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Hair Loss - Symptoms and Causes: How Functional Food Can Help

  • USF Health Morsani College of Medicine
  • Functional Food Center Functional Food Institute

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Background: The impact that hair loss has on an individual's psychological wellness, and subsequent quality of life, is widespread and long lasting. The current standard treatments for hair loss include surgery and medications, ranging from over-the-counter treatments to corticosteroid injections and immunosuppressants. Unfortunately, these current treatments are either expensive, invasive, or have extremely negative side effects. Recently, the role of vitamins, minerals, and functional foods with their associated bioactive compounds, have gained increasing recognition as a potential means to address this issue. Some of these compounds have been shown to decrease the risk of specific forms of hair loss, particularly alopecia, a form of balding that results due from an autoimmune disorder. These include experimental studies using black raspberry extract and egg yolks as well as epidemiological studies using Mediterranean diets and various micronutrients. Other compounds have been shown to promote hair growth on a more general scale, including in vivo studies using rice bran extract and mouse models using red ginseng oil and annurca apple polyphenols. This review identifies key hair growth promoting vitamins, minerals, and functional foods, as well as summarizes the relevant mechanisms of action of these compounds that have been elucidated. Knowledge regarding the effects of these nutriceuticals on reducing hair loss is rapidly expanding. However, it is imperative that further research be done in order to delineate mechanisms of actions for all compounds related to managing and treating hair loss and subsequently integrate these dietary modifications into clinical treatment recommendations for hair loss.Keywords: Hair loss, alopecia, berry extract, mediterranean diet, rice bran, ginseng, annurca apple, thuja orientalis, marine supplement, honey, egg yolk, functional foods, bioactive compounds
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Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 94 of 125
Review Article Open Access
Hair loss: A review of the role of food bioactive compounds
Grace Wei1,2 and Danik Martirosyan1
1Functional Food Institute, 5050 Quorum Drive, Suite 700, #338, Dallas, TX, 75254, USA
2Boston University School of Public Health, 715 Albany St, Boston, MA 02118, USA
Corresponding Author: Danik Martirosyan, PhD, 4659 Texas Str., Unit 15, San Diego, CA
92116, USA
Submission Date: April 9th, 2018. Acceptance Date: May 29th, 2019. Publication Date: May
30st, 2019.
Citation: Wei G., Martirosyan, D. Hair Loss: A Review of the Role of Food Bioactive
Compounds. Bioactive Compounds in Health and Disease 2019; 2(5): 94-125. DOI:
The impact that hair loss can have on an individual's psychological wellness, and subsequent
quality of life, is widespread and long lasting. Current standard care for hair loss includes surgery
and medications, ranging from over-the-counter treatments to corticosteroid injections and
immunosuppressants. Unfortunately, these current treatments are either expensive, invasive, or
have extremely negative side effects on patients utilizing these therapies. Recently, the role of
vitamins, minerals, and foods with their associated bioactive compounds, have gained increasing
recognition as a potential mean to address this issue. Some of these compounds have been shown
to decrease the risk of specific forms of hair loss, particularly alopecia, a form of balding that
results due from an autoimmune disorder. These include experimental studies using black
raspberry extract and egg yolks as well as epidemiological studies using Mediterranean diets and
various micronutrients. Other compounds have been shown to promote hair growth on a more
general scale, including in vivo studies using rice bran extract and mouse models using red ginseng
oil and Annurca apple polyphenols. This review identifies key hair growth promoting vitamins,
minerals, and other food bioactive compounds, summarizing relevant mechanisms of action of
these elucidated compounds. However, it is imperative that further research be done to delineate
exact dosage of those compounds, to check if in that effective dosage they are not toxic, and to
subsequently integrate these dietary modifications into clinical treatment recommendations for
hair loss.
Keywords: Hair loss, alopecia, berry extract, Mediterranean diet, rice bran, ginseng, Annurca
apple, Thuja orientalis, marine supplement, honey, egg yolk, functional foods, bioactive
Psychological wellness and overall quality of life is severely impacted in individuals suffering
from hair loss. The resulting change in cosmetic appearance is associated with reduced self-
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 95 of 125
confidence and self-esteem, poor self-image perceptions, and feelings of embarrassment and
vulnerability [1, 2]. These damaging impacts on the human psyche negatively affect one’s ability
to engage in social interactions and have been associated with increased risk of mental health
conditions, such as depression and anxiety [3]. Studies have shown that patients experiencing hair
loss report reduced quality of life and higher prevalence of clinical depressive symptoms compared
to comparable populations who are not suffering from hair loss [2].
Importantly, nutrition has also been shown to play key roles in the risk of developing hair loss.
Hair follicles, in particular, have high turnover rates and high metabolic activity requiring an ample
supply of energy from nutrients [4]. For example, a primary component of hair is keratin, which
relies on adequate protein intake to maintain sufficient levels in the body. Thus, individuals
suffering from malnourishment, including conditions such as Kwashiorkor, have been found
displaying higher rates of hair loss [5]. Malnourishment commonly results in deficiency in these
key amino acids: histidine, leucine, valine, alanine, and cysteine; low levels of these protein
building blocks have been found to be associated with individuals suffering from hair loss [6]. We
have already illustrated how protein deficiencies are common in many hair loss conditions, but
other nutrients such as fatty acids, vitamins, and minerals have important roles as well [6]. It is,
thus, not surprising that a number of food ingredients have risen in popularity as a means to address
various forms of hair loss.
Prior to delving into foods or food ingredients that have immense potential to address hair loss
conditions, it is critical to first define what functional foods are. Functional foods describe food
products containing bioactive compounds that exhibit positive health benefits for preventing,
treating, and managing chronic diseases [7]. It is the bioactive compounds present in functional
foods that are primarily responsible for their potency as a hair loss treatment strategy, often due to
their natural antioxidants, antifungals, and anti-inflammatory agents healing properties [7].
Among other bioactive molecules, vitamins and minerals also contribute to treating abnormal hair
growth pathologies, such as by addressing oxidative stress or by modulating immune responses
[8]. Overall, the use of foods with different bioactive compounds to prevent and manage hair loss
could provide many benefits over current treatment options. As a whole, they are more cost-
effective and produce less side effects. Despite being less specific compared to synthetic
medications, functional foods are considered safe for consumption, addressing not only hair loss
problems but also provide benefits for other health concerns as well. This review of the literature
will identify, consolidate, and review key food ingredients, food bioactive compounds,
vitamins, minerals, polyphenols, bioactive proteins, and other ingredients for their effectiveness
and potential in addressing hair loss and promoting hair growth. Relevant mechanisms of action
that have been elucidated for each nutraceutical will also be summarized. Finally, in addition to
improving knowledge surrounding functional and healthy foods for managing hair loss, this review
aims to inform current strategies for addressing hair loss and propose future directions for this
The life cycle of a hair follicle proceeds through three phases: anagen, catagen, and telogen. The
anagen phase is the growth stage, catagen is the degeneration stage, and telogen is the resting stage.
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 96 of 125
The hair matrix milieu during the anagen phase is known to be extremely sensitive to external
impacts, including hormonal abnormalities, medication use, stress, and immunological changes
[9]. At the same time as these 3 phases are occurring, hair follicles are described to proceed through
8 morphological stages during this period, heavily influenced by autocrine, paracrine, and
endocrine signaling [10].
The primary mechanism through which hair loss occurs is via disruption of the
aforementioned follicular cycling, i.e. perturbations of the anagen, catagen, and telogen phase
cycling processes [9]. Extended telogen duration as well as delayed anagen onset and reduced
duration are common molecular mechanisms observed in hair loss [10]. A second mechanism
through which hair loss conditions can developed are abnormalities in molecular signaling during
the morphological stages [10]. Finally, loss of epithelial stem cells is a third common mechanism
behind the development of hair loss [10]. As a whole, triggers for these alterations in hair growth
are a combination of inflammation, hormonal changes, genetics, and environmental impacts [10].
These manifest in the form of hair-related medical conditions, nutritional deficiencies, endocrine
imbalances, drug-related side effects, bacterial and viral infections, and certain diseases include
various forms of cancer [1].
In general, the functional foods to be analyzed in this review article focus on treating and
managing hair loss caused by hair-related medical conditions. The most common hair-related
medical conditions will be briefly discussed. Hair loss caused by hair-related medical conditions
take two forms, namely, diffuse and focal hair loss, which is further divided into subsets of hair
loss conditions [15]. The most common condition that causes hair loss is hereditary hair loss [110].
Other common hair loss conditions include male or female pattern hair loss (MPHL or FPHL,
respectively). MPHL, often denoted as androgenetic alopecia, is the most common root cause of
baldness in men, with FPHL similarly being the most common root cause for women. Study
estimates show that the prevalence of pattern baldness can be as high as 70% in men and as high
as 40% in women [16, 17, 18, 19], depending on the study being reviewed. Androgenetic alopecia,
whether occurring in males as MPHL or in females as FPHL, is believed to result from androgen
imbalance in genetically susceptible individuals [16, 17, 18]. Other common forms of hair loss
include Alopecia areata and Telogen effluvium [16]. Alopecia areata is an autoimmune disorder
that often results in patch-like losses of hair on the scalp and body [11, 12]. Alopecia areata is the
most common cause of hair loss in adolescents [20]. Unlike, Alopecia areata, telogen effluvium is
not thought to have underlying genetic predispositions, but rather is caused by a myriad of
physiological and psychological stressors, including malnutrition, chronic illness, and certain
medications [11, 12]. Telogen effluvium results in the specific loss of telogen hair, due to abnormal
follicular cycling in the anagen, catagen, and telogen phases of hair growth [16].
Common symptoms for hair loss include abrupt or gradual onset of hair loss, patchy or diffuse
hair loss, and thinning. A physical examination and patient history are then performed to
differentially diagnose the form of hair loss in the suffering patients. This includes determining if
the hair loss is localized or systemic, family history or medication use, hair pull tests, and presence
of scarring [11, 12]. Although, there are generally no routine tests available to diagnose hair loss,
laboratory testing or histological examination are often conducted to determine any underlying
endocrine abnormalities and structural damages to hair including hair breakings [11, 12, 13]. For
example, levels of testosterone, dehydroepiandrosterone (DHEA), iron, iron-binding capacity, and
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 97 of 125
thyroid hormones are commonly used to identify underlying causes of hair loss, particularly in
premenopausal women [14].
Current treatment methods for hair loss vary depending on the specific condition, however,
most strategies consist of medications (synthetic therapeutics), surgeries, and the recent
development of low-level light therapies. Corticosteroids and immunosuppressive agents are often
used, however, their negative side effects make them less than ideal choices [21]. These include
topical, oral, and intralesional steroids, topical minoxidil, and topical immunotherapies [15]. Hair
transplant surgeries have displayed impressive hair graft survival rates, with clinical study success
rates ranging from 90% to 100% [22]. In reality, however, under non-experimental conditions,
graft survival rates in common clinical practice often fall below 100%, due to issues including
donor scalp issues, operative-related graft damage [22]. The advent of low-level light therapies,
approved by the FDA in 2007 to treat hair loss, has been touted to be safe but its’ effectiveness has
still yet to be confirmed [16].
A systematic review of published literature on food ingredients related to hair growth was
conducted via electronic searches on PubMed, Google Scholar, and Web of Science databases.
Articles not available in English were excluded, but no other limitations were imposed. Both
review and primary research articles were included. Eligible articles provided relevant scientific
evidence on hair growth benefits of any food item. Keywords for the searches included: anagen,
Annurca apple, apple, alopecia, baldness, berry, bioactive compounds, catagen, dermal, dermal
papilla, egg, epidermal, female pattern hair loss, follicular, functional foods, ginseng, hair growth,
hair loss, health, honey, keratinocyte, male pattern hair loss, marine supplements, Mediterranean
diet, physiological, prevention, psychological, rice bran, risk, supplement, symptoms, telogen,
Thuja orientalis, and treatment.
Berry Fruits as a Candidate Functional Food
Berry fruits, particularly blackberries and raspberries, have long been known for their nutritive and
medicinal benefits. They are high in dietary fiber and contain important micronutrients, including
Vitamin C, Vitamin K, and essential minerals, copper, and manganese [23]. In addition to being
nutritionally rich, berries also contain high levels of phytochemicals and bioactive compounds,
including steroids, glycosides, terpenes, and acids [24]. Beyond these, they are known for their
abundance of phenolic compounds, notably anthocyanins, flavonols, and tannins, as seen in Figure
1 [25]. These phenolic compounds are especially important for the medicinal benefits berries
provide, contributing antioxidant, anti-inflammatory, and anticancer properties [26]. Blackberries,
in the form of pulp formulations, have shown high cytotoxic effects against MCF-7 and SKBR3
breast cancer cell lines [26]. While oral consumption and subsequent digestion of blackberries will
likely alter these anti-carcinogenic properties in vivo, the positive health benefits they display
beyond basic nutritive needs are still medicinally beneficial. Sources show blackberries have anti-
aging benefits, including protection against neurological decline and bone loss that occur during
the aging process [25]. Traditionally, berries have also often been used in herbal medicine as
antimicrobial, antidiarrheal, antidiabetic, and antiviral agents [23, 24].
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Anthocyanins are one of the most well-known bioactive compounds present in berries.
Anthocyanins, the glycosidic form of anthocyanidins, are water-soluble pigments responsible for
the vibrant colors of fruits and vegetables [27]. They fall under the category of flavonoids, which
further falls under the greater category of polyphenols [28]. Blackberries are particularly high in
anthocyanin content, with an estimated nearly 66 mg of anthocyanin per 100 grams of fruit,
compared to 30 mg of anthocyanin per 100 grams of fruit in raspberries [29]. Importantly,
bioavailability studies have shown that anthocyanins are uniquely absorbed intact, in their
glycosidic form [30, 31]. Unfortunately, the overall bioavailability of anthocyanins in human
studies have been shown to be consistently low [32, 33]. Despite this, anthocyanins have still been
shown to have significant positive effects on human health, including as an antioxidant and
protecting against vision degeneration, obesity, diabetes, and cancer [28]. As an antioxidant,
anthocyanins are potent free radical scavengers and inhibitors of lipid oxidation, including
inhibition of human low-density lipoprotein (LDL) [34]. Anthocyanin extracts produced from
berries have been used in numerous studies and have been shown to improve night vision both in
animal and human studies [35]. In regards to obesity and diabetes, anthocyanins are protective not
only in antioxidative benefits, but also an insulin secretagogue [36]. It is thought that anthocyanins
have anti-proliferative and pro-apoptotic effects, in addition to antioxidant effects, that contribute
to their anti-carcinogenic functionality [28].
Figure 1. Chemical structures of major bioactive compounds present in berries.
Functionality of Berry Fruits in Treating Hair Loss
Recent research has provided evidence that berries may serve as potent natural treatments for hair
loss, as seen in Table 1 [37, 38, 40]. Firstly, the hair promoting benefits of berry fruits have been
described jointly with anti-aging effects. Dan et al. studied hair loss as it relates to anti-aging
properties by applying four different berry formulations (black raspberry, blueberry, raspberry,
and blabina, a powered black raspberry extract) to cell culture [37]. They found all four
formulations increased hair growth via increasing growth of dermal follicular cells by up to 20%
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 99 of 125
and promoting expression of type 17 collagen and heat shock protein 47 (HSP47) mRNA in
follicular stem cells [37]. Expression of type 17 collagen and HSP47 are key, as hair loss can be
associated with reduced levels of the type 17 collagen protein or HSP47, an inhibitor of type 17
collagen proteolysis [37]. Thus, increased levels of either of these proteins is thought to reverse
the effects of hair loss. Importantly, Dan et al. also found that all four formulations increased hair
growth via inhibition of the enzyme, 5-alpha-reductase, in dermal follicular cells [37]. This
enzyme, 5-alpha-reductase, is responsible for converting testosterone into dihydrotestosterone
(DHT). Because high levels of DHT have been found to be associated with hair loss, inhibition of
5-alpha-reductase has become a prime target for hair growth therapies, and incorporation of berries
or berry-based formulations to target this enzyme may be a strong option.
Secondly, the hair promoting benefits of berries have also been shown to occur through
activation of sensory neurons, through a similar mechanism as capsaicin, a compound found in
chili peppers. Topical capsaicin activates sensory neurons, causing the release of calcitonin-gene
related peptide (CGRP), and subsequent release of insulin-like growth factor-1 (IGF-1) in the
dermis [38,39]. IGF-1 is known to play a role in the follicular hair growth cycle and has been
shown to promote maturation of hair follicles. Raspberries contain an aromatic compound known
as raspberry ketone (RK), which is similar in structure to capsaicin. Because of their structural
similarities, Harada et al. tested the ability of raspberry ketone to comparably activate sensory
neurons, causing release of CGRP and IGF-1, and subsequent hair growth [40]. They found that
topical application of raspberry ketone resulted in increased levels of CGRP release from sensory
neurons, increased IGF-1 in the dermis, and increased hair growth in wild-type mice [40].
Importantly, topical application of raspberry ketone did not result in increased IGF-1 in the dermis
of CGRP knockout mice, indicating that the molecular mechanism of raspberry ketone-induced
hair growth is mediated through CGRP [40]. Finally, Harada et al. found that topical application
of raspberry ketone resulted in improved hair growth in 50% of alopecia study participants [40].
Third, the ability of berries to promote hair growth has been mechanistically linked to the
JAK-STAT signaling pathway. Certain forms of hair loss have been associated with an inability
of follicular cells to proceed from the telogen (resting phase) to the anagen (growth phase) of the
hair growth cycle. A study by Harel et al. showed that inhibition of the JAK-STAT pathway, using
a topical inhibitor, promoted rapid entry from telogen to anagen [41]. This rapid entry showed
similar kinetics to those promoted by sonic hedgehog (Shh) agonists, which is a pathway known
to promote initiation of the anagen hair growth phase [41]. A later study conducted by Martin et
al in the same year identified numerous bioactive compounds capable of inhibiting JAK, including
blackberries, boysenberries, and strawberries [42]. The potency of the JAK inhibition by these
berries was thought to be due to the presence of high levels of ellagitannins, a subset of tannins
known to inhibit kinases [42]. It is thus highly probable that berries containing high levels of
ellagitannins are capable of inhibiting JAK and inducing hair growth. Collectively, these studies
suggest that incorporating berries or berry extracts into diets or topical formulations for individuals
suffering from a hair loss condition may be a potent natural alternative or complement to drug-
based treatment strategies.
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Table 1. Summary of Research on Berry-based Hair Growth Studies
Type of
Intervention and/or
Bioactive Ingredients
Dosage and
Administration Time
In vitro
In vitro: 99.9% pure
raspberry ketone (RK)
on DRG cells
In vitro: 1, 10, and 100
μM RK at 30 min.
incubation period
Increased CGRP release
from DRG cells;
RK increases hair
growth via upregulating
IGF-1 secretion in a
In vivo
In vivo: Topical RK on
WT or CGRP-KO mice
In vivo: Topical 100 μL
of 0.01% RK for 30
minutes, also 1/day for
4 weeks
Increased IGF-1 and hair
growth in WT mice,
(part 1)
Clinical trial 1:
Topical RK to 10
alopecia (7 males and 3
females) volunteers (all
receive treatment)
Clinical trial 1:
Alopecia volunteers
(0.01% RK 1/night for 5
Increased hair growth in
50% of volunteers at 5
(part 2)
Clinical trial 2:
Topical RK to 10 healthy
female volunteers (5
treatment, 5 control)
Clinical trial 2:
Healthy female
volunteers (0.01% RK
1/day for 2 weeks)
Increased cheek skin
In vivo
inhibitors of the JAK-
STAT pathway, e.g.
tofacitinib and
inhibitor dissolved in
DMSO 1/day for 4
days, with biopsies
taken on Day 0 and 5.
Rapid entry into anagen
phase, increased
proliferation of follicular
stem cells.
Inhibition of JAK-STAT
signal transduction
upregulates hair
growth pathways.
In vitro cell
49 different food
extracts, including 10
hydrophobic fractions of
each, to find JAK2
10 fractions for each of
the 49 extracts,
ranging from 101 to
107-fold dilutions.
Blackberry, boysenberry,
and strawberry were
observed to potently
inhibit JAK2.
Berries may be capable
of promoting hair
growth via inhibition of
JAK pathways.
In vitro cell
Blackberry extract
(BRE), blueberry extract
(BBE), raspberry extract
(RBE), Blabina
(powdered formulation
containing BRE)
101 to 105-fold dilutions
of 9mg/ml with
incubation ranging
from 1 hour to 48
Blabina & BRE:
Upregulation of α-
crystallin, inhibited 5α-
Blabina, BRE, BBE, RBE:
Increased dermal papilla
Berry extracts,
particularly blackberry
extract, have potent
anti-aging properties,
including promoting
hair growth.
In summary, in vivo and in vitro studies, and one clinical experiment was conducted to test
the hair growth potential of berries. The study by Harada et al., was a strong collection of in vivo,
in vitro, and clinical investigation that detailed the mechanism of action of berry bioactive
compounds, however, the number of participants in the clinical component of the study was very
limited [40]. The remaining in vivo and in vitro studies showed promising results, however, these
studies did not directly show the impact of berry bioactive compounds on hair growth. Harel et al.
and Martin et al. provided a mechanism through which berries may increase hair growth through
inhibition of JAK-STAT, while Dan et al. did clearly use berry-based bioactive compounds, but
showed increased dermal papillae growth [37, 41, 42]. While this is not a direct observation of
increased hair growth, increased dermal papillae growth is expected to increase hair growth.
Importantly, another limitation is none of these studies looked at toxicity dosing.
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 101 of 125
The Functionality of the Mediterranean Diet
The Mediterranean diet is a dietary pattern growing in popularity as a means of preventing,
treating, and managing a variety of health conditions. The Mediterranean diet mainly consists of
one cup of daily red wine, with high consumption of fruits, vegetables, and virgin olive oil, and
low consumption of fish and meat [43]. Virgin olive oil is a staple of the Mediterranean diet, due
to its high content of bioactive phenolic compounds [44]. Red wine and tomatoes are also of key
importance, due to their high levels of resveratrol and lycopene, respectively [45]. The
combination of resveratrol, phenolic compounds, and lycopene in the Mediterranean diet have
been associated with decreased risk of colorectal cancer [45]. Furthermore, epidemiological
observation has shown decreased prevalence and incidence of chronic conditions, including
cardiovascular disease and subsequent risk of stroke, myocardial infarction, and so on, in addition
to, cancer, metabolic syndrome and diabetes, and cognitive neurodecline [46], in those adhering
to Mediterranean diets. Experimental intervention studies have further supported these findings,
illustrating that Mediterranean diets result in decreased risk of cardiovascular disease, metabolic
syndrome and diabetes, and cognitive neurodecline, in treatment groups assigned to Mediterranean
diets [46].
Functionality of Mediterranean Dietary Ingredients in Treating Hair Loss
Research on the role of the Mediterranean diet in treatment of hair loss remains relatively limited,
however, a few key components of the Mediterranean diet have proven promising in the addressing
hair loss (Table 2) [47, 48, 49]. One recent case-control study by Fortes et al. showed that
individuals who followed a Mediterranean diet with high vegetable and herb intake had about a
56-57% reduced odds of developing androgenetic alopecia [47]. While androgenetic alopecia has
been known to stem mainly from genetic factors, this study demonstrated that androgenetic
alopecia may be heavily impacted by diet as an environmental factor.
Additionally, an important ingredient in Mediterranean diets are tomatoes, vegetables rich in
lycopene. Research has shown that Lycopersicon esculentum extracts have potent abilities to
promote hair growth in a C57BL/6 murine model [48]. This increase in hair growth was observed
both histologically and via gene expression, with Lycopersicon esculentum extracts application
resulting in increased vascular endothelial growth factor, keratinocyte growth factor, and insulin-
like growth factor [48]. Increased expression of these growth factors and subsequent action of hair
follicles is suggested to be one of the main mechanisms through which lycopene induces hair
growth [48]. Another integral component of the Mediterranean diet, red oranges have been shown
to also have beneficial effects on keratinocyte populations within the epidermis. Cardile et al.
showed that treatment with red orange extract resulted in decreased inflammatory activity,
measured via inflammatory markers, in human keratinocyte cell lines [49]. This is key as it
enhances hair growth by creating a cellular milieu favoring keratin production, the main
component of hair. The implementation of Mediterranean diets or components of Mediterranean
diets, such as lycopene-rich ingredients, are strong options for those interested in incorporating
natural therapeutics into hair growth regimens.
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 102 of 125
Table 2. Summary of Research on Mediterranean diet-based Hair Growth Studies
Type of Study
Intervention and/or
Bioactive Ingredients
Dosage and Administration
Cardile et
al., 2009
In vitro cell
line (human
Red orange complex
from Moro, Tarocco,
Sanguinello citrus
10 and 100 μg/mL red orange
complex at 48 hour incubation
Downregulated ICAM-1
expression and MCP-1 and IL-8
Choi et al.,
2013 [48]
In vivo
mouse model
esculentum extracts
3% ethyl acetate extract (EAE),
supercritical CO2 extract (SCE)
of L. esculentum, lycopene
Tween 80 solution (LTS), and
test hair tonic (THT) containing
LTS 1/day for 4 weeks
Increased hair growth and
anagen phase induction;
increased expression of VEGF,
KGF, and IGF-1.
Fortes et al.,
2018 [47]
based case-
control study
(104 alopecia
cases and 108
No intervention,
exposure was
categorized as
frequency of
consumption of
Mediterranean diet-
based components.
No dosage or time
administration due to case-
control study design. Frequency
of consumption was considered
high (≥ 3 times/week) or low
(up to 2 times/week) for a
variety of Mediterranean diet
items, including: cooked, raw,
leafy green, and cruciferous
vegetables, herbs, fruits, nuts,
olive, oil, etc.
Adjusted OR*:
High vs. low raw vegetable
consumption: 0.43***
High vs. low fresh herb
consumption: 0.44***
*Adjusted for age, education,
BMI and family history of AGA.
Overall, the in vitro and in vivo studies demonstrated potential mechanisms of Mediterranean
diet based bioactive compounds on increasing hair growth through modulating expression of
growth factors, cytokines, and cell mediators [48, 49]. The inclusion of a case-control study
provides a unique epidemiological perspective demonstrating plausible association between
Mediterranean-diet and hair growth, however, potential bias and confounding should be taken into
consideration [47]. While the results of these studies are encouraging, unfortunately, the impact of
Mediterranean diet based bioactive compounds on hair growth are limited by a lack of clinical
experiments and consistency in dosing regimens.
Rice Bran as a Candidate Functional Food
Rice has served as a staple component of dietary lifestyles across the world for centuries. The
production of rice results in removal of a protective husk under which lies the rice bran, the
innermost rice kernel. Rice bran has been found to contain high amounts of macronutrients,
including dietary fiber, proteins, and lipids [50]. Bioactive compounds present in rice bran are also
extensive, most notably antioxidants, including ubiquinones, tocopherols, tocotrienols, and y-
oryzanol [50, 52]. In addition to antioxidant activity, rice bran-derived nutraceuticals display anti-
inflammatory, anti-diabetic, and anti-cancer characteristics [53]. In particular, tocotrienols have
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 103 of 125
been shown to inhibit HMG-COA Reductase and contribute to lowering endogenous cholesterol
production [52].
Functionality of Rice Bran in Treating Hair Loss
A few studies within the past decade have shown the natural therapeutic potential of rice bran for
treating various forms of hair loss, as summarized in Table 3 [54, 55, 58]. Manosroi et al.,
demonstrated the potential application of rice bran-based niosomes as a topical therapeutic for
androgenic alopecia [54]. The depth of dermal penetration by topical medicines in treating hair
loss is an important component of their efficacy. Manosroi et al. have shown that components of
rice bran Oryza sativa, particularly unsaturated fatty acids, are potent inhibitors of 5a-reductase
and thus work to inhibit hair loss [54]. Despite this, these researchers discovered that the depth of
penetration by components of the Oryza sativa was limited. In this study, they developed a topical
gel containing Oryza sativa rice bran components packaged into cationic niosomes [54]. Using an
in vitro analysis of porcine skin, Manosroi et al. found greater penetration through topical gel when
compared to control delivery methods [54]. Importantly, they also found the penetration did not
extend into the receiver compartment, analogous to beyond the dermal layer, indicating high
dermal effects but low systemic effects of the rice bran gel preparation [54].
Further, Choi et al. tested the in vivo ability of rice bran to promote hair growth by applying
rice bran extracted using supercritical carbon dioxide (RB-SCE) to shaved C57BL/6 mice in the
telogen phase of the follicular cycle [55]. Histological examinations showed higher rates of hair
restoration and induction into anagen phase occurred in mice treated with RB-SCE, compared to
controls [55]. RB-SCE-treated mice showed similar histological growth profiles to minoxidil-
treated controls; minoxidil is a topical agent currently approved by the FDA to treat androgenetic
alopecia [55]. These researchers also found that application of the rice bran extract induced mRNA
expression of a number of growth factors related to hair growth. In particular, mice treated with
RB-SCE showed increased MRNA expression of vascular endothelial growth factor (VEGF),
insulin-like growth factor-1 (IGF-1), and keratinocyte growth factor (KGF), as well as decreased
mRNA expression of TGF-b [55]. This particular pattern of expression has been shown to play a
role in increasing the maintenance of the anagen phase of hair growth [56, 57].
Choi et al. also tested the ability of supercritical carbon dioxide extracted-rice bran to treat
androgenic alopecia in a clinical trial [58]. During a double-blind randomized control trial
performed over 16 weeks, 25 participants received topical RB-SCE treatment (0.5% RB-SCE or 8
mL/d) while the control group of 25 participants received a placebo [58]. Their results showed
statistically significant increases in total hair count, hair diameter, and overall hair density in male
patients receiving the RB-SCE treatment [58]. Importantly, increases were observed in female
patients as well, however these were not statistically significant [58]. This suggests potential
differences in the physiological effects of the RB-SCE treatment between biological sex
characteristics. Additionally, Choi et al. found a positive improvement in patient satisfaction with
the RB-SCE treatment and the impact it had on their hair growth and scalp appearance [58]. This
study suggests high potential for rice bran extracts to be used as natural therapeutic treatments for
hair loss, particularly in males. As a whole, these studies support the recommendation of including
rice bran into dietary patterns to prevent or treat hair loss.
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 104 of 125
Table 3. Summary of Research on Rice Bran-based Hair Growth Studies
Type of Study
Intervention and/or
Bioactive Ingredients
Dosage and
Administration Time
et al., 2012
In vitro
penetration of
porcine skin
Cationic niosomes
containing Oryza
sativa rice bran.
48.23% (w/w) or 2% (w/v)
O. sativa extracts loaded
into 20 mM niosomes at
1:1:0.5 M ratio
Rice bran based-niosomes
exhibited 8 times greater skin
penetration compared to rice
bran-based gel and 6 times
greater compared to a rice-bran
based solution.
Choi et al.,
2014 [55]
In vivo (C57BL/6)
mouse model
Rice bran
supercritical CO2
extract (RB-SCE)
100 µL 3% in 10% ethanol
RB-SCE topical 1/day for 4
Increased hair follicle count,
anagen phase induction, and
expression of VEGF, KGF, and IGF-
1. Decreased TGF-b expression.
Choi et al.,
2015 [58]
Controlled Trial
of 28 men and
22 women
Rice bran
supercritical CO2
extract (RB-SCE) or
placebo treatment
0.5% RB-SCE or placebo 4
mL twice/day at 12-hour
intervals (total 8 mL/day)
for 16 weeks
Increased total hair count, hair
diameter, and overall hair density
in male patients, not significant in
female patients.
A series of pre-clinical tests followed by a clinical trial provide strong support for a causal
association between rice and bran and hair growth [54, 55, 58]. However, these studies are limited
by lack of consistency in dosing and a small sample size in the clinical trial. Because of the lack
of significance observed in women, controlling for sex in future studies will be important.
Additionally, although the mouse model provides a potential mechanism of action for the observed
increase in hair growth by rice bran, the specific rice bran bioactive molecule responsible for this
effect still remains unclear.
Ginseng as a Candidate Functional Food
Ginseng is a plant belonging to the Panax genus commonly used in traditional herbal medicines
[59]. The primary bioactive components of ginseng are saponins, specifically ginsenosides, with
the chemical structure of steroid glycosides, seen in Figure 2[60]. Ginsenosides have been shown
to have numerous beneficial effects on physiological functioning, including anti-oxidative, anti-
inflammatory, anti-fatigue, anti-cancer, anti-diabetic, anti-obesity, anti-microbial and protective
effects on the respiratory, cardiovascular, neurologic, and immune systems [60]. Importantly, non-
saponin components of ginseng, including polyacetylenes, polyphenols, and vitamins and
minerals, have also been shown to have potent medicinal properties as well [59]. In a 2016 study
by Kim et al. studying the non-saponin contents of ginseng, it was found that the ginseng leaves
contained the highest levels of phenolic compounds, which have been described to have potent
antioxidant activities [59]. Kim also showed that the ginseng root hairs contained high levels of
water-soluble vitamins, particularly thiamine, and pantothenic acid, with average total water-
soluble vitamin contents at nearly 800 mg/100g of dry ginseng [59].
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 105 of 125
Figure 2. Chemical structures of major ginsenosides present in ginseng.
Functionality of Red Ginseng Oil in Treating Hair Loss
The efficacy of using ginseng to treat various forms of hair loss has been extensively documented
in the literature, in both pre-clinical and clinical studies. Table 4 displays a number of in vitro
experiments that have documented protective effects of ginseng on epidermal components and
promotion of hair growth [61, 62, 64, 71, 72, 73]. Park et al. demonstrated the ability of Fructus
panax ginseng extract to increase hair growth by targeting human dermal papilla cells (DPCs) and
increase their proliferation in a C57BL6 murine model, resulting in visible hair regeneration in the
treatment group compared to the control [61]. Researchers also showed that Fructus panax ginseng
extract was able to increase BCL-2 and decrease BAX expression, anti-apoptotic and pro-apoptotic
mediators, respectively, thus, increasing the survival of human dermal papilla cells [61]. It was
noted that treatment with ginseng extract resulted in extended length of the anagen phase of hair
growth, compared to controls [61]. Additionally, Park et al. also investigated the ability of red
ginseng extract and associated ginsenosides to promote hair growth specifically in an in vitro
human hair follicle cultures and in an in vivo C57BL/6 murine model [62]. In the in vitro model,
they found that application of red ginseng resulted in increased proliferation of human dermal
papilla cells, particularly keratinocytes, whereas improved hair growth was also observed in the in
vivo murine model [62].
More recent studies have added substantial evidence to support the benefits that ginseng
nutraceuticals can add to standard treatments of hair loss [63,64]. Keum et al. demonstrated the
ability of Korean Red Ginseng (KRG) to inhibit alopecia in chemotherapy-related hair loss [63].
It was found that Korean Red Ginseng was able to block cyclophosphamide-induced hair loss in
an ex vivo human hair organ culture by inhibiting cyclophosphamide-induced apoptosis of
keratinocytes [63]. This inhibition was mediated by inhibition of cyclophosphamide-induced
increases in expression of p53 and BAX and inhibition of cyclophosphamide-induced decreases
in BCL2 expression [63]. Lee et al. further demonstrated the ability of Panax ginseng extract to
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 106 of 125
increase cell growth and inhibit apoptosis of keratinocytes, by increasing gene expression of BCL-
2 and inhibiting gene expression of BAX [64]. They also found that the ginseng extract blocked
DKK-1 induced hair growth inhibition in an ex vivo human hair culture [64].
The potent hair regenerative properties of ginseng have also been well-documented in murine
models. Murata et al. investigated the hair regenerative properties of ginseng rhizome and
Ginsenoside Ro in treating androgenetic alopecia [65]. Researchers found that ginseng rhizome
was able to inhibit testosterone 5-alpha reductase in a dose-dependent manner [65]. They also
demonstrated that ginseng rhizome and ginenosidero blocked testosterone-induced hair growth
suppression in a C57BL/6 murine model [65]. They concluded that ginseng rhizomes containing
oleanane- and dammarane-ginsenosides were capable of enhancing hair growth to treat
androgenetic alopecia [65]. Li et al. investigated the mechanisms by which Ginsenosides, a main
component of ginseng, are able to promote hair growth [66]. By comparing treatment of topical
ginsenosides to a control treatment in a C57BL/6 murine model, researchers found that
ginsenosides resulted in increased detection of p63, a modulator of keratinocyte stem cells, in the
treatment group [66]. They concluded that activation of p63, is a potentially novel mechanism by
which ginsenosides exert their effects within the dermis and epidermis [66].
To build on these, Truong et al. demonstrated the hair regenerative abilities of topical red
ginseng oil in a C57BL/6 murine model pre-treated with testosterone to induce delayed hair growth
[67]. They found that topical red ginseng oil displayed similar hair growth properties as linoleic
acid (LA) and beta-sitosterol (SITOS), through upregulation of Wnt/Beta-catenin and Shh/Gli
pathways [67]. Red ginseng oil was uniquely found to increase expression of BCL-2, an anti-
apoptotic modulator, which further enhances the survival of dermal follicular cells [67].
In addition to ginseng, a novel study by researchers from Chungnam National University in
the Republic of Korea found that the natural herb Eclipta Alba could have even more potent hair
regenerative properties compared to ginseng [68]. E. Alba is a traditional medicinal herb that has
been used widely in Asian and Ayurvedic alternative medicines. They investigated the ability of
panax ginseng to promote hair growth in nude mice, when either compared to or combined with
other herbs with follicular therapeutic properties [68]. Interestingly, it was found that nude mice
treated with panax ginseng extract did not differ significantly from controls in a number of
measures, including hair density and staging of hair morphogenesis [68]. Instead, they found that
the herbal compound known as E. alba was much more effective in promoting hair regeneration
in nude mice, exhibiting higher hair length and hair density measurements [68]. Further research
should be done to further characterize the beneficial effects of E. alba as another potent mediator
The potent hair growth promoting characteristics of ginseng in pre-clinical studies have
prompted researchers to test the safety and efficacy of ginseng in treating hair loss in clinical
models. Oh and Son investigated the ability of Korean Red Ginseng (KRG) to treat alopecia areata
in conjunction with a standard corticosteroid treatment compared to treatment with a corticosteroid
alone, in a trial of 50 patients [69]. It was found that patients treated with ginseng in conjunction
with a standard corticosteroid exhibited higher levels of hair density, hair thickness, and hair
growth by visual assessment, when compared to groups receiving only the corticosteroid treatment
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 107 of 125
[69]. Importantly, these differences were not statistically significant, indicating a need for further
studies done with potentially larger sample sizes [69]. A 2014 study by Ryu et al. further supports
these findings by illustrating that minoxidil in conjunction with Korean red ginseng was much
more effective than minoxidil alone in treating female pattern baldness [70]. In a trial of 41 female
patients randomly assigned to either a standard minoxidil treatment or a combined minoxidil and
Korean red ginseng treatment, those receiving the combination treatment exhibited greater hair
density and hair thickness compared to the standard treatment, although it is important to note
these differences were not statistically significant [70].
In addition to these studies illustrating the promotion of hair growth, key studies have been
done elucidating potential mechanisms of action behind ginseng’s effects on epidermal cell
populations. Kim et al. produced evidence that suggests panax ginseng may exert its effects in a
similar mechanism to minoxidil, a current FDA-approved hair loss therapeutic [71]. In an ex vivo
model of human hair follicle organs, researchers found that panax ginseng resulted in an increase
in cellular proliferation of human dermal papilla cells, increased expression of VEGF, and
increased activation of potassium channels, in dose-dependent manners [71].
In order to further elucidate the mechanisms underlying the hair promoting abilities of ginseng
and ginsenosides, Shin et al. demonstrated that Ginsenoside Rg3 led to an increase in expression
of VEG-F in both human dermal papilla cells and murine hair follicles [72]. Thus, there is high
probability that ginsenosides, particularly Ginsenoside Rg3, stimulates hair growth through
interaction with epidermal stem cells [72]. In another study by Li et al., researchers found that
panax ginseng, and its associated ginsenosides, promoted hair growth in both in vivo and ex vivo
murine models [73]. They also found evidence to suggest that this hair growth was mediated
through ginsenoside-induced inhibition of TGF-b pathways within the epidermis [73].
Researchers have also characterized novel bioactive compounds within panax ginseng as
mediators of ginseng’s potent effects on hair growth [74]. Whereas the hair regenerative properties
of ginseng had been traditionally been attributed to saponins, Suzuki et al. found evidence
suggesting that it was polyacetylene bioactive compounds contained within ginseng that play a
large role in hair growth via inhibition of neurotrophin-receptor binding [74]. The evidence for
ginseng in playing important roles in hair growth is extensive. In addition to the numerous other
health benefits it provides, sufferers of hair loss might consider adding ginseng-based options,
such as ginseng tea, into their normal dietary routines.
As evidenced in Table 4, numerous in vivo and in vitro studies have provided strong evidence
supporting the causal association between ginseng and hair growth. Both C57BL/6 murine models
and dermal papillae cell cultures were consistently used, however, these studies were limited by a
lack of dosing consistency and consistency in type of ginseng, with some using panax ginseng,
korean red ginseng, and ginsenosides. While two clinical experiments were conducted, detailed
information regarding dosing was limited and results varied with regard to significance.
Additionally, one study administered ginseng via tablet or capsule form, which would prevent it
from being classified as a functional food [70]. Future research should be done to focus on clinical-
based testing with ginseng in non-tablet or capsule forms.
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 108 of 125
Table 4. Summary of Research on Ginseng-based Hair Growth Studies
Type of Study
Intervention and/or
Bioactive Ingredients
Dosage and Administration Time
In vitro cell line
(human dermal
papilla cells)
Fructus panax ginseng
(FPG) extract
In vitro: 10 μl of FPG extract with
increasing doses (0.8, 4, 20, 100,
500 μg/ml) for 24, 48, and 72 hours
In vitro: Increased proliferation,
upregulated Bal-2, and downregulated
Bax in human dermal papilla cells
In vivo (C57BL/6)
mouse model
In vivo: 100 μl
1 mg/ml FPG extract per day for 21
days with data collected at 1, 4, 7,
14, and 21 days
In vivo: Improved hair growth, including
lengthened anagen phase cycling
In vivo (C57BL/6)
mouse model
Topical red ginseng
(2 mg/mouse) and
ginsenoside Ro
(0.2 mg/mouse)
100μL 2% (w/v) RG rhizome extract
or 0.2% (w/v) ginsenoside Ro1/day
30 min. following 100μL
testosterone treatment for 30 days
Ginenoside contents are highest in the
rhizome region of the ginseng plant;
rhizomes and ginenosides inhibit 5a-
reductase and promoted hair re-
Active control
trial with 50
alopecia patients
Corticosteroid ILI +
Korean Red Ginseng
(KRG) or corticosteroid
ILI alone
12-week treatment period (dose
not provided)
Increased hair density by 130%, hair
thickness by 40%, and hair growth by
visual assessment (note: differences
were not statistically significant).
In vivo (C57BL/6)
mouse model
ginsenosides Rb1 and
300mg or 1.5ml per kg body weight
of 5mg/ml protopanaxadiol-type
ginsenosides Rb1 and Rd35 in 20%
9:1 ethanol:methanol for 35 days
Increased hair growth, potentially
through upregulation of p63 signaling.
Athymic Balb/c
male nude mice
Eclipta alba, Asiasari
radix, and Panax
ginseng extracts
2.5% daily application of A. radix, E.
alba, and P. ginseng extracts for 2
hair growth cycles
Highest effectiveness of the three
compounds tested for promoting hair
loss was E. Alba
Active control
trial with 41
female pattern
hair loss patients
Only topical 3%
minoxidil or topical 3%
minoxidil and oral
Korean Red Ginseng
1 oral capsule per day for 24 weeks
with data collected before
treatment, at 12 weeks, and at 24
Improved hair density by 13% and hair
thickness by 21% (note: not statistically
In vitro cell line
(human dermal
papilla cells)
Ginsenoside Rg3
In vitro: 1, 5, and 10μM Rg3 for 48-
hour incubation
In vitro: Increased dermal cell
proliferation and VEGF upregulation
In vivo (C57BL/6)
mouse model
In vivo: 100, 500, or 1000μMRg3
daily for 1 week
In vivo: Increased stemness markers
CD8, CD34, and Ki‐67
In vitro cell line
(human dermal
papilla cells and
anagen hair
Panax ginseng (PG)
2, 5 and 10 μg/ml PG extracts and 1
μM of the ginsenosides Rb1, Re and
Rg1 for 5 days
Increased dermal cell proliferation,
increased BEGF expression, and hair
growth promotion
In vitro cell line
(human dermal
papilla cells and
Korean red ginseng
extract (RGE)
In vitro:
Papilla cells 15 mins 0-300
lg/mL RGE or 0-15 lg/mL
Keratinocytes 100 lg/mL RGE
or 10 lg/mL ginsenoside-Rb1 for
2 days
In vitro: Increased dermal cell and
keratinocyte proliferation, upregulation
of ERK and AKT pathways
In vivo (C57BL/6)
mouse model
In vivo: 100 μl subcutaneous
injection of 3% 100mg/mL RGE
every other day for 7 weeks
In vivo: Increases hair growth
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 109 of 125
Type of Study
Intervention and/or
Bioactive Ingredients
Dosage and Administration Time
hair follicle organ
culture model
Korean red ginseng
Pre-treatment with 100 mg/mL or
500 mg/mL KRG for 1 day prior to
cyclophosphamide 1 day incubation
Protects against cyclophosphamide-
induced hair loss, premature catagen,
keratinocyte downregulation and
apoptosis, and p53 and Bax/Bcl2
In vitro cell line
(vibrissa hair
follicles and HeLA
Ginsenoside Re (GRe)
In vitro:
Vibrissa follicles 10, 50 mg/L
ginsenoside Re
HeLA cells 10 mg/L
ginsenoside Re
In vitro: Hair shaft growth in cultured
vibrissa hair follicles and upregulation
of ERK signaling in HeLa cells
In vivo (C57BL/6)
mouse model
In vivo: 1 mg/d and 5 mg/d
ginsenoside Re daily for 45 days
In vivo: Early onset and elongated
anagen phase, downregulation of TGF-b
In vitro cell line
keratinocyte) and
human hair
follicle organ
Panax ginseng (PG)
In vitro: 20 ppm PG extract or 1 µM
ginsenosides with or without DKK-1
for 1 day incubation
Organ culture: 20 ppm or 50 µM PG
extract renewed every 2 days for 7
Increased proliferation and decreased
apoptosis in keratinocytes, inhibited
DKK-1 and Bax expression, increased
Bcl-2 expression.
In vivo (C57BL/6)
mouse model
Red Ginseng Oil (RGO)
10% RGO daily for 28 days
Restoration of hair growth in mice pre-
treated with testosterone-induced
anagen delay, upregulation of Wnt/b-
catenin and Shh/Gli signaling, and
increased Bcl-2 but decreased TGF-b
Receptor Binding
Inhibition Assay
Various polyacetylenes
isolated from Panax
10, 30, and 100 µM sample solution
of each polyacetylene isolated from
Panax Ginseng
Inhibition of brain-derived neurotrophic
factor (BDNF)-TrkB and β-nerve growth
factor (β-NGF)-p75 neurotrophin
receptor (p75NTR) binding, highly due
to hydroxyl moiety.
Annurca Apple as a Candidate Functional Food
The Annurca Apple is type of apple commonly cultivated in Southern Italy. Highly abundant
within these apples are polyphenols, specifically flavonoids, exhibiting high antioxidant,
anticancer, antiproliferative, and antiatheroslcerotic activities. Clinical research has shown that
Annurca apple consumption is capable of reducing hypercholesterolemia and creating healthy
plasma cholesterol balances [75]. While polyphenols of Annurca apple are known to serve as
antioxidants, Annurca apple nutraceuticals have also been shown in vitro to have pro-oxidant and
pro-apoptotic effects when directed towards tumorigenic cell types, including breast cancer cell
lines, in addition to protective effects against cell stress and cell aging in normal cells [76, 77].
Evidence also suggests that Annurca apple polyphenols have dose-dependent manner free-radical
scavenging abilities. [77]. Polyphenols from the Annurca Apple have also been shown to have
promising positive, therapeutic effects on skin diseases, including psoriasis and dermatitis [76].
Annurca Apple for Treating Hair Loss
Two key studies have been conducted investigating the potential relationship between Annurca
apple and hair growth (Table 5) [78, 79]. Ricco et al. demonstrated that an Annurca Apple
Polyphenolic Extract (AAE) possesses hair growth promoting abilities, in specific regard to
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 110 of 125
treating chemotherapy-induced alopecia (CIA), although it is likely Annurca Apple can also be
applied to other hair loss disorders [78]. Researchers found that Annurca Apple was able to protect
follicular cells from taxane-induced dystrophy in a mouse model, through shunting of ATP
production to mitochondrial beta-oxidation, and downregulation of the pentose phosphate pathway
(PPP) and subsequent reduction of nucleotide production and DNA replication [78].
Simultaneously, they found that Annurca Apple also promoted hair growth via upregulation of
prostaglandins [78].
Researchers have also isolated polyphenols from the Annurca Apple and created a
nutraceutical formulation called Apple Mets, that was topically applied in both in vitro cell lines
and a clinical trial model [79]. The Annurca Apple nutraceutical formulation improved cell
viability and keratin production in vitro and improved hair growth, density, and keratin content in
human subjects [79]. While Annurca apples may be difficult to acquire given their nativity to Italy,
Annurca apple-based nutraceutical formulations are potent options that, once approved and
marketed, can contribute to natural-based remedies for preventing or treating hair loss.
Table 5. Summary of Research on Annurca Apple-based Hair Growth Studies
Type of Study
Intervention and/or Bioactive
Dosage and
Administration Time
Ricco et
al., 2018
Ex vivo (C57BL/6)
mouse model
Annurca Apple Extract (AAE)
AnnurtriComplex formulation
(MB-Med: Turin, Italy)
Ex vivo: 400 mg/L AAE
renewed every 3 days
incubated for 8 days
Increased PUFA content
and PUFA b-oxidation;
follicular protection and
keratin preservation
against taxane-induced
In vivo (C57BL/6)
mouse model
In vivo: 2 cm3 AAE
foam (containing
AnnurtriComplex 6%
(w/v)) for 4 weeks
Tenore et
al., 2018
In vitro cell line
In vitro: Annurca apple-based
formulation, AppleMetS
In vitro: 0.23 and 0.46
mg/mL AppleMetS
over 48-hour range
In vitro: Enhanced keratin
250 patient trial
Clinical trial: Annurca apple
formulation* or placebo
*(1) AMS: AFA polyphenol
extract + maltodextrins
(2) AMSbzs: AFA polyphenol +
maltodextrins, biotin,
selenomethionine, zinc acetate
Clinical trial: 2 gastric-
capsules/day of AMS
or AMSbzs orally (1
evening and 1
morning) for 16
Clinical trial: Increased hair
number by 125%, hair
weight by 42%, and keratin
content by 40%
In summary, the potential connection between Annurca apple and hair growth is promising
but is limited to a few research studies. The in vivo and in vitro study provide a mechanistic basis
for Annurca apple’s effect on hair growth, but are lacking in dosing consistency and duration of
administration. While the clinical trial possessed a large sample size, it did not address potential
weaknesses in adherence to treatment or compare pre-protocol versus intent-to-treat analysis.
Furthermore, the use of capsule-based administration of Annurca apple prevents its consideration
as a functional food product [79]. Thus, further research should be done focused on direct oral
consumption of Annurca apple with large sample sizes in a clinical setting.
Thuja Orientalis as a Candidate Functional Food
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 111 of 125
Thuja orientalis is an evergreen coniferous tree found mainly in East Asia, where it has been
traditionally used in herbal medicine. Essential oils extracted from this tree have been shown to
contain high levels of bioactive sesquiterpenes, which have been shown to have anti-proliferative
characteristics [80]. Thus, it is not surprising that Thuja orientalis possesses strong anti-cancer
properties, including protective capabilities against breast cancer as demonstrated in murine
models [81], brain cancer, through antiproliferative and proapoptotic effects on cancer cells [82]
and lung cancer, in a zebrafish-based teratogenic assay [83]. Research has shown that these
antineoplastic properties may also be due to immunomodulation of key immune cell populations,
particularly proliferation of B and T immune cells [84]. Having commonly been used in treating
amenorrhea, cystitis, and uterine cancer, Thuja orientalis has also been shown to be a potent natural
therapeutic in the treatment of polycystic ovary syndrome [85].
Thuja orientalis extracts were also shown to have antiviral efficacy, specifically anti-influenza
activity, inducing improved cell viability following influenza infection in an in vitro model [86].
Thuja orientalis displays antioxidant properties [87] in addition to protective capabilities against
dermatologic conditions, including atopic dermatitis, through anti-inflammatory activity [106].
These anti-inflammatory properties have also been shown to be beneficial in reducing
inflammation of the airway in an asthmatic murine model [88]. Research has shown a portion of
the anti-inflammatory properties of Thuja orientalis may be due to a labdane diterpene that induces
suppression of NF-kB signal transduction and phosphorylation of the ERK protein [89]. Further
research has also shown the anti-inflammatory potential of Thuja orientalis may be due to
downregulation of neutrophils, cyclooxygenase and prostaglandin activity, ad TNF-a signal
transduction [90].
Thuja Orientalis for Treating Hair Loss
Detailed in Table 6, preliminary research has shown that Thuja orientalis may also serve as a
potent natural therapeutic for treating various forms of hair loss [91]. Zhang et al. demonstrated
that topical application of Thuja orientalis extract to shaved C57BL/6 mice arrested in the telogen
phase resulted in progression into the anagen phase of follicular development [91]. In addition to
an earlier progression into the anagen phase, compared to the control or minoxidil drug, Thuja
orientalis treated mice also exhibited a lengthened anagen phase, mediated by upregulation of B-
catenin and Shh pathways [91]. Although research regarding Thuja orientalis as a natural
formulation for treating hair loss is still in its early stages, it provides promising results for a natural
topical-based nutraceutical formulation to support hair growth. Future research should investigate
the effects of Thuja orientalis in a clinical model.
Table 6. Summary of Research on Thuja orientalis-based Hair Growth Studies
Type of Study
Intervention and/or
Bioactive Ingredients
Dosage and Administration
Zhang et
al., 2013
In vivo
mouse model
Thuja orientalis
5.05 mg/cm2 or 200 μl per day
of Thuja orientalis extract for
21 days with data recorded at
0, 7, 14, and 21 days
Induction of earlier and prolonged
anagen phase, increased hair
follicle size and count, and
expression of B-catenin and Shh
Marine Supplements as a Candidate Functional Food
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 112 of 125
Marine ecosystems are an abundant resource for human health and nutrition. There are numerous
marine organisms that have been looked to for biomedical and biofunctional uses, including fish,
mollusks, bacteria, algae, cyanobacteria, sponges, and more. Marine fish, for instance, are
abundant with protein, essential fatty acid, and vitamins and minerals, have been used in the
treatment and management of many health conditions, including cancer, Alzheimer’s, and
hypertension [92]. Marine-derived peptides have been shown to have bioactive properties
including antimicrobial, immunomodulatory, and antihypertensive characteristics through the
function of ACE inhibition [92]. One major subset of marine supplements are algae-
based foods, which are rich in amino acids, essential lipids such as long chain-polyunsaturated
fatty acids and sterols, key polysaccharides including alginate, ulvans and laminarans, B and C
vitamins, and inorganic iron and iodine [93]. These are thought to contribute to protective
cardiovascular health benefits, improved cognitive functioning, and anticancer properties [93].
Algae is also rich is bioactive compounds, notably antioxidants and phytochemicals, carotenoids,
anthocyanins, and phenols [93]. In regards to dermatological health algae is known for anti-
infective, anti-aging, whitening, and skin cancer therapeutic uses [94].
Marine Supplements for Treating Hair Loss
The action of various marine nutraceuticals has been shown to display potent protective effects
against hair loss (Table 7). Researchers at Jeju National University in Korea found that,
Undariopsis peterseniana, an edible brown alga, increased hair length and progression into anagen
phase in an in vivo murine model [95]. Furthermore, it was found that the mechanism behind this
promotion of hair growth was potentially due to activation of potassium-ATP channels, reduction
of 5-alpha-reductase activity, and upregulation of Wnt/β‐catenin and ERK pathways [95]. The
Wnt/β‐catenin pathway has been extensively implicated in follicular development and subsequent
hair growth while the ERK pathway has been associated with cellular proliferation. These are also
the main pathways targeted by the drug, minoxidil, used to treat hair loss.
In addition to cell culture and murine models, clinical studies have also been conducted testing
the efficacy of marine nutraceuticals in treating various forms of hair loss [96, 97, 98]. Ablon et
al. utilized a randomized, double-blind, placebo-controlled trial to investigate the ability of a
marine supplement to treat thinning hair in men [96]. They found the treatment group exhibited
increases in total hair count, total hair density, and terminal hair density, in addition to improved
visual assessment of hair growth by study investigators [96]. Additionally, key reviews by
Hornfeldt et al. in 2015 and Hornfeldt in 2018 further details an open-label pilot study by Stephens
et al. and numerous subsequent randomized, double-blind, control trials, investigating the ability
of an oral marine formulation, particularly Viviscal ® (Lifes2good, Inc., Chicago, IL), to treat hair
thinning in both males and females [97, 98]. These studies utilized oral marine supplement
containing shark and mollusk powder, silica, and acerola cherry-based Vitamin C, biotin, and zinc
[97, 98]. Collectively in these studies, subjects receiving the marine treatment displayed overall
greater increases in amount of hair and hair diameter, with additional improvement in self-reported
hair volume, scalp coverage, hair shine, and other Quality of Life and Self-Assessment
measurements [97, 98]. These findings demonstrate the potent benefits of adding marine
supplements into new or current supplement regimens for individuals seeking to prolong initiation
of hair loss or manage current hair loss.
Table 7. Summary of Research on Marine-based Hair Growth Studies
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 113 of 125
Type of Study
Intervention and/or
Bioactive Ingredients
Dosage and
Administration Time
trial of 60 subjects
Marine complex
supplement (Viviscal®
Man; Lifes2good, Inc.,
Chicago, IL, USA)
2 tablets/day (1 morning
and 1 evening) for 6
Increased hair count by 8%, hair
density by 8%, terminal hair density
by 7%, less hair removed in hair pull
tests, and improved quality of life
Kang et
al., 2017
Ex vivo model of Rat
Vibrissa Follicles; In
vivo (C57BL/6)
mouse model
peterseniana, an
edible brown alga,
Ex vivo: (1, 10, and 100
μg/mL per day for 21
days with data recorded
at 0, 7, 14, and 21 days
Ex vivo: Increased rat vibrissa
follicle length by 206.5% and
165.6%, via 1μg/mL and 10 μg/mL
In vivo
In vivo: 0.1, 1, and 10
μg/mL per day for 34
In vivo: Increased induction into
anagen phase, inhibition of 5α‐
reductase by up to 42%, increased
proliferation of dermal papilla cells
up to 150%, increased Wnt/b-
catenin and ERK signaling
While the aforementioned murine model and clinical trial display encouraging results for
using murine-based supplements to improve hair growth, further research, particularly clinical
studies, should be done to evaluate both the safety and efficacy of murine supplements on
promotion of hair growth. The dosing and duration of administration between the mouse model
and clinical trial vary widely; an additional limitation is the small sample of the clinical
experiment. The use of tablet-based routes of administration limit the validity of marine
supplements as potential functional foods [96]. Further studies should focus on direct, oral
consumption of marine-based foods with large sample sizes in clinical settings.
Egg Yolks as a Candidate Functional Food
In addition to being a rich source of dietary nutrients, egg yolks have been increasingly shown to
serve as a potent healthy food in the management of a number of health conditions. Roughly 65%
of the egg yolk is made up of lipids, including triacylglycerides, phospholipids, cholesterol, and
free fatty acids, with roughly two-thirds consisting of monounsaturated and polyunsaturated fats
[99]. These unsaturated fatty acids, particularly omega-3-fatty acids, have been shown to have
protective benefits on cognitive and visual functioning [99]. In addition to lipids, egg yolks also
contain high levels of both water-soluble and fat-soluble vitamins, including B vitamins and A, D,
E, and K vitamins, respectively [99].
Egg yolk contains the enzyme lysozyme, which has been shown to have potent antimicrobial
and antiviral activities. In particular, yolk immunoglobulins provide antigenic properties,
ovalbumin-derived peptides display antihypertensive activity, yolk-derived phosphotin exhibits
antioxidant properties, and egg albumen components display anti-cancer activities [99, 100].
Importantly, the high cholesterol content of egg yolks has prompted dietary suggestions to reduce
consumption of egg yolks. Some studies have shown that dietary cholesterol has limited impacts
on blood cholesterol concentrations, in comparison to endogenously produced cholesterol [101].
Nonetheless, these are important considerations and care should be taken when integrating egg-
based functional food suggestions into hair loss treatment strategies for individuals concurrently
diagnosed with hypercholesterolemia.
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 114 of 125
Egg Yolks for Treating Hair Loss
While studies regarding the use of egg yolks in treating hair loss remains limited, one study has
suggested that key peptides within egg yolks contain growth factor-stimulating properties that
contribute to induction of hair growth (Table 8) [102]. Nakamura et al. found that water-soluble
hair growth peptides (HGP) contained within egg yolks were capable of stimulating vascular
endothelial growth factor (VEGF) and subsequent proliferation of human dermal papilla cells
[102]. Hair growth was also observed in a murine model and in a female pattern hair loss model
[102]. Additionally, they found that HGP likely promotes VEGF expression via activation of an
insulin-like growth factor-1 receptor and subsequent induction of a hypoxia-inducible factor-
transcription pathway [102].
Table 8. Summary of Research on Egg-based Hair Growth Studies
Type of Study
Intervention and/or
Bioactive Ingredients
Dosage and
Administration Time
Nakamura et
al., 2018
In vivo (C3H)
mouse model
Water-soluble egg yolk
peptide (hair growth
peptide (HGP)) or
In vivo: 0.1% (w/w) HGP
diet for 17 days
In vivo: Increased VEGF
expression, dermal papilla
cell proliferation, and overall
murine hair growth.
trial of 76 subjects
Clinical trial: HGP tablet
(250mg) per day by oral
administration for 24
Clinical Trial: Increased hair
density and growth, via IGF-1
receptor activation and VEGF
Limitations of this study included a small sample size and lack of specific quantification of
increased hair growth, which was instead qualitatively assessed via visual assessment. The
therapeutic effects of egg yolk in treating hair loss appears quite promising, however, further
investigations to determine its benefits on hair loss is necessary and until such time, substantial
recommendations cannot be warranted. Future research should focus on clinical testing to evaluate
the safety and efficacy of egg-yolk based treatments to increase hair growth
Honey has been known for its natural therapeutic properties for thousands of years in cultures
across the globe. While the major component of natural honey by weight consists of carbohydrate
sugars, its therapeutic value is primarily attributed to the presence of over 300 bioactive
compounds, including phenolic antioxidants, inhibine’s rich in antibiotics, amino acids, vitamins,
and minerals [103]. The uses of honey in treating ailments is widespread, ranging from chronic
conditions such as diabetes and cancer to acute conditions such as gastrointestinal upset, menstrual
pain, viral infection, fever, respiratory distress, and so on [103]. The antioxidative properties of
honey are heavily attributed to its high concentrations of phenolic compounds, including
flavonoids, as well as reducing sugars and amino acids, translating into protective effects against
cardiovascular disease, metabolic syndrome, diabetes, and cognitive neurodegeneration [104]. It
has also been shown that honey serves as a potent source of probiotics additionally serving as a
prebiotic agent stimulating growth of intestinal flora by providing oligosaccharide-based energy
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 115 of 125
sources for gut microbes [104]. Studies have also attempted to utilize propolis additives to honey
in order to enhance the natural therapeutic properties of honey. It has been shown that the honey
formulations with added propolis exhibited a boost in antimicrobial, antioxidant, and anti-
inflammatory properties [105].
Specifically pertaining to its effects within the integumentary system, the beneficial
dermatological properties of honey are multifold. Firstly, honey has been growing in popularity as
an effective wound healing agent [103]. In addition to moisturizing and hydration of healing
wounds, honey also carries anti-inflammatory, antimicrobial, and antiseptic effects, all critical to
wound healing processes [106]. In addition, honey has been shown to have involvement in cellular
pathways that increase expression of tissue repair mediators and keratinocyte proliferation [106].
Honey has also been shown to have protective benefits in the treatment of acne, by reducing
aqueous availability of water in the skin and thus preventing microbial growth [107]. While
common commercial recommendations for hair loss prevention have revolved around the use of
honey, research surrounding the ability of honey to promote hair growth remains relatively limited.
EVALUATING SCIENTIFIC EVIDENCE: FFC’s Standards for Functional Food Products
Prior to creating functional food products, it is critical to first understand the definition of
functional foods. Strictly speaking, functional foods have been not provided a standardized
definition by any regulatory body in the United States, and a standardized definition across
countries has not been established by global regulatory authority [108]. Examples of independent
definitions developed by national and international agencies include: modified foods that provide
health benefits beyond traditional nutrients, fortified and enriched foods to be consumed at
intervals and amounts needed to derive health benefits, and substances that provide nutrients
beyond those necessary for normal functioning [108]. However, as a front runner in advancing the
field of functional foods, the latest definition by the Functional Food Center (FFC) for functional
foods provides a unified, proper definition that aims to enable exchange of functional food
knowledge and products across domestic and international borders. The latest definition is as
follows, “Natural or processed foods that contain biologically-active compounds; which, in
defined, effective non-toxic amounts, provide a clinically proven and documented health
benefit utilizing specific biomarkers, for the prevention, management, or treatment of
chronic disease or its symptoms.” [7]. This definition highlights the importance of dosage
consideration, natural or processed production, inclusion of bioactive compounds, and evidence of
clinically proven and documented health benefits in the creation of functional food products. This
definition will guide our evaluation of the foods that have been discussed in this paper, in
determining if they can be recommended as a functional food product. In order to determine if the
aforementioned foods can be established as functional food products for the prevention, treatment,
and management of hair loss, a standardized review system linking scientific evidence to health
claims is needed. While the US Food and Drug Administration (FDA) does not provide a strict
definition for functional foods, it does provide an evidence-based review system for evaluating
scientific evidence of health claims. A health claim establishes the relationship between a food
product and a health-related condition. In order to establish authorized health claims, the FDA
evaluates the extent of evidence supporting the claim and overall agreement among experts in the
field, while those claims with extensive evidence but lacking overall agreement are deemed
qualified health claims [109]. Additionally, the FFC has also developed a review system for the
evaluation of functional food product scientific evidence, which integrate the FDA health claims
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 116 of 125
described above. The system requires the following steps in order: researching a relationship
between the food and health-related impacts, conducting in vitro and in vivo studies, identifying
target bioactive compounds, and determining appropriate dosages and mechanisms of action [109].
Next, human studies with evaluation of safety and efficacy, development of appropriate food
vehicles, labelling, establishing health claims, marketing and education, and post-marketing
effectiveness and safety monitoring studies are required [109]. The FFC definition of functional
foods, FDA evaluation of health claims, and FFC standards for functional food products will be
used to determine the recommendation of aforementioned food items as functional food products
for addressing hair loss.
Growth-Promoting Functional Foods
The FDA-proposed method of evaluation of health claims will first be applied to analyze the
relationships between the aforementioned functional foods and treatment of hair loss. While both
observational and interventional studies are valuable sources of information for analysis of health
claims, observational studies do not provide causal conclusions and thus provide weaker evidence
for causal relationships between food or food ingredients and hair loss conditions. Therefore,
functional food items with intervention studies, both pre-clinical and clinical, will be focused on
evaluating the validity of health claims. Six of the nine food ingredients: berries, rice bran, ginseng,
Annurca apple, marine supplementation, and egg yolk, which were reviewed provided evidence
for both pre-clinical and clinical testing of health claims. For each of these food items, the
conclusion of each study was in general agreement regarding the beneficial effects on hair growth.
Out of six potential functional food ingredients, ginseng provided the most extensive totality of
evidence supporting its hair growth-promoting properties health claims. This totality of evidence
and agreement among the conclusions of this scientific evidence provides support for the food
product, ginseng, to promote hair growth and serves as a strong basis to continue research with the
end goal of validating if ginseng can be confirmed as a functional food for the treatment of hair
loss. Unfortunately, until further evidence is obtained, health claims regarding ginseng’s impact
on hair growth cannot be validated. Additionally, the remaining five food items also have potential
to have authorized health claims on promotion of hair growth, but even more extensive evidence
is needed prior to approving these health claims.
The FFC standards for establishing a functional food product will then be applied to determine
if the food ingredients or products can be recommended as functional food products for the
treatment of hair loss. Studies on all nine food ingredients were examined for their link to hair
promotional capacities. Both in vitro and in vivo studies conducted in five of these nine food
products namely, berries, Mediterranean diets, rice bran, ginseng, and Annurca apple found a
target bioactive compound. In addition, all five of these also provided dosing regimens and
potential mechanisms of action of the target bioactive compound. Moving stepwise down the FFC
system for creation of functional food products, four of the five food items including berries, rice
bran, ginseng, and Annurca apple were applied in human studies and vehicles of application were
developed for each. In general, these were either oral or topical formulations. However, some of
these ingredients were often administered in capsule or tablet form. Because the FFC’s definition
of functional foods delineates natural or processed food, but not capsules or tablets, further
research aimed towards establishing these ingredients as functional foods must shift away from
capsule or tablet administration. Health claims, all focused on promotion of hair growth, were
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 117 of 125
made for each of these food items. These health claims were analyzed in the previous section with
evidence for ginseng providing the greatest support for an approved health claim. Thus, out of the
nine food items analyzed, ginseng is the strongest candidate to be considered a functional food
product for the management of hair loss. Notably, in many cases, ginseng was not used as a food
but rather as a tablet, and it was unclear if benefits of ginseng on hair growth were clinically
associated with biomarkers. An additional limitation was that exact quantities of hair growth
improvement were often not provided but were determined through visual ascertainment. Creation
of regulatory labels would benefit further studies establishing a standardized dosing, safety,
efficacy, and toxicity profile. Additionally, further studies elucidating the specific ginsenosides
responsible for hair growth promotion and their associated mechanisms of action are needed.
Berries, rice bran, and Annurca apple were secondarily found to be the next most potent candidates,
requiring further research studies to substantiate the current evidence regarding these foods as hair
growth promoter. Further research to validate current conclusions would improve the totality of
evidence on these four food items, supporting the probability of approving their associated health
While future research is required to further elucidate the safety, efficacy, and mechanisms of action
of these food ingredients in the prevention and treatment of hair loss, it is clear that the potential
benefits of numerous bioactive compounds in hair growth promotion are promising. The
applications of oral consumption or topical application of these hair growth-promoting foods or
food ingredients are also multifold. Incorporating these foods into dietary and lifestyle patterns
can be adopted as personal homemade remedies or clinical treatment regimens to treat conditions
such as male and female pattern hair loss, androgenetic alopecia, and chemotherapy-induced
alopecia. It is likely that they can be used either in conjunction with or independently from drug-
based treatment methods. The natural-based origin of these bioactive compounds will potentially
reduce the amount of side effects observed with synthetic treatments. Additional benefit of
incorporating these foods into dietary and lifestyle patterns is their widespread beneficial effects
on physiological health. As seen throughout, each compound possesses numerous other benefits
beyond hair growth promotion, including antioxidant, anti-inflammatory, and cardioprotective
activities. The ultimate goal for functional foods is not only focused on promoting hair growth but
also on improving self-confidence, self-esteem, and self-image perceptions normally associated
with hair loss conditions.
Future research should focus on investigating the safety and efficacy of these food ingredients,
particularly ginseng, in clinical settings, as well as establish specific dosing regimens and address
potential toxicity profiles. Additionally, biomarkers used to assess hair growth improvement
should be clarified, along with relevant mechanisms of action.
List of abbreviations: Annurca Apple Polyphenolic Extract, AAE; Bcl-2-associated X protein,
BAX; B-cell Lymphoma 2, BCL-2; Beta-sitosterol, SITOS; Calcitonin-gene Related Peptide,
CGRP; Chemotherapy-induced Alopecia, CIA; Dihydrotestosterone, DHT; Female Pattern Hair
Loss, FPHL; Food and Drug Administration, FDA; Hair Growth Peptide, HGP; Heat Shock
Protein 47, HSP47; Insulin-like Growth Factor-1, IGF-1; Keratinocyte Growth Factor, KGF;
Korean Red Ginseng, KRG; Linoleic Acid, LA; Low-density Lipoprotein, LDL; Male Pattern Hair
Loss, MPHL; Pentose Phosphate Pathway, PPP; Raspberry Ketone, RK; Rice Bran Supercritical
Bioactive Compounds in Health and Disease 2019; 2(5):94-125 Page 118 of 125
CO2 Extract, RB-SCE; Sonic Hedgehog, Shh; Transforming Growth Factor Beta, TGF-β; Tumor
Necrosis Factor Alpha, TNF-α; Vascular Endothelial Growth Factor, VEG-F
Competing Interests: The authors have no financial interests or any other conflicts of interest to
Authors’ and Contributions: All authors contributed to this review.
Acknowledgements and Funding: No funding was received for this manuscript
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... Kaempferol is a natural flavonoid that contains potent antioxidant activity and anti-inflammatory while isoquercetin also in flavonoids group that has the effect of anti-oxidant, anti-inflammatory and protective effect REVIEW eISSN: 2550-2166 © 2020 The Authors. Published by Rynnye Lyan Resources in cancer due to it can react on lipid peroxidation (Di Camillo Orfali et al., 2016;Yardimci, 2017;Deng et al., 2019;Wei and Martirosyan, 2019). In animal studies, this plant extract can induce earlier anagen phase and help in longer the mature anagen phase that can help promote hair growth and treat hair loss. ...
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Hair loss or alopecia is a common dermatological issue that can affect millions of human population of all ages and both gender, male and female. Frequently, alopecia has been found to be associated with significant adverse effects or reduction of psychological and self-esteem. Consequently, this may lead to psychological problems such as depression and anxiety, thus it may negatively impact the quality of life as well. There are several types of hair loss including androgenetic alopecia (AGA), alopecia areata (AA), alopecia totalis (AT), Alopecia Universalis (AU), cicatricial alopecia (CA), senescent alopecia (SA), traction alopecia (TA) and telogen effluvium. However, this review will focus on the androgenic alopecia only. Androgenic alopecia (AGA) also known as male pattern baldness is referred to as hair loss that often occurs in men after puberty caused by the androgen. In addition, this review will discuss on the hair growth cycles and their mechanism on the androgenic alopecia and lastly the management of androgenic alopecia using plant derivatives and methods used in order to prolong the efficacy of androgenetic alopecia treatment.
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Fish-derived collagen has recently emerged as an alternative collagen source with bioactive properties, including the enhancement of hair and skin health. It is also cost-effective and has high bioavailability, in addition to having fewer side-effects compared to collagen from porcine skin or bovine skin. Collagen peptides (CPs) extracted from the scales of Mozambique tilapia (Oreochromis mossambicus) reportedly promote hair and skin health. This study sought to evaluate the effects of CPs on hair growth using in vitro and in vivo models. CP significantly enhanced hair regrowth and the proliferation of human dermal papilla cells (hDPCs) in vitro. CP was orally administered to C57BL/6 mice for 6 weeks to confirm the hair-growth-promoting effects. The mice were divided into four groups: negative control (distilled water), positive control (1 mg/kg of finasteride), CP500 (500 mg/kg of CP), and CP1000 (1000 mg/kg of CP). CP treatment significantly enhanced the proliferation of hDPCs compared to 0.2 μM finasteride, in addition to enhancing hair regrowth. Particularly, CP1000 treatment achieved a hair-growth index similar to that of the PC. In H&E staining, the CP groups exhibited a high A/T ratio. Furthermore, CP increased the expression of hair growth factors (IGF-1, VEGF, krt27, Gprc5d, and Ki67) and decreased the growth inhibitory factor (TGF-β1). Furthermore, CP significantly upregulated the Wnt/β-catenin pathways and downregulated the BMP pathways. Therefore, these results indicate that CP could be used as food supplements and nutraceuticals for hair loss prevention as well as hair regrowth during alopecia.
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Citation: Zambrano A., Raybaudi-Massilia R., Arvelo F., Sojo F. Cytotoxic and antioxidant properties in vitro of Functional beverages based on blackberry (Rubus glaucus B.) and soursop (Annona muricata L.) pulps. ABSTRACT Background: There are many kinds of tropical fruit available in Venezuela. Two of these fruits are the focus of our study: blackberry ("mora") and soursop ("guanábana"). These fruits have extraordinary bioactive components. For example, blackberry has antioxidant compounds such as anthocyanins, which are characteristic of the Rosaceae family. Acetogenins present in the Annonaceae family have been shown to possess cytotoxic properties that act against different types of tumor cells. In previous research, we have discovered how lyophilized soursop pulp has an elevated cytotoxic effect with an IC 50 of 7.19±1.06 in human cervix carcinoma cells (HeLa) and 0.84±1.29 in human prostate carcinoma cells (PC3). Objective: This study focused on the health benefits and properties of the soursop and blackberry. Our focus was to determine the antioxidant and cytotoxic properties in a formulated beverage containing blackberry, soursop, and yogurt containing probiotics and prebiotics. Methods: The research includes the study of soursop pulp (SP), blackberry pulp (BP), and two formulations of the functional beverage selected through a sensorial analysis, F2 (BP + SP + Yogurt + Truvía® + Sacarose) and F3 (BP + SP + Yogurt + Truvía® + Sacarose + Sodium tripolyphosphate). Cell viability of prostate carcinoma cells (PC3), breast carcinoma without over-expression of the HER2/c-erb-2 gene (MCF-7), breast carcinoma in which the HER2/c-erb-2 gene is over-expressed (SKBr3) and healthy cells of human connective tissue used as control (Fibroblasts). The previous indicated samples were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide). The antioxidant activity of the functional beverage was also done using a fresh preparation of 1,1-diphenyl-2-picrylhydrazyl (DPPH). Results: The BP demonstrated the highest cytotoxicity for both lines of breast cancer cell lines, MCF-7 and SKBR3. The values of the minimum concentration required to inhibit 50 % of the cell population (IC 50) was 0.12 ± 1.10 and 1.81 ± 1.68% v / v respectively, followed by SP in MCF-7 and PC3 with values of 1.40 ± 1.03 and 1.34 ± 1.06 respectively. At the same time, the effectiveness of the formulations used found that 3.60 ± 1.04% v / v of F2 beverage was necessary to achieve 50 % inhibition of cell viability of MCF-7 line. For the formulation F3, it was necessary to use a concentration of 5.21 ± 1.04% v / v for that tumor cell line. However, the F2 and F3 formulations demonstrated IC 50 values of 3.69 ± 1.08% v / v and 2.50 ± 1.08% v / v respectively for the PC3 cell line. On the other hand, the antioxidant capacity of BP and SP reached elevated values at 30 minutes of exposure to DPPH, obtaining a rate of 85.28 ± 0.11 and 80.94 ± 0.07 % respectively by using a concentration of 12.5 %, F2 and F3 formulations also reached values of 83.97 ± 0.46 and 85.62 ± 0.11 % at 100 % concentration of both drinks respectively. Conclusion: We discovered that the cytotoxic activity of both formulations prepared, as well as the pulps were fairly good, revealing highly effective consequences for the inactivation of breast tumor cells MCF-7 and prostate tumor cells PC3. Moreover, BP and SP demonstrated a high antioxidant activity, with a synergistic effect accomplished by the mixture on F2 and F3.
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Chemotherapy-induced alopecia (CIA) is a common side effect of conventional chemotherapy and represents a major problem in clinical oncology. Even months after the end of chemotherapy, many cancer patients complain of hair loss, a condition that is psychologically difficult to manage. CIA disturbs social and sexual interactions and causes anxiety and depression. Synthetic drugs protecting from CIA and endowed with hair growth stimulatory properties are prescribed with caution by oncologists. Hormones, growth factors, morphogens could unwontedly protect tumour cells or induce cancer cell proliferation and are thus considered incompatible with many chemotherapy regimens. Nutraceuticals, on the contrary, have been shown to be safe and effective treatment options for hair loss. We here show that polyphenols from Malus Pumila Miller cv Annurca are endowed with hair growth promoting activity and can be considered a safe alternative to avoid CIA. In vitro, Annurca Apple Polyphenolic Extract (AAE) protects murine Hair Follicles (HF) from taxanes induced dystrophy. Moreover, in virtue of its mechanism of action, AAE is herein proven to be compatible with chemotherapy regimens. AAE forces HFs to produce ATP using mitochondrial β-oxidation, reducing Pentose Phosphate Pathway (PPP) rate and nucleotides production. As consequence, DNA replication and mitosis are not stimulated, while a pool of free amino acids usually involved in catabolic reactions are spared for keratin production. Moreover, measuring the effect exerted on Poly Unsaturated Fatty Acid (PUFA) metabolism, we prove that AAE promotes hair-growth by increasing the intracellular levels of Prostaglandins F2α (PGF2α) and by hijacking PUFA catabolites toward β-oxidation.
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Background: To create functional food products based on scientific evidence, we must first define functional foods. Previous definitions describe how functional foods improve health and mitigate disease. However, more refined definitions provide a reason for their efficacy–through the activity of bioactive compounds and the measurement of biomarkers, which are the essential tools for gauging the effectiveness of functional foods.Functional foods are generally linked to health promotion. The physiological effects of functional food or bioactive compounds may vary, but their categories of action include physical performance, cognitive, behavioral, and psychological function, organ or system function, and combating chronic disease [1, 2].Therefore, establishing a formal definition for these foods will help bring legitimate functional foods to the market. The addition of bioactive compounds, or biochemical molecules that improve health through the physiological mechanisms, improves the definition of functional foods. As a result, the advancement of the functional food definition by the Functional Food Center (FFC) has developed to provide clarity and a more comprehensive understanding of its meaning.
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It is well established that Androgenetic Alopecia (AGA) occurs in genetically predisposed individuals but little is known of its non-genetic risk factors. The aim of the study was to investigate the role of the Mediterranean diet in determining the risk of AGA. A hospital-based case-control study was conducted in the outpatient clinics of the hospital “Istituto Dermopatico dell’Immacolata, Rome, Italy”. We included 104 males and 108 controls not affected by AGA. Controls were frequency matched to cases. Information on socio-demographic characteristics, medical history, smoking and diet were collected for all patients. Logistic regression was used to estimate odds ratio and 95% confidence intervals. After controlling for age, education, body mass index and family history of AGA, protective effects for AGA were found for high consumption (≥ 3 times weekly) of raw vegetables (OR 0.43; 95% CI 0.21–0.89) and high consumption of fresh herbs (3 or more regularly) (OR 0.44; 95% CI 0.22–0.87). We suggest that some foods of the Mediterranean diet, say fresh herbs and salad, may reduce the risk of AGA onset.
Background: To maintain good health, it is important to eliminate extra reactive oxygen generated in the body. Furthermore, ingesting foods containing antioxidants is beneficial. The oxygen radical absorbance capacity (ORAC) values for black raspberry extract (BRE), blueberry extract (BBE), and raspberry extract (RBE) are 62, 66, and 49 µM Trolox equivalents (TE)/g respectively. These values are higher than those for typical antioxidant foods that have been discovered so far (3–30 µM TE/g). Our aim was to find new functionality from the food with the high ORAC value. Therefore, we have prepared these four berry extracts and examined whether they have anti-aging effects and if those effects correlate with their antioxidant activities.Methods: We studied the following effects of 4 berry extracts: 1) lens cell protective effects; 2) effects against alopecia; 3) induction of uncoupling protein-1 (UCP1), a regulator of fat and energy consumption in adipocytes, and stimulation of irisin secretion from skeletal muscle cells; and 4) inhibitory effects on melanocyte tyrosinase activity. The evaluation method was based on below; 1) a-crystallin, type 17 collagen, heat shock protein 47 (HSP47), UCP1 and Irisin - mRNA by qRT-PCR, 2) the amount of the UCP1 and Irisin protein by ELISA. 3) Inhibition of tyrosinase activity was measured by dopachrome production using L-tyrosine.Results: In lens cells, a-crystallin mRNA expression was induced 1 hour after treatment of the cell with Blabina (a powdered formulation containing BRE) and BRE. The extracts of all four berry species promoted the growth of follicle dermal papilla cells by 3-20% in a concentration-dependent manner. These berry extracts were also discovered to markedly induce the expression of mRNAs of type 17 collagen and HSP47 in the hair follicle stem cell and elevate the expression levels of UCP1 mRNA and its protein in adipocytes in a concentration-dependent manner. BRE and Blabina inhibited 5a-reductase in follicle dermal papilla cells and tyrosinase activity in melanocytes at the concentrations which inhibited dopachrome production by at least 50%. Finally, Blabina was discovered to stimulate the irisin secretion from skeletal muscles.Conclusion: These results suggest that berry extracts, particularly BRE, have anti-aging effects through their higher antioxidant activities.Keywords: Anti-aging; antioxidant; alopecia; black raspberry; weight loss; oxygen radical, absorbance capacity; skin whitening
Background: Garlic, or Allium savitum, has long been used to treat various diseases, including cancer. The anticancer effects of garlic are linked to the several garlic-derived organosulfur compounds, such as allicin, ajoene, DAS, DADS, DATS, and SAMC. Animal and in vitro studies have demonstrated that garlic bioactive compounds may prevent cancer through mechanisms such as inducing cell cycle arrest, promoting apoptosis, and inhibiting angiogenesis in different cancer cells. Observational studies, including case-control and cohort studies, have been conducted to confirm the protective effect against colorectal, gastric, and other cancers associated with garlic-derived bioactive compounds and raw garlic consumption, but results have been mixed. Analysis of cell and animal model studies and epidemiological studies using the FDA’s evidence-based review system for health claims and FFC’s proposed standard for evaluating and developing functional food, it has been concluded that garlic cannot yet be considered as a functional food primarily due to the inconclusive data from observational studies and insufficient evidence from randomized clinical trials. Keywords: Garlic, cancer, allicin, bioactive compound, functional food
Background Berries are known for their antioxidant activity due to the presence of flavonoids. Antioxidants’ usage guarantees skin protection against free radicals and, flavonoids, especially, can act as sunscreen. The aim of this paper was to evaluate solar protection factor (SPF) and antioxidant activity in vitro of blackberry and raspberry extracts incorporated in topical formulation and study their stability. Results Raspberry presented 29.93 mg of anthocyanins/100 g of fruit and blackberry 65.58 mg of anthocyanins/100 g of fruit. In vitro solar protection factor was 54.57 to blackberry and 37.32 to raspberry. When incorporated in O/W emulsions, final formulations showed light pink color, creamy aspect, and typical fruity odor. Formulations submitted to indirect light and stove showed odor and color alterations. Conclusions Based on the results, formulations containing extracts should be kept under refrigeration in opaque package to ensure stability due to the presence of flavonoids. In addition, blackberry and raspberry extracts are potential natural alternatives to be used as sunscreen and to prevent skin aging.
Lung cancer is a malignant tumour with minimal survival rate and the current treatments are not showing complete remission of tumour and have many side effects. Thus a natural herbal medicine with good anti-cancer properties is highly demanded. Thuja orientalis L. is a traditionally used medicine to cure cough, bronchitis, excessive menstruation, asthma, skin infection and premature baldness. In addition, recent studies have revealed that it has anti-proliferative and anti-cancer activity. Angiogenesis is the main reason for the propagation and metastasis of cancers. We therefore intended to study the effects of the leaf extract of Thuja orientalis L. on angiogenesis as well as lung cancer cell growth. We have tested the anti-angiogenesis efficiency by alkaline phosphatase assay and also analysed the in vivo toxicity and teratogenic effects of various concentration of Thuja orientalis L. extract by establishing an in vivo zebra fish (Danio rerio), a promising model for cancer research which share genetic structure similarity to that of human beings. Also we demonstrated an anti-cancer effect of leaf extract from Thuja orientalis L. on human lung cancer cell line (A549) by MTT and trypan blue assay. The results revealed that the Thuja orientalis L. extract is efficient in repressing lung tumour cell growth significantly (p ≤ 0.01) in all treatments (2.4 mg/ml to 0.3 mg/ml) except 0.15 mg/ml compared to the control. The in vivo toxicity assay has proven that it is non-toxic at concentrations 0.6 mg/ml, 0.3 mg/ml and 0.15 mg/ml in zebrafish. The teratogenic assays revealed the therapeutic index (TI) as 0.808 with 0.7029 mg/ml as LC50 concentration at 24 h which is within the desirable value (below 1) for drug administration. Noticeable inhibition of angiogenesis also was observed in treatment with 2.4 mg/ml to 0.3 mg/ml. Overall we found that Thuja orientalis L. plant leaf extract exhibits better anti-cancer properties as we have validated by in vitro and in vivo analysis.
Alopecia is divided into two categories: androgenic alopecia and nonandrogenic alopecia. An androgen-dependent abnormality of biological functions causes alopecia in males, but the role of androgens is not yet elucidated in female pattern hair loss (FPHL). Modulation of androgenic activity is not effective in certain kinds of androgenic alopecia in females, as well as in cases of nonandrogenic alopecia in males and females. The hair growth drug, minoxidil, stimulates vascular endothelial growth factor (VEGF) production as well as vascularization and hair growth in females. Yet, because minoxidil has side effects with long-term use, a safe alternative hair growth agent is needed. Whereas hair develops after birth in mammalian species, hair mostly grows in a precocial bird, in the chicken, between hatching day 14 and 15. Therefore, we hypothesized that the chicken egg contains a key hair growth factor. In this study, we demonstrated that water-soluble peptides derived from the egg yolk stimulate VEGF production and human hair follicle dermal papilla cell growth. We also found that these peptides enhance murine hair growth and improve hair growth in FPHL. Finally, we characterized that water-soluble egg yolk peptides induce VEGF expression through insulin growth factor-1 receptor activation-induced hypoxia-inducible factor-1α transcription pathway. We have given the name 'hair growth peptide (HGP)' to this water-soluble egg yolk peptide.
Hair loss is often distressing and can have a significant effect on the patient's quality of life. Patients may present to their family physician first with diffuse or patchy hair loss. Scarring alopecia is best evaluated by a dermatologist. Nonscarring alopecias can be readily diagnosed and treated in the family physician's office. Androgenetic alopecia can be diagnosed clinically and treated with minoxidil. Alopecia areata is diagnosed by typical patches of hair loss and is self-limited. Tinea capitis causes patches of alopecia that may be erythematous and scaly and must be treated systemically. Telogen effluvium is a nonscarring, noninflammatory alopecia of relatively sudden onset caused by physiologic or emotional stress. Once the precipitating cause is removed, the hair typically will regrow. Trichotillomania is an impulse-control disorder; treatment is aimed at controlling the underlying psychiatric condition. Trichorrhexis nodosa occurs when hairs break secondary to trauma and is often a result of hair styling or overuse of hair products. Anagen effluvium is the abnormal diffuse loss of hair during the growth phase caused by an event that impairs the mitotic activity of the hair follicle, most commonly chemotherapy. Physician support is especially important for patients in this situation.