Eritadenine (mg 100 g1dry weight) 642.8 Afrin et al. (2016)
GABA (mg 100 g1dry weight) 62.2 Lo et al. (2012)
Ergothioneine (mg 100 g1dry weight) 1.22 Lo et al. (2012)
Fatty acids (LA:LLA:OA) % 75.8:0.28:3.5 Cohen et al. (2014)
Phellinus linteus Eritadenine (mg 100 g1dry weight) 9.4 Afrin et al. (2016)
Flammulina velutipes GABA (mg 100 g1dry weight) 26.0 Cohen et al. (2014)
Fatty acids (LA:LLA:OA) % 51.2:13.0:10.7 Cohen et al. (2014)
Ergothioneine (mg 100 g1dry weight) 9.9 Cohen et al. (2014)
Boletus edulis GABA (mg/kg) 202.1 Chen et al. (2012)
Fatty acids (LA:LLA:OA) % 33.8:1.7:31.1 Kavishree et al. (2008)
Pleurotus ostreatus Ergothioneine (mg 100 g1dry weight) 244.4 Cohen et al. (2014)
GABA (mg 100 g1dry weight) 130.5
Grifola frondosa Fatty acids (LA: OA) % 35.1:44.1 Cohen et al. (2014)
Ergothioneine (mg 100 g1dry weight) 113 Dubost et al. (2007)
Sparassis crispa Fatty acids (LA:OA) % 31.3:49.0 Kavishree et al. (2008)
Hypsizus marmoreus GABA (mg 100 g1dry weight) 11.4 Chen et al. (2012)
Ergothioneine (mg 100 g1dry weight) 41.0
Cantharellus cibarius Fatty acids (LA:OA) % 17.3:35.4 Kavishree et al. (2008)
Note: LA:LLA:OA refers to linoleic acid:linolenic acid:oleic acid respectively.
2652 RAUF ET AL.

downregulation (Caz et al., 2015). The same research group investi-
gated hypocholesterolemic activity of lard functionalized with mush-
room extracts. On evaluating mRNA levels of 17 cholesterol-related
genes in cecum, jejunum, and liver of high cholesterol-fed mice, they
postulated cholesterol-lowering effect was related to post-
transcriptional mechanism (Caz et al., 2016). Eritadenine is another
important bioactive attributed to exert hypotensive effect due to its
role in upregulating CYP7A1 expressions in the liver of hypercholes-
terolemic mice fed with L. edodes (Yang et al., 2013). When S. crispa
extracts were administered to hypertensive rat models, lipid profiles
were significantly improved due to induced upregulation of CYP7A1
mRNA gene expression and HMG-CoA reductase inhibition resulting
in cholesterol and bile excretion (Hong et al., 2015). Administering
A. brasiliensis to hypertensive rats exhibited lower cholesterol levels in
blood serum and promoted its excretion attributed to induced activity
of LDLR upregulation (de Miranda et al., 2017). We already discussed
about eritadenine and ergosterol and their influences on reducing
cholesterol in Section 5.
It is evident from in vivo model studies that certain specific gene
expression and their pathways are key biochemical features that need
detailed investigation. Rather than performing solitary mushroom
studies, a comparative study assessing different mushroom varieties
and their influence on genes regulating cholesterol metabolism and
excretion is yet elusive. Most studies utilized stem extracts, fruit cap
extracts, and sometimes whole fruiting body extracts that does not
fully substantiate the efficacy. Thus, a fresh assessment is essential to
determine bioavailability of mushroom constituents especially those,
exerting hypotensive effects with an investigation on particular genes
regulating cholesterol homeostasis, transport, and excretion.
5.2 |Safety, limitations, and other considerations
Agaritin is a poisonous bioactive constituent first isolated from
A. bisporus and is postulated to be a weak mutagen. Another carcino-
genic bioactive compound called gyromitrin was isolated from wild
edible Gyromitra esculenta mushrooms (Gry & Andersson, 2012). The
carcinogenicity of agaritin and gyromitrin is attributed to the presence
of N N bonds either as hydrazine ( NH
2
NH
2
) or diazo functional-
ities (Scheme 3). Agaritine and gyromitrin can react with stomach
acids and transform to toxins leading to vomiting and allergic reac-
tions. Hygrophorus eburneus is a white edible mushroom that produces
a potential neurotoxin called harmane and norharmane in their fruit
caps. They are called β-carbolines and are natural indole alkaloids.
Harmane could breakdown into tryptamine, a proven hallucinogen
(structurally similar to psilocybin) (Araújo et al., 2015). Some studies
are yet elusive to determine safety on consuming mushrooms. One
such case is bicyclic hemiacetals, a novel molecule obtained from edi-
ble Ramaria madagascariensis mushrooms (Liu et al., 2015). The rela-
tionship of bicyclic hemiacetal to its toxicology and SAR studies is
elusive thereby it can be considered as an antioxidant bioactive due
to OH groups and CO NH linkage. However, this is an inconclu-
sive claim and its metabolite toxicity needs detailed epidemiological
investigation.
SCHEME 3 Selected toxins in edible mushrooms and their toxic metabolites.
RAUF ET AL.2653

An attempt to link heart health with mushroom consumption was
performed by reviewing clinical studies, meta-analysis, and systematic
reviews. The cardioprotective functionalities are understood by unra-
veling effect of mushroom bioactive constituents on typical bio-
markers such as homocysteine and lipid levels. D. H. Lee, Yang, et al.
(2019) examined the correlation of consuming mushrooms in their
cohort study among US population. They reflected on the direct cor-
relation with reduced hypertension as a flawed correlation; until com-
plete epidemiologic study is performed. Systematic review by
Krittanawong et al. (2021) found the interlinking of CVDs to consum-
ing mushrooms to be inconclusive. This could be attributed to the fact
that most studies were in vitro models and detailed epidemiologic
studies were not covered.
It is also reiterated that epidemiological studies must be per-
formed across different human races and other mediated biomarkers
of CVD conditions. A systematic review on randomized controlled
clinical trial revealed that consuming mushrooms decreased total tri-
glyceride levels (Uffelman et al., 2022). However, evidences from the
report only revealed interlink between plasma triglycerides and mush-
room consumption; other lipids and lipoproteins influences were not
considered. Even though these clinical studies are inconclusive, it may
be a false negative outcome. Most meta-analysis and clinical studies
suffered from misclassification of study groups, few biomarkers of
CVDs and inefficient window period of mushrooms intake (≥5 times/
week is high intake). Hence, it is quite challenging to determine food-
disease link especially with scant literature and human volunteer stud-
ies. As mushrooms are rich in proteins, allergenicity is another concern
which was seminally addressed using in silico technique on shiitake
mushrooms (Vashisht et al., 2023). In silico prediction tool is essen-
tially used to determine protein allergens in FFs and crops. Docking
studies elucidate protein-ligand/protein–protein interactions that can
unravel crucial toxicological information for mushroom proteins as
lead drug candidates and therapeutics.
6|CONCLUSIONS AND FUTURE
OUTLOOK
This review described the correlation of bioactive constituents and
their influence on ameliorating hypertension. We compared the anti-
hypertensive drugs and the reason to shift toward FFs and dietary
changes such as DASH and MedDiet for chronic hypertension. We
also found most of the claims to be widely empirical and reliant on the
chemistries of different bioactive compounds of mushrooms. We pos-
tulated the correlation of structural moieties of mushroom bioactives
with hypotensive effects and detailed some toxic allergens and their
metabolites. Although, clinical studies are inconclusive, it does not
take away the positive effects of consuming mushrooms. Another rea-
son for the inconclusive clinical and cohort study findings is postu-
lated to the synergistic role of bioactive and their metabolites in
regulating hypertension. Out of the various mushroom bioactives, cor-
dycepin, lovastatin, eritadenine, and ergosterol are postulated to
directly influence gene expressions that induce cardiovascular func-
tionalities due to their structural similarities either with adenosine or
cholesterol moieties. These molecules could act as potential drug can-
didates that reduce hypertension which also necessitates evidences
from pharmacology and clinical biochemistry. Thus, an effort in collat-
ing SARs of bioactive constituents along with epidemiological studies
is essential to unravel the metabolic pathways and cholesterol homeo-
stasis. Dietary interventions with edible mushrooms are supposedly
effective only in the early onset of hypertension and thus, cannot be
considered therapeutic for chronic hypertensive patients. Hence, one
can proclaim dietary interventions with edible mushrooms as prophy-
lactic that does not circumvent antihypertensive drug treatment. As
discussed in Section 4, there are multitude of cascading reactions in
cholesterol biosynthesis which are influenced by mushroom bioactive
statins and other bioactive constituents. Besides cholesterol absorp-
tion, in vivo studies revealed that mushroom bioactives exert influ-
ence on certain gene expressions that regulate cholesterol transport,
metabolism, and bile acid excretion. More clinical trials are required to
be conducted, especially about mushroom polysaccharides such as
β-glucans and D-mannitol on modulating cholesterol biosynthesis and
absorption. Most clinical studies remain inconclusive and require
detailed investigation to identify different biomarkers of CVDs and
gene expressions. These challenges are responsible for the poor trans-
lation of in vivo model studies in clinical trials and in silico docking
evaluations. Today, with advances in stem cell engineering, creating
in vitro cardiac models called “heart-on-the-chip”may serve as supe-
rior templates over traditional rat models and provide better insights
to cardiovascular functionalities (Dou et al., 2022). As mushrooms are
utilized in fortified foods and meat-substitute diets at an accelerated
pace, detailed investigations involving in silico studies for allergenicity
seeks immediate attention. No studies have been reported on lactose
intolerance and their relation with mushroom consumption that
requires fresh assessment by epidemiologists through cohort studies.
The causal link of ameliorating hypertension and mushroom consump-
tion has certainly moved leap ahead of mere speculation and is fore-
seen to be robust with changes in vitro and in vivo models itself. Due
to the wide varieties of mushrooms, continued exploration is under-
taken to isolate novel compounds. Thus, there is a continuous need to
update the chemical literature and elucidate their pharmacological and
toxicological investigations of novel mushroom bioactive compounds.
Thus, edible mushrooms have a lot of scope in clinical evaluations that
necessitates phylogenetic and toxicological analysis of mushroom bio-
active constituents. So, next time when you stir up a “mushroom
risotto;”appreciate the potential of biologically and nutritionally
unique fungus à la “edible mushrooms.”
AUTHOR CONTRIBUTIONS
Abdur Rauf: Investigation. Payal B. Joshi: Investigation. Zubair
Ahmad: Investigation. Hasan A. Hemeg: Investigation. Ahmed Ola-
tunde: Investigation. Saima Naz: Investigation. Nabia Hafeez: Investi-
gation. Jesus Simal-Gandara: Investigation.
ACKNOWLEDGMENT
All the authors express their earnest gratitude to anonymous
reviewers for their insightful suggestions that helped to improve the
paper significantly.
2654 RAUF ET AL.

FUNDING INFORMATION
Open access fee is supported by Universidade de Vigo/CISUG.
CONFLICT OF INTEREST STATEMENT
All authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
Data available on request from the authors.
ORCID
Abdur Rauf https://orcid.org/0000-0003-2429-5491
Payal B. Joshi https://orcid.org/0000-0003-4132-5576
Zubair Ahmad https://orcid.org/0000-0001-9645-6042
Hassan A. Hemeg https://orcid.org/0000-0002-0394-4512
Ahmed Olatunde https://orcid.org/0000-0002-8300-4538
Saima Naz https://orcid.org/0000-0002-7748-0490
Nabia Hafeez https://orcid.org/0000-0002-4835-2000
Jesus Simal-Gandara https://orcid.org/0000-0001-9215-9737
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