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 Rhodiola 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 plant 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 plants 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 Crassulaceae 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. Rhodiola rosea 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.