Biomedicine & Pharmacotherapy 87 (2017) 496–502

Available online at ScienceDirect www.sciencedirect.com

Review

Golden root: A wholesome treat of immunity

Kunjan Khanna, K.P. Mishra*, Lilly Ganju, Shashi Bala Singh

Immunomodulation Laboratory, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India

A R T I C L E I N F O A B S T R A C T

Article history:

Received 30 November 2016 is native to the high altitude regions of Asia, Europe and Northern Hemisphere. It has a long

Received in revised form 21 December 2016 history of use as a medicinal in various ailments, boosting immunity, increasing energy and mental

Accepted 31 December 2016

capacity. It is also known as “Adaptogen” to help the body to adapt and resist stress. The part of the plant,

which is used for medicinal values, is rhizome, which is an underground stem. The rhizome contains

Keywords: mainly salidroside, rosin, rosavin and p-tyrosol. There are many studies, which have reported the effects

Rhodiola

of Rhodiola spp. on different organs and health conditions. In this review, we have selected the articles

Immunity

from Pubmed and Google Scholar from year 1992–2016 to report the effects of Rhodiola spp. and their role

Rhizome

in curtailing various diseases and stress. The present review emphasizes the medicinal and therapeutic

NK cell

applications of Rhodiola spp. on different experimental models. Overall conclusion is that Rhodiola spp.

Antiviral

has immense therapeutic potential and hence, this review would give impetus to new research for the

development of Rhodiola based herbal nutraceuticals as well as pharmaceuticals.

© 2017 Elsevier Masson SAS. All rights reserved.

Contents

1. Introduction ...... 496

2. Phytochemistry of rhizome ...... 497

3. Applications in health promotion and disease prevention ...... 497

3.1. Rhodiola strengthens immune system ...... 497

3.1.1. Immunomodulatory effects ...... 497

3.1.2. Rhodiola enhances antibody response in combination with antigens (Adjuvant effect) ...... 497

3.1.3. Effect on Mucosal Immunity ...... 498

3.1.4. Angioinhibitory, anti-tumor and anti-cancer effect ...... 498

3.2. Anti-viral effect by enhancing innate immune factors ...... 498

3.3. Anti-oxidative effect ...... 499

3.4. Anti-aging effect ...... 499

3.5. Anti-depression effect ...... 499

3.6. Effect on nervous system, stress and other life style disorders ...... 499

4. Conclusion ...... 500

Conflict of interest statement ...... 500

Acknowledgement ...... 500

References ...... 500

1. Introduction regulating or maintaining the immunity of a person, medications

like immunomodulators could be used. Many immunomodulators

Chronic or long-term stress may lead to symptoms like anxiety, have been derived from and have been used for many years

depression, sleep problems and weak immune system. For to serve as enhancers of immunity. There are about 210,000 kinds

of natural products discovered and known for human use as per the

Dictionary of Natural Products [1]. Rhodiola, also known as Golden

root is one such immunomodulator that has been known for about

* Corresponding author.

E-mail address: [email protected] (K.P. Mishra). 2000 years. Enormous research is being done on it to unfold its

http://dx.doi.org/10.1016/j.biopha.2016.12.132

0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

K. Khanna et al. / Biomedicine & Pharmacotherapy 87 (2017) 496–502 497

various roles of enhancing immunity and other applications. anti-microbial compounds. They are also known in preventing

Rhodiola, a member of the family is a perennial plant, several immune-related diseases such as rheumatic diseases,

which grows at high altitude in regions of Asia, Europe and Canada. cancer, eczema, asthma, inflammatory conditions etc. Rhodiola is

Active compounds have been isolated mainly from the rhizome, one such plant with potential immune stimulatory properties.

which shows various medicinal properties. Many species of Genus Studies revealed that salidroside, a major phenylpropanoid

Rhodiola, which have been discovered and studied for therapeutic glycoside of Rhodiola ameliorate the inflammation and memory

purposes, are included in Table 1. is one of the most loss via SIRT1/NF-kB signalling pathway in D-gal induced

beneficial medicinal plant that has been thoroughly studied and Alzheimer rat model [54].

accepted as an adaptogen that provide nonspecific resistance by Another condition in which Rhodiola has shown its effects is

suppressing physical, chemical and biological stressors. Also, ‘Endotoxemia’. Endotoxemia refers to the presence of endotoxins

Rhodiola rosea reduces fatigue [2], oxidative stress [3], works as in blood. It leads to sepsis, which is caused by the release of

anti-tumour [4] and anti-viral agent [5]. Other species of Rhodiola endotoxin like lipopolysaccharide (LPS), by Gram-negative bacte-

family also show different medicinal advantages like R. sacra is ria. In humans, bacterial infections can cause septic shock leading

used as anti-aging agent and R. imbricata for increasing immunity to multi-organ failure. It has been shown that TNF-a,IL-6, IL-8 and

[19,48]. The aim of this review is to provide the information on IL-1b increase rapidly in the early stages of sepsis, mediating

therapeutic and prophylactic effects of Rhodiola spp. on various inflammation [55]. Salidroside, an active compound of Rhodiola

experimental models. decreases the apoptosis of immune cells in spleen & thymus and

inhibits proinflammatory immune response in sepsis model. Thus,

2. Phytochemistry of rhizome Rhodiola is a potent anti-inflammatory and anti-apoptotic agent as

proved in experimental sepsis mice model and thus might be used

The extracts of Rhodiola rhizome have shown many medicinal as therapeutics for sepsis [56].

properties and thus the rhizome is considered as the most In order to check the anti-inflammatory role of salidroside,

important part of the plant. HPLC (High Performance Liquid human mast cell line-1 (HMC-1) was treated with phorbol-12-

Chromatography) has revealed constituents of its Rhodiola rhizome myristate-13-acetate (PMA) plus A23187 to induce inflammation.

(Table 2). The constituent such as salidroside has been investigated Salidroside was given prior to the treatment and it was found that

by many researchers and has shown anti-inflammatory [55], anti- levels of pro-inflammatory cytokines and NF-kB expression were

viral [5] and anti-cancerous [20] activities. Also, the constituents reduced. The results conferred the role of salidroside as anti-

Rhodionin and rhodiosin decrease the lipids in blood and thus, help inflammatory agent by blocking mitogen-activated protein kinases

in prevention of life style disorders [13]. (MAPK) and NF-kB signalling pathways [72].

3. Applications in health promotion and disease prevention 3.1.2. Rhodiola enhances antibody response in combination with

antigens (Adjuvant effect)

3.1. Rhodiola strengthens immune system Adjuvants are compounds that enhance antibody response

when mixed with antigens, however alone they do not elicit

3.1.1. Immunomodulatory effects specific antibody response. Alum has been known and widely

Agents that are capable of interacting with the immune system accepted adjuvant suitable for human use [57] but it has some

to up-regulate or down-regulate the immune response are called limitations as it enhances Th2 immune response but not Th1

“Immunomodulators” or biological response modifiers. Several of immune response. In a study, Mishra et al. [46] has identified the

these products possess pharmacological properties and act as adjuvant activity of Rhodiola rhizome with tetanus toxoid and

immuno-stimulant, neuro-stimulant, antiseptic, anti-ageing and ovalbumin in rats. There was increase in antigen specific antibodies

Table 1

Different species of Rhodiola and their medicinal importance.

Rhodiola Species Uses References

R. rosea Anti-tumor, anti-angiogenic, anti-viral, anti-angiogenic, anti-oxidative [6,7,5,8–15]

R. crenulata Anti-oxidative, improves mucosal immunity [7,16–18]

R. sacra Anti-aging [19]

R. brevipetiolata – [20]

R. quadrifida Immunestimulant, anti-oxidative [21,26]

R. yunnanensis –– [23]

R. coccinea – [24]

R. gelida Anti-oxidative [25,26]

R. heterodonta Anti-hypoxic [27,28]

R. integrifolia – [29]

R. dumulosa – [22,30]

R. rhodantha – [31]

R. sachalinensis Anti-oxidative [32]

R. himalensis – [33]

R. serrata – [34]

R. wolongensis – [35]

R. kirilowii Anti-viral [36]

R. fastigiata – [37]

R. alsia – [38]

R. henryi – [39]

R. algida Immunomodulatory effect [42]

R. alterna – [43]

R. sedoides – [44]

R. imbricate Anti-oxidative, Anti-cancerous [45,46–48]

498 K. Khanna et al. / Biomedicine & Pharmacotherapy 87 (2017) 496–502

Table 2

Percentage of constituents in rhizome with roots of Rhodiola rosea [34,51–53,74,75].

Constituents Important markers Percentage (%)

Phenylpropanoids Rosarin 0.025

Rosavin 0.208

Rosin 0.121

Phenylethanol derivatives Tyrosol 0.077

Salidroside 0.155

Flavonoids Catechins 0.165

Phenolic acids Gallic acid, Caffeic acid, Chlorogenic acid 0.067

stimulating the humoral immune response. Delayed Type Hyper- increasing immunity and decreasing the quantity of oral ulcers in

sensitivity (DTH) response was observed; showing role of Rhodiola breast cancer patients [42].

in stimulation of cell mediated immune response also [46]. The In addition, R. algida in a study on MCF-7 breast cancer cells

results were strengthened by the study showing Rhodiola showed anti-carcinogenic effect by suppressing the levels of HIF-

enhancing the production of IL-6 and thus it has a role in 1a and HIF-2a, which are over expressed in hypoxic conditions

formation of Plasma cells by the activation of B-cells eventually [40]. Another study on human colorectal cancer cells HT-29

leading to antibody generation [47]. showed salidroside can induce apoptosis and autophagy via PI3K/

Akt/mTOR signalling pathway and thus can be a potent anti-

3.1.3. Effect on Mucosal Immunity proliferative agent [73].

Rhodiola has been known to affect many organs. In many Rhodiola imbricata has also known anti-cancer properties but

studies, Rhodiola has shown protective effects on gut immunity the exact mechanism is still not clear. In order to study the

also. In one of the study on Drosophila melanogaster, Rhodiola mechanism, Rhodiola aqueous extracts were validated as a novel

crenulata was mixed in the diet of the Drosophila and the TLR4 activator increasing NK/CTL activity, this gives indication of

morphological changes of the intestine, Reactive oxygen species its anti-cancer property [48]. Different species of Rhodiola that

and antimicrobial peptides were analysed upon feeding with shows anti-cancer effect are summarized in Fig. 1.

pathogenic microorganisms and toxic compounds. The results

showed that R. crenulata showed better Gut immunity when 3.2. Anti-viral effect by enhancing innate immune factors

administered with pathogens and toxins [17]. In another study of

gut in Broilers, three groups were studied in which one was fed Aqueous extract of Rhodiola rhizome (RAE) has shown anti-viral

with basal diet, second with basal diet along with low R. crenulata immune response against Dengue virus by promoting ISG, RIG-I

(0.5%) and third with basal diet along with 1.5% R. crenulata. The and MDA 5 gene expression in human peripheral blood mononu-

group with High R. crenulata showed significantly decreased body clear cells and THP1 cells [60].

weight at 28 and 42 day of 6-week study and average daily feed Salidroside from Rhodiola rosea has shown potent anti-viral

intake during the study as compared to two other groups. It was effect against Coxsackie virus B3, which is known to cause viral

also found that low R. crenulata diet significantly decreased total myocarditis. Salidroside has been effective in lowering down virus

mortality in Broilers [18]. titres, pro- and anti- inflammatory cytokines and modulate various

heart enzymes [5].

3.1.4. Angioinhibitory, anti-tumor and anti-cancer effect In other in vitro study conducted on MDCK cells with 14

The aqueous and hydroalcoholic extracts of R. rosea suppresses flavonoids from Rhodiola rosea, Kaempferol has shown anti viral

the angiogenesis by inhibiting the pro-angiogenic factors in the activity against Influenza virus, H1N1 and H9N2 strains. All the

model of tumour induced angiogenesis [6]. in vivo and in vitro flavonoids have shown neuraminidase inhibitory property and the

studies on salidroside, a glucoside of tyrosol extracted from chemical structure may be a reason for the anti-viral activity [10].

Rhodiola rosea showed that it can inhibit glioma growth and thus R. kirilowii has shown anti-viral effect by inhibiting the serine

improve the tumor microenvironment. Also, it has a protective proteases in chronic Hepatitis C virus infection. Twelve compounds

effect on central nervous system (CNS) and make oxidative stress isolated from the active fraction of this plant revealed that

and astrocytes return to normal [4]. The R. rosea and R. quadrifida presence of hydroxyl group in B-ring show a minor effect in anti-

extracts have also shown potent anti-angiogenic effect [58].Anti- viral activity as shown in previous studies whereas structure

oxidative and anti-proliferative effects of extracts of R. imbricata activity relationship (SAR) with anti-viral natural entities has

rhizome were seen in the studies of HT-29 human colon cancer major effect [36].

cells. The presence of polyphenols in Rhodiola rhizome resulted in Although, a study was performed to see the anti-viral effect of

anti-proliferative activity and anti-oxidative activity of these crude ethanol extract of the Golden root i.e. Rhodiola rosea on Avian

extracts is due to their metal chelating capacity [45]. In vitro

studies on cultured lung cancer A549 cells showed that salidroside

decreased intracellular Reactive Oxygen Species (ROS) levels and

phosphor-p38 expression, which is a signalling protein, associated

with oxidative stress and therefore it can be used as potent R.rosea R.quadrifida

treatment for lung cancer [59].

In a study to improve the condition of breast cancer patients for

Anti-Cance r

chemotherapy induced oral mucositis, 130 cancer patients were properties

given R. algida orally for 14 days after each chemotherapy cycle and

checked for the oral ulcerations. It was found that one week after

R. algida R.imbricata

each cycle of chemotherapy white blood cells count in Rhodiola

treated group was returned faster to normal levels as compared to

the control group. This study infers the role of Rhodiola algida in

Fig. 1. Rhodiola spp. having anti-cancer properties.

K. Khanna et al. / Biomedicine & Pharmacotherapy 87 (2017) 496–502 499

infectious bronchitis virus (IBV), but results showed that these has shown mild or strong inhibitory activity against superoxide

crude extracts could not inhibit the virus[61]. anion radical or inhibited the hydroxyl radical when evaluated

Anti-viral studies have also been shown in marathon atheletes. with Electron Resonance spin technique [19].

Rhodiola rosea extracts when given orally to athletes 30 days prior In a recent study, pre-treatment with salidroside has shown to

to the marathon, and serum was collected pre-and post- marathon reverse the effect of UVB induced premature senescence in human

(2–15 min and 1.5 h after race) and incubated with HeLa cells for dermal fibroblast cells in a dose dependent manner. The

4 h and then infected with recombinant wild-type VSV (Vesicular mechanism by which premature senescence is protected involves

stomatitis virus such as rabies and influenza virus). Results shown attenuating the proinflammatory cytokines and levels of UVB

that Rhodiola rosea delays virus infection immediately post induced MMP-1 while increasing cell viability. Therefore,

marathon [12]. highlighting the role of salidroside as photoprotector and anti-

aging agent against UVB premature senescence [65].

3.3. Anti-oxidative effect In a study on male Wistar rats, salidroside has shown to

increase immunity with aging when given for 45 days continu-

Oxidative stress occurs when there is an imbalance in the ously. There was increase in total T cells as well as T helper cells.

Reactive Oxygen Species (ROS). ROS can damage DNA, proteins as Also, T cell mediated immune response and anti-KLH IgG, anti-KLH

well as lipids. Rhodiola crenulata has shown improvement in IgG1 & anti-KLH IgG2 were elevated, suggesting the role of

neurogenesis by protecting the nervous system from oxidative salidroside in rejuvenation and as an anti- aging agent [66].

damage induced by free radicals, therefore preventing the neural

stem cells from apoptosis or necrosis. Continuous consumption of 3.5. Anti-depression effect

Alcoholic extract of R. crenulata has reduced oxidative stress in

brain and has declined learning or memory disabilities caused by Recent studies suggested that depressive like behaviour may

streptozotocin in rats [7]. Also, Studies performed with the develop due to inflammation in brain where innate and adaptive

compound herbacetin glycosides, extracted from the root of R. immune system interacts with neurotransmitters [49]. Role of

sachalinens is showed anti-oxidative activity in LPS stimulated salidroside has been elucidated in decreasing the neuroinflamma-

RAW 264.7 cells [32]. A recent study on Parkinson’s disease (PD), a tion in mice model where Lipopolysaaachride (LPS) has developed

neurodegenerative disease showed that the major active constitu- depressive like behaviour. Salidroside significantly decreased the

ent of Rhodiola i.e. salidroside can protect the primary cortical cells proinflammatory cytokines in serum and neurotransmitters such

as well as DA neuronal cell lines (SN4741) from ER stress by as norepinephrine (NE) and 5-hydroxytryptamine (5-HT) in the

reducing neurotoxin induced ROS and calcium levels. It also prefrontal cortex. However, it increased the expression levels of

reduces ER stress- induced cell death by cleaving Caspase-12. Also anti-depressant, Brain derived neurotrophic factor (BDNF) and

in the study, salidroside reduces ER stress by preventing 6- tropomyosin-related kinase B (TrkB) [41].

hydroxydopamine (6-OHDA) – induced cytotoxicity. Results Other recent studies have shown that Rhodiola can act as better

indicated that these cells can be prevented from neurotoxicity therapy for the patients than the drugs available in market today. A

by attenuation of ER stress and thus can be used for therapeutic study that has been conducted on 57 humans with mild to

usage for PD [3]. moderate depression showed that people who took Rhodiola for 12

In another study, salidroside has been reported as anti- weeks showed 1.4 odds of improvement in comparison to

oxidative, anti-inflammatory and anti-fibrotic agent when given conventional therapy drug Sertraline which showed 1.9 odds of

in different doses for 28 days to SD rats, which were induced with improvement but the side effects were lesser in case of Rhodiola

lung fibrotic injuries with bleomycin [62]. Hence proving Rhodiola therapy(30%) in comparison to Sertraline (63%) [11]. In order to

as potent anti-oxidative and anti-inflammatory immunomodula- check for the anxiolytic and antidepressant effect of salidroside,

tor. single dose of salidroside was given to wild type adult mice and it

was observed that it enhanced fear memory and could be used to

3.4. Anti-aging effect cure mood disorders [14]. Therefore, Rhodiola has been considered

a better anti-depressant.

Immune system gradually deteriorates with advancing age. The Insulin resistance has been seen to be positively associated with

hematopoietic stem cells are the progenitors of leukocytes and are Depression in many studies [68]. In a recent study, Rhodiola

differentiated into specialized immune cells like B- & T- crenulata root (RCR) extract was fed to rats in drinking water with

Lymphocytes, dendritic cells, etc. The self-renewal capacity of liquid fructose for over 18 weeks to check its role in amelioration of

these cells is declined due to limitation of DNA damage repair and insulin resistance. It was found that RCR could suppress fructose

shortening of the telomeric terminal of chromosome with the induced hyperinsulinemia, restored the ratios of glucose to insulin

advancing age [63]. Decline in the immunity causes increased & non-esterified fatty acids (NEFA) to insulin and increased the

occurrence of infectious diseases, autoimmune disorders, cancer, clearance of plasma NEFA. It was suggested from the study that

etc. Also, innate and adaptive immune responses are affected by insulin resistance is improved by modulating sarcolemmal and

aging, where latter is affected more. intracellular CD36 redistribution in skeletal muscle [69].

In a study conducted on Drosophila, it has been suggested that

Rhodiola rosea can be used to increase the lifespan of the organism. 3.6. Effect on nervous system, stress and other life style disorders

Researchers fed adult fruit flies with diets of yeast paste

supplemented with four herbs known for their anti-aging In vivo studies on Rhodiola crenulata showed that continuous

properties. The flies ate this diet for the duration of their lives. consumption of its alcoholic extract could improve hippocampal

Three of the herbs were found to have no effect on fruit fly neurogenesis via neural stem cells. It scavenges intracellular ROS,

longevity, but Rhodiola significantly reduced the mortality by can reduce oxidative stress in the hippocampus of Alzheimer’s

increasing survival by 3.5 days in males and by 3.2 days in females disease rats, and thus can treat the disease [16]. It has been shown

[64]. that pre-treatment with salidroside can reduce damage to blood

In another study conducted on R. sacra has revealed that it has brain barrier and can decrease the expression level of pro-

an anti-aging effect by inhibiting the oxidative stress caused due to inflammatory cytokine i.e. TNF-a in rats with focal cerebral

free radical accumulation. Also, 19 active compounds from R. sacra ischemia-reperfusion injury [67]. In order to check the ability of

500 K. Khanna et al. / Biomedicine & Pharmacotherapy 87 (2017) 496–502

Rhodiola rosea in suppressing the withdrawal symptoms of Conflict of interest statement

nicotine for treatment of tobacco smoking, Rhodiola rosea L.

extracts were given to mice which confirmed that it can prevent Authors report no conflict of interest.

relapse as well as reduce rewarding symptoms of nicotine in

animals [50]. Acknowledgement

Rhodionin and rhodiosin are the active components of R. rosea

which when given orally were found to suppress the blood Authors are thankful to the Defence Research and Development

triglyceride level and hence could be given to ameliorate lifestyle Organization, Ministry of Defence, Government of India for

related diseases [13]. Nonalcoholic fatty liver disease is linked to financial support in the form of DIP-265. KK thanks DRDO for

obesity, insulin resistance, hyperglycemia and high levels of fats in the fellowship in the form of JRF and SRF.

the blood. Lin et al. reported the role of R. crenulata root extract

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