Rhodiola rosea L.: an Herb with Anti-Stress, Anti-Aging, and Immunostimulating Properties for Cancer Chemoprevention
- 320 Downloads
Purpose of Review
Rhodiola rosea extracts have been used as a dietary supplement in healthy populations, including athletes, to nonspecifically enhance the natural resistance of the body to both physical and behavior stresses for fighting fatigue and depression. We summarize the information with respect to the new pharmacological activities of Rhodiola rosea extracts and its underlying molecular mechanisms in this review article.
In addition to its multiplex stress-protective activity, Rhodiola rosea extracts have recently demonstrated its anti-aging, anti-inflammation, immunostimulating, DNA repair, and anti-cancer effects in different model systems. Molecular mechanisms of Rhodiola rosea extracts’ action have been studied mainly along with one of its bioactive compounds, salidroside. Both Rhodiola rosea extracts and salidroside have contrast molecular mechanisms on cancer and normal physiological functions. For cancer, Rhodiola rosea extracts and salidroside inhibit the mTOR pathway and reduce angiogenesis through downregulation of the expression of HIF-1α/HIF-2α. For normal physiological functions, Rhodiola rosea extracts and salidroside activate the mTOR pathway, stimulate paracrine function, and promote neovascularization by inhibiting PHD3 and stabilizing HIF-1α proteins in skeletal muscles. In contrast to many natural compounds, salidroside is water-soluble and highly bioavailable via oral administration and concentrated in urine by kidney excretion.
Rhodiola rosea extracts and salidroside can impose cellular and systemic benefits similar to the effect of positive lifestyle interventions to normal physiological functions and for anti-cancer. The unique pharmacological properties of Rhodiola rosea extracts or salidroside deserve further investigation for cancer chemoprevention, in particular for human urinary bladder cancer.
KeywordsChemoprevention Rhodiola Salidroside Hypoxia mTOR and DNA repair
This work was supported in part by NIH award 1R01CA193967-01A1 and 1R21CA152804-01A1 (to X. Zi.). Victor Pham is currently supported by NSF graduate research fellowship program DGE-1321846.
Compliance with Ethical Standards
Conflict of Interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.•• American Cancer Society [June 28, 2017, 2017]; https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-3rd-edition.pdf; Global Cancer Facts & Figures 3nd Edition. Major common cancer occurs often in elders. The cancer burden is predicted to double by 2020.
- 2.Johansen NJ, Saunders CM. Value-based care in the worldwide battle against cancer. Cureus. 2017;9:e1039. https://doi.org/10.7759/cureus.1039.
- 3.Dy GW, Gore JL, Forouzanfar MH, Naghavi M, Fitzmaurice C. Global burden of urologic cancers, 1990–2013. Eur Urol. 2017;71:437–46. https://doi.org/10.1016/j.eururo.2016.10.008.
- 5.•• Yokoyama NN, Denmon A, Uchio EM, Jordan M, Mercola D, Zi X. When anti-aging studies meet cancer chemoprevention: can anti-aging agent kill two birds with one blow? Curr Pharmacol Rep. 2015;1:420–33. https://doi.org/10.1007/s40495-015-0039-5. Agents that targets nutrient sensing pathway may contain anti-aging and anti-cancer effects. Unlike chemotherapy or radiation therapy, these agents avoid molecular damage and so less reselection resistance may occur; and thus, these agents may be benificial for cancer chemoprevention.
- 6.•• Fahey JW, Kensler TW. Health span extension through green chemoprevention. Virtual Mentor. 2013;15:311–8. https://doi.org/10.1001/virtualmentor.2013.15.4.stas1-1304. Chemoprevention help delay the process of cancer progression for a few years.
- 7.Vieira AR, Abar L, Chan D, Vingeliene S, Polemiti E, Stevens C, et al. Foods and beverages and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, an update of the evidence of the WCRF-AICR Continuous Update Project. Ann Oncol. 2017; https://doi.org/10.1093/annonc/mdx171.
- 9.Samanta SK, Sehrawat A, Kim SH, Hahm ER, Shuai Y, Roy R, et al. Disease subtype-independent biomarkers of breast cancer chemoprevention by the ayurvedic medicine phytochemical withaferin A. J Natl Cancer Inst. 2016;109 https://doi.org/10.1093/jnci/djw293.
- 10.Liu Z, Xu X, Li X, Liu S, Simoneau AR, He F, et al. Kava chalcone, flavokawain A, inhibits urothelial tumorigenesis in the UPII-SV40T transgenic mouse model. Cancer Prev Res (Phila). 2013;6:1365–75. https://doi.org/10.1158/1940-6207.
- 11.Stewart BW, Bray F, Forman D, Ohgaki H, Straif K, Ullrich A, et al. Cancer prevention as part of precision medicine: ‘plenty to be done’. Carcinogenesis. 2016;37:2–9. https://doi.org/10.1093/carcin/bgv166.
- 12.Adhami VM, Mukhtar H. Human cancer chemoprevention: hurdles and challenges. Top Curr Chem. 2013;329:203–20. https://doi.org/10.1007/128_2012_342.
- 14.Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine. 2010;17:481–93. https://doi.org/10.1016/j.phymed.2010.
- 15.Booker A, Jalil B, Frommenwiler D, Reich E, Zhai L, Kulic Z, et al. The authenticity and quality of Rhodiola rosea products. Phytomedicine. 2016;23:754–62. https://doi.org/10.1016/j.phymed.2015.
- 16.• Xin T, Li X, Yao H, Lin Y, Ma X, Cheng R, et al. Survey of commercial Rhodiola products revealed species diversity and potential safety issues. Sci Rep. 2015;5:8337. https://doi.org/10.1038/srep08337. DNA barcoding may be use to authenticate extracts in a safety manner.
- 17.Khanna K, Mishra KP, Ganju L, Singh SB. Golden root: a wholesome treat of immunity. Biomed Pharmacother. 2017;87:496–502. https://doi.org/10.1016/j.biopha.2016.12.132.
- 18.Radomska-Leśniewska DM, Skopiński P, Bałan BJ, Białoszewska A, Jóźwiak J, Rokicki D, et al. Angiomodulatory properties of Rhodiola spp. and other natural antioxidants. Cent Eur J Immunol. 2015;40:249–62. https://doi.org/10.5114/ceji.2015.52839.
- 19.Kosanovic D, Tian X, Pak O, Lai YJ, Hsieh YL, Seimetz M, et al. Rhodiola: an ordinary plant or a promising future therapy for pulmonary hypertension? a brief review. Pulm Circ. 2013;3:499–506. https://doi.org/10.1086/674303.
- 20.Ishaque S, Shamseer L, Bukutu C, Vohra S. Rhodiola rosea for physical and mental fatigue: a systematic review. BMC Complement Altern Med. 2012;12:70. https://doi.org/10.1186/1472-6882-12-70.
- 21.Amsterdam JD, Panossian AG. Rhodiola rosea L. as a putative botanical antidepressant. Phytomedicine. 2016;23:770–83. https://doi.org/10.1016/j.phymed.2016.02.009.
- 22.Parisi A, Tranchita E, Duranti G, Ciminelli E, Quaranta F, Ceci R, et al. Effects of chronic Rhodiola Rosea supplementation on sport performance and antioxidant capacity in trained male: preliminary results. J Sports Med Phys Fitness. 2010;50:57–63.Google Scholar
- 24.Mao JJ, Xie SX, Zee J, Soeller I, Li QS, Rockwell K, et al. Rhodiola rosea versus sertraline for major depressive disorder: a randomized placebo-controlled trial. Phytomedicine. 2015;22:394–9. https://doi.org/10.1016/j.phymed.2015.01.010.
- 25.Panossian A, Hovhannisyan A, Abrahamyan H, Gabrielyan E, Wikman G. Pharmacokinetic and pharmacodynamic study of interaction of Rhodiola Rosea SHR-5 extract with warfarin and theophylline in rats. Phytother Res. 2009;23:351–7. https://doi.org/10.1002/ptr.2631.
- 27.Yousef GG, Grace MH, Cheng DM, Belolipov IV, Raskin I, Lila MA. Comparative phytochemical characterization of three Rhodiola species. Phytochemistry. 2006;67:2380–91. https://doi.org/10.1016/j.phytochem.2006.07.026.
- 28.Ali Z, Fronczek FR, Khan IA. Phenylalkanoids and monoterpene analogues from the roots of Rhodiola rosea. Planta Med. 2008;74:178–81. https://doi.org/10.1016/j.phytochem.2006.10.021.
- 30.Ming DS, Hillhouse BJ, Guns ES, Eberding A, Xie S, Vimalanathan S, et al. Bioactive compounds from Rhodiola rosea (Crassulaceae). Phytother Res. 2005;19:740–3. https://doi.org/10.1002/ptr.1597.
- 31.Tolonen A, Pakonen M, Hohtola A, Jalonen J. Phenylpropanoid glycosides from Rhodiola rosea. Chem Pharm Bull (Tokyo). 2003;51:467–70.Google Scholar
- 32.[No authors listed] Rhodiola rosea. Monograph. Altern Med Rev. 2002;7:421–3.Google Scholar
- 33.•• Ganzera M, Yayla Y, Khan IA. Analysis of the marker compounds of Rhodiola rosea L. (golden root) by reversed phase high performance liquid chromatography. Chem Pharm Bull (Tokyo). 2001;49:465–7. HPLC offers a reliable means of detecting and evaluating extracts.Google Scholar
- 34.WS Y, Chen XM, Li H, Yang L. Polyphenols from Rhodiola crenulata. Planta Med. 1993;59:80–2. https://doi.org/10.1055/s-2006-959610.
- 35.Mao Y, Li Y, Yao N. Simultaneous determination of salidroside and tyrosol in extracts of Rhodiola L. by microwave assisted extraction and high-performance liquid chromatography. J Pharm Biomed Anal. 2007;45:510–5. https://doi.org/10.1016/j.jpba.2007.05.031.
- 36.Grech-Baran M, Sykłowska-Baranek K, Pietrosiuk A. Biotechnological approaches to enhance salidroside, rosin and its derivatives production in selected Rhodiola spp. in vitro cultures. Phytochem Rev. 2015;14:657–74. https://doi.org/10.1007/s11101-014-9368-y.
- 37.Schriner SE, Abrahamyan A, Avanessian A, Bussel I, Maler S, Gazarian M, et al. Decreased mitochondrial superoxide levels and enhanced protection against paraquat in Drosophila melanogaster supplemented with Rhodiola rosea. Free Radic Res. 2009;43:836–43. https://doi.org/10.1080/10715760903089724.
- 38.Bayliak MM, Lushchak VI. The golden root, Rhodiola rosea, prolongs lifespan but decreases oxidative stress resistance in yeast Saccharomyces cerevisiae. Phytomedicine. 2011;18:1262–8. https://doi.org/10.1016/j.phymed.2011.06.010.
- 39.•• Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman G, Post JA. Plant adaptogens increase lifespan and stress resistance in C. elegans. Biogerontology. 2009;10:27–42. https://doi.org/10.1007/s10522-008-9151-9. Adaptogens help expand the lifespans and increase stress resistance in nematode C elagan.
- 40.Yin D, Yao W, Chen S, Hu R, Gao X. Salidroside, the main active compound of Rhodiola plants, inhibits high glucose-induced mesangial cell proliferation. Planta Med. 2009;75:1191–5. https://doi.org/10.1055/s-0029-1185717.
- 41.van Diermen D, Marston A, Bravo J, Reist M, Carrupt PA, Hostettmann K. Monoamine oxidase inhibition by Rhodiola rosea L. roots. J Ethnopharmacol. 2009;122:397–401. https://doi.org/10.1016/j.jep.2009.01.007.
- 42.•• Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry. 2007;61:343–8. https://doi.org/10.1080/08039480701643290. Extract SHR-5 from Rhodiola rosea was shown to have anti-depressive potential in patients suffering from mild to moderate depression.
- 43.•• Olsson EM, von Schéele B, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009;75:105–12. https://doi.org/10.1055/s-0028-1088346. Repeated administration of extract SHR-5 from Rhodiola Rosea was able to increase mental performance in individual suffering from stress-related fatigue.
- 44.Shevtsov VA, Zholus BI, Shervarly VI, Vol'skij VB, Korovin YP, Khristich MP, et al. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine. 2003;10:95–105. https://doi.org/10.1078/094471103321659780.
- 45.Bocharova OA, Matveev BP, Baryshnikov AI, Figurin KM, Serebriakova RV, Bodrova NB. The effect of a Rhodiola rosea extract on the incidence of recurrences of a superficial bladder cancer (experimental clinical research). Urol Nefrol (Mosk). 1995;2:46–7.Google Scholar
- 47.Blomkvist J, Taube A, Larhammar D. Perspective on roseroot (Rhodiola rosea) studies. Planta Med. 2009;75:1187–90. https://doi.org/10.1055/s-0029-1185720.
- 48.Mishra KP, Ganju L, Chanda S, Karan D, Sawhney RC. Aqueous extract of Rhodiola imbricata rhizome stimulates Toll-like receptor 4, granzyme-B and Th1 cytokines in vitro. Immunobiology. 2009;214:27–31. https://doi.org/10.1016/j.imbio.2008.04.001.
- 49.Pooja, Bawa AS, Khanum F. Anti-inflammatory activity of Rhodiola rosea—“a second-generation adaptogen”. Phytother Res. 2009;23:1099–102. https://doi.org/10.1002/ptr.2749.
- 51.Ross SM. Rhodiola rosea (SHR-5), part I: a proprietary root extract of Rhodiola rosea is found to be effective in the treatment of stress-related fatigue. Holist Nurs Pract. 2014;28:149–54. https://doi.org/10.1097/HNP.0000000000000014.
- 52.Ross SM. Rhodiola rosea (SHR-5), part 2: a standardized extract of Rhodiola rosea is shown to be effective in the treatment of mild to moderate depression. Holist Nurs Pract. 2014;28:217–21. https://doi.org/10.1097/HNP.0000000000000030.
- 53.Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G, Wagner H. Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine. 2000:365–71. https://doi.org/10.1016/S0944-7113(00)80055-0.
- 54.Spasov AA, Wikman GK, Mandrikov VB, Mironova IA, Neumoin VV. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine. 2000;7:85–9. https://doi.org/10.1016/S0944-7113(00)80078-1.
- 55.Bystritsky A, Kerwin L, Feusner JD. A pilot study of Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD). J Altern Complement Med. 2008;14:175–80. https://doi.org/10.1089/acm.2007.7117.
- 56.Hernández-Santana A, Pérez-López V, Zubeldia JM, Jiménez-del-Rio M. A Rhodiola rosea root extract protects skeletal muscle cells against chemically induced oxidative stress by modulating heat shock protein 70 (HSP70) expression. Phytother Res. 2014;28:623–8. https://doi.org/10.1002/ptr.5046.
- 57.Uyeturk U, Terzi EH, Gucuk A, Kemahli E, Ozturk H, Tosun M. Prevention of torsion-induced testicular injury by Rhodiola rosea. Urology. 2013;82:254.e1–6. https://doi.org/10.1016/j.urology.2013.04.018.
- 58.Uyeturk U, Terzi EH, Kemahli E, Gucuk A, Tosun M, Çetinkaya A. Alleviation of kidney damage induced by unilateral ureter obstruction in rats by Rhodiola rosea. J Endourol. 2013;27:1272–6. https://doi.org/10.1089/end.2013.0319.
- 59.Si PP, Zhen JL, Cai YL, Wang WJ, Wang WP. Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress. Neurosci Lett. 2016;618:19–24. https://doi.org/10.1016/j.neulet.2016.02.056.
- 60.Zhang J, Zhen YF, Pu-Bu-Ci-Ren, Song LG, Kong WN, Shao TM, et al. Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav Brain Res. 2013;244:70–81. https://doi.org/10.1016/j.bbr.2013.01.037.
- 61.Verpeut JL, Walters AL, Bello NT. Citrus aurantium and Rhodiola rosea in combination reduce visceral white adipose tissue and increase hypothalamic norepinephrine in a rat model of diet-induced obesity. Nutr Res. 2013;33:503–12. https://doi.org/10.1016/j.nutres.2013.
- 62.Asea A, Kaur P, Panossian A, Wikman KG. Evaluation of molecular chaperons Hsp72 and neuropeptide Y as characteristic markers of adaptogenic activity of plant extracts. Phytomedicine. 2013;20:1323–9. https://doi.org/10.1016/j.phymed.2013.07.001.
- 63.Panossian A, Hambardzumyan M, Hovhanissyan A, Wikman G. The adaptogens rhodiola and schizandra modify the response to immobilization stress in rabbits by suppressing the increase of phosphorylated stress-activated protein kinase, nitric oxide and cortisol. Drug Target Insights. 2007;2:39–54.CrossRefPubMedPubMedCentralGoogle Scholar
- 64.Lee WJ, Chung HH, Cheng YZ, Lin HJ, Cheng JT. Rhodiola-water extract induces β-endorphin secretion to lower blood pressure in spontaneously hypertensive rats. Phytother Res. 2013;27:1543–7. https://doi.org/10.1002/ptr.4900.
- 65.Xia N, Li J, Wang H, Wang J, Wang Y. Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress. Exp Ther Med. 2016;11:353–9. https://doi.org/10.3892/etm.2015.2882.
- 66.Boon-Niermeijer EK, van den Berg A, Wikman G, Wiegant FA. Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis. Phytomedicine. 2000;7:389–99. https://doi.org/10.1016/S0944-7113(00)80060-4.
- 67.Chen C, Song J, Chen M, Li Z, Tong X, Hu H, et al. Rhodiola rosea extends lifespan and improves stress tolerance in silkworm, Bombyx mori. Biogerontology. 2016;17:373–81. https://doi.org/10.1007/s10522-015-9622-8.
- 68.Tang H, Gao L, Mao J, He H, Liu J, Cai X, et al. Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-κB and TGF-β1/Smad-2/-3 pathways. Cell Stress Chaperones. 2016;21:239–49. https://doi.org/10.1007/s12192-015-0654-4.
- 69.Yuan XY, Pang XW, Zhang GQ, Guo JY. Salidroside’s protection against UVB-mediated oxidative damage and apoptosis is associated with the upregulation of Nrf2 expression. Photomed Laser Surg. 2017;35:49–56. https://doi.org/10.1089/pho.2016.4151.
- 70.••Epel ES, Lithgow GJ. Stress biology and aging mechanisms: toward understanding the deep connection between adaptation to stress and longevity. J Gerontol A Biol Sci Med Sci. 2014;69(Suppl 1):S10–6. https://doi.org/10.1093/gerona/glu055. The rate of aging alongside with hormetic stress may promote stress resistance in human.
- 71.López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217. https://doi.org/10.1016/j.cell.2013.05.039.
- 72.Hamilton KL, Miller BF. What is the evidence for stress resistance and slowed aging? Exp Gerontol. 2016;82:67–72. https://doi.org/10.1016/j.exger.2016.06.001.
- 73.Hulsurkar M, Li Z, Zhang Y, Li X, Zheng D, Li W. Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1. Oncogene. 2017;36:1525–36. https://doi.org/10.1038/onc.2016.319.
- 74.• Le CP, Nowell CJ, Kim-Fuchs C, Botteri E, Hiller JG, Ismail H, et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun. 2016;7:10634. https://doi.org/10.1038/ncomms10634. Reducing stress-induced neural signaling and inflammation may help limit the effect of the sympathetic nervous system (SNS) that drives cancer progression.
- 75.Szpunar MJ, Burke KA, Dawes RP, Brown EB, Madden KS. The antidepressant desipramine and α2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev Res (Phila). 2013;6:1262–72. https://doi.org/10.1158/1940-6207.
- 76.• Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939–44. https://doi.org/10.1038/nm1447. Stress may promote malignant cell growth through mediated angiogenesis.
- 77.Schriner SE, Coskun V, Hogan SP, Nguyen CT, Lopez TE, Jafari M. Extension of drosophila lifespan by Rhodiola rosea depends on dietary carbohydrate and caloric content in a simplified diet. J Med Food. 2016;19:318–23. https://doi.org/10.1089/jmf.2015.0105.
- 78.Zhang B, Li Q, Chu X, Sun S, Chen S. Salidroside reduces tau hyperphosphorylation via up-regulating GSK-3β phosphorylation in a tau transgenic Drosophila model of Alzheimer’s disease. Transl Neurodegener. 2016;5:21. https://doi.org/10.1186/s40035-016-0068-y.
- 79.Fitzenberger E, Deusing DJ, Wittkop A, Kler A, Kriesl E, Bonnländer B, et al. Effects of plant extracts on the reversal of glucose-induced impairment of stress-resistance in Caenorhabditis elegans. Plant Foods Hum Nutr. 2014;69:78–84. https://doi.org/10.1007/s11130-013-0399-0.
- 80.Bayliak MM, Burdyliuk NI, Izers'ka LI, Lushchak VI. Concentration-dependent effects of Rhodiola Rosea on long-term survival and stress resistance of yeast saccharomyces cerevisiae: the involvement of YAP 1 and MSN2/4 regulatory proteins. Dose Response. 2013;12:93–109. https://doi.org/10.2203/dose-response.
- 81.Gospodaryov DV, Yurkevych IS, Jafari M, Lushchak VI, Lushchak OV. Lifespan extension and delay of age-related functional decline caused by Rhodiola rosea depends on dietary macronutrient balance. Longev Healthspan. 2013;2:5. https://doi.org/10.1186/2046-2395-2-5.
- 82.Schriner SE, Lee K, Truong S, Salvadora KT, Maler S, Nam A, et al. Extension of Drosophila lifespan by Rhodiola rosea through a mechanism independent from dietary restriction. PLoS One. 2013;8:e63886. https://doi.org/10.1371/journal.pone.0063886.
- 86.Liu Z, Li X, Simoneau AR, Jafari M, Zi X. Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Mol Carcinog. 2012;51:257–67. https://doi.org/10.1002/mc.20780.
- 87.Zhao G, Shi A, Fan Z, Du Y. Salidroside inhibits the growth of human breast cancer in vitro and in vivo. Oncol Rep. 2015;33:2553–60. https://doi.org/10.3892/or.2015.3857.
- 88.Bassa LM, Jacobs C, Gregory K, Henchey E, Ser-Dolansky J, Schneider SS. Rhodiola crenulata induces an early estrogenic response and reduces proliferation and tumorsphere formation over time in MCF7 breast cancer cells. Phytomedicine. 2016;23:87–94. https://doi.org/10.1016/j.phymed.2015.11.014.
- 89.Fan XJ, Wang Y, Wang L, Zhu M. Salidroside induces apoptosis and autophagy in human colorectal cancer cells through inhibition of PI3K/Akt/mTOR pathway. Oncol Rep. 2016;36:3559–67. https://doi.org/10.3892/or.2016.5138.
- 90.Huo J, Qin F, Cai X, Ju J, Hu C, Wang Z, et al. Chinese medicine formula “Weikang Keli” induces autophagic cell death on human gastric cancer cell line SGC-7901. Phytomedicine. 2013;20:159–65. https://doi.org/10.1016/j.phymed.2012.10.001.
- 91.Zhang Y, Yao Y, Wang H, Guo Y, Zhang H, Chen L. Effects of salidroside on glioma formation and growth inhibition together with improvement of tumor microenvironment. Chin J Cancer Res. 2013;25:520–6. https://doi.org/10.3978/j.issn.1000-9604.2013.10.01.
- 92.Wang J, Li JZ, AX L, Zhang KF, Li BJ. Anti-cancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho-p38 expression. Oncol Lett. 2014;7:1159–64. https://doi.org/10.3892/ol.2014.1863.
- 93.Sun C, Wang Z, Zheng Q, Zhang H. Salidroside inhibits migration and invasion of human fibrosarcoma HT1080 cells. Phytomedicine. 2012;19:355–63. https://doi.org/10.1016/j.phymed.2011.09.070.
- 94.Hu X, Lin S, Yu D, Qiu S, Zhang X, Mei R. A preliminary study: the anti-proliferation effect of salidroside on different human cancer cell lines. Cell Biol Toxicol. 2010;26:499–507. https://doi.org/10.1007/s10565-010-9159-1.
- 95.Tu Y, Roberts L, Shetty K, Schneider SS. Rhodiola crenulata induces death and inhibits growth of breast cancer cell lines. J Med Food. 2008;11:413–23. https://doi.org/10.1089/jmf.2007.0736.
- 96.Mishra KP, Padwad YS, Dutta A, Ganju L, Sairam M, Banerjee PK, et al. Aqueous extract of Rhodiola imbricata rhizome inhibits proliferation of an erythroleukemic cell line K-562 by inducing apoptosis and cell cycle arrest at G2/M phase. Immunobiology. 2008;213:125–31. https://doi.org/10.1016/j.imbio.2007.07.003.
- 97.Panossian A, Hamm R, Wikman G, Efferth T. Mechanism of action of Rhodiola, salidroside, tyrosol and triandrin in isolated neuroglial cells: an interactive pathway analysis of the downstream effects using RNA microarray data. Phytomedicine. 2014;21:1325–48. https://doi.org/10.1016/j.phymed.2014.07.008.
- 98.Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76. https://doi.org/10.1016/j.cell.2017.02.004.
- 99.Kennedy BK, Lamming DW. The mechanistic target of Rapamycin: the grand ConducTOR of metabolism and aging. Cell Metab. 2016;23:990–1003. https://doi.org/10.1016/j.cmet.2016.05.009.
- 100.Liu Z, Yokoyama NN, Blair CA, Li X, Avizonis D, XR W, et al. High sensitivity of an Ha-RAS transgenic model of superficial bladder cancer to metformin is associated with ∼ 240-fold higher drug concentration in urine than serum. Mol Cancer Ther. 2016;15:430–8. https://doi.org/10.1158/1535-7163.
- 101.Liu Z, Antalek M, Nguyen L, Li X, Tian X, Le A, et al. The effect of gartanin, a naturally occurring xanthone in mangosteen juice, on the mTOR pathway, autophagy, apoptosis, and the growth of human urinary bladder cancer cell lines. Nutr Cancer. 2013;65(Suppl 1):68–77. https://doi.org/10.1080/01635581.2013.785011.
- 102.Liu Z, Li X, Liu S, Xu X, Tian X, Simoneau AR, et al. Rhodiola rosea L. extract, SHR-5, and metformin exhibit potent activity against bladder carcinogenesis in the UPII-mutant Ha-ras transgenic model. Cancer Res. 2012;72(8 Supplement):618. 618.Google Scholar
- 105.Tang Y, Vater C, Jacobi A, Liebers C, Zou X, Stiehler M. Salidroside exerts angiogenic and cytoprotective effects on human bone marrow-derived endothelial progenitor cells via Akt/mTOR/p70S6K and MAPK signalling pathways. Br J Pharmacol. 2014;171:2440–56. https://doi.org/10.1111/bph.12611.
- 106.MC X, Shi HM, Wang H, Gao XF. Salidroside protects against hydrogen peroxide-induced injury in HUVECs via the regulation of REDD1 and mTOR activation. Mol Med Rep. 2013;8:147–53. https://doi.org/10.3892/mmr.2013.1468.
- 107.Zheng XT, ZH W, Wei Y, Dai JJ, GF Y, Yuan F, et al. Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis. Mol Cell Biochem. 2017;425:125–38. https://doi.org/10.1007/s11010-016-2868-x.
- 108.Chen X, Wu Y, Yang T, Wei M, Wang Y, Deng X, et al. Salidroside alleviates cachexia symptoms in mouse models of cancer cachexia via activating mTOR signalling. J Cachex Sarcopenia Muscle. 2016;7:225–32. https://doi.org/10.1002/jcsm.12054.
- 109.Salikhova RA, Aleksandrova IV, Mazurik VK, Mikhaĭlov VF, Ushenkova LN, Poroshenko GG. Effect of Rhodiola rosea on the yield of mutation alterations and DNA repair in bone marrow cells. Patol Fiziol Eksp Ter. 1997;4:22–4. [Article in Russian]Google Scholar
- 110.•• Li X, Sipple J, Pang Q, Du W. Salidroside stimulates DNA repair enzyme Parp-1 activity in mouse HSC maintenance. Blood. 2012;119:4162–73. https://doi.org/10.1182/blood-2011-10-387332. Salidroside antioxidant properties could affect the homeostasis and function of HSCs through the activation of PARP-1.
- 111.Li X, Erden O, Li L, Ye Q, Wilson A, Du W. Binding to WGR domain by salidroside activates PARP1 and protects hematopoietic stem cells from oxidative stress. Antioxid Redox Signal. 2014;20:1853–65. https://doi.org/10.1089/ars.2013.5600.
- 112.Kumar H, Choi DK. Hypoxia inducible factor pathway and physiological adaptation: a cell survival pathway? Mediators Inflamm. 2015:584758. https://doi.org/10.1155/2015/584758.
- 113.Qi YJ, Cui S, DX L, Yang YZ, Luo Y, Ma L, et al. Effects of the aqueous extract of a Tibetan herb, Rhodiola algida var. tangutica on proliferation and HIF-1α, HIF-2α expression in MCF-7 cells under hypoxic condition in vitro. Cancer Cell Int. 2015;15:81. https://doi.org/10.1186/s12935-015-0225-x.
- 114.Zheng KY, Zhang ZX, Guo AJ, Bi CW, Zhu KY, Xu SL, et al. Salidroside stimulates the accumulation of HIF-1α protein resulted in the induction of EPO expression: a signaling via blocking the degradation pathway in kidney and liver cells. Eur J Pharmacol. 2012;679:34–9. https://doi.org/10.1016/j.ejphar.2012.01.027.
- 116.Wu T, Zhou H, Jin Z, Bi S, Yang X, Yi D, et al. Cardioprotection of salidroside from ischemia/reperfusion injury by increasing N-acetylglucosamine linkage to cellular proteins. Eur J Pharmacol. 2009;613:93–9. https://doi.org/10.1016/j.ejphar.2009.04.012.
- 117.Zheng KY, Guo AJ, Bi CW, Zhu KY, Chan GK, Fu Q, et al. The extract of Rhodiolae Crenulatae Radix et Rhizoma induces the accumulation of HIF-1α via blocking the degradation pathway in cultured kidney fibroblasts. Planta Med. 2011;77:894–9. https://doi.org/10.1055/s-0030-1250627.
- 118.Li L, Wang H, Zhao X. Effects of Rhodiola on production, health and gut development of broilers reared at high altitude in Tibet. Sci Rep. 2014;4:7166. https://doi.org/10.1038/srep07166.
- 119.ZW X, Chen X, Jin XH, Meng XY, Zhou X, Fan FX, et al. SILAC-based proteomic analysis reveals that salidroside antagonizes cobalt chloride-induced hypoxic effects by restoring the tricarboxylic acid cycle in cardiomyocytes. J Proteome. 2016;130:211–20. https://doi.org/10.1016/j.jprot.2015.09.028.
- 121.Hsu SW, Chang TC, YK W, Lin KT, Shi LS, Lee SY. Rhodiola crenulata extract counteracts the effect of hypobaric hypoxia in rat heart via redirection of the nitric oxide and arginase 1 pathway. BMC Complement Altern Med. 2017;17:29. https://doi.org/10.1186/s12906-016-1524-z.
- 122.Rabinowitz MH. Inhibition of hypoxia-inducible factor prolyl hydroxylase domain oxygen sensors: tricking the body into mounting orchestrated survival and repair responses. J Med Chem. 2013;56:9369–402. https://doi.org/10.1021/jm400386j.
- 123.•• Zhang J, Kasim V, Xie YD, Huang C, Sisjayawan J, Dwi Ariyanti A, et al. Inhibition of PHD3 by salidroside promotes neovascularization through cell-cell communications mediated by muscle-secreted angiogenic factors. Sci Rep. 2017;7:43935. https://doi.org/10.1038/srep43935. Salidroside may be a novel inhibitor in treating peripheral artery and potential in therapeutic angiogenesis.
- 124.Lu L, Yuan J, Zhang S. Rejuvenating activity of salidroside (SDS): dietary intake of SDS enhances the immune response of aged rats. Age (Dordr). 2013;35:637–46. https://doi.org/10.1007/s11357-012-9394-x.
- 125.Guan S, He J, Guo W, Wei J, Lu J, Deng X. Adjuvant effects of salidroside from Rhodiola rosea L. on the immune responses to ovalbumin in mice. Immunopharmacol Immunotoxicol. 2011;33:738–43. https://doi.org/10.3109/08923973.2011.567988.
- 126.•• Zhao X, Lu Y, Tao Y, Huang Y, Wang D, Hu Y, et al. Salidroside liposome formulation enhances the activity of dendritic cells and immune responses. Int Immunopharmacol. 2013;17:1134–40. https://doi.org/10.1016/j.intimp.2013.10.016. Salidroside in a liposome formulation may be an effective way as a vaccine delivery system.
- 127.Peng H, Dong R, Wang S, Zhang Z, Luo M, Bai C, et al. A pH-responsive nano-carrier with mesoporous silica nanoparticles cores and poly(acrylic acid) shell-layers: fabrication, characterization and properties for controlled release of salidroside. Int J Pharm. 2013;446:153–9. https://doi.org/10.1016/j.ijpharm.2013.01.071.
- 128.Diwaker D, Mishra KP, Ganju L, Singh SB. Rhodiola inhibits dengue virus multiplication by inducing innate immune response genes RIG-I, MDA5 and ISG in human monocytes. Arch Virol. 2014;159:1975–86. https://doi.org/10.1007/s00705-014-2028-0.
- 129.Liu MW, Su MX, Zhang W, Zhang LM, Wang YH, Qian CY. Rhodiola rosea suppresses thymus T-lymphocyte apoptosis by downregulating tumor necrosis factor-α-induced protein 8-like-2 in septic rats. Int J Mol Med. 2015;36:386–98. https://doi.org/10.3892/ijmm.2015.2241.
- 130.Xu X, Li P, Zhang P, Chu M, Liu H, Chen X, et al. Differential effects of Rhodiola Rosea on regulatory T cell differentiation and interferon-γ production in vitro and in vivo. Mol Med Rep. 2016;14:529–36. https://doi.org/10.3892/mmr.2016.5278.
- 131.Marchev AS, Dimitrova P, Koycheva IK, Georgiev MI. Altered expression of TRAIL on mouse T cells via ERK phosphorylation by Rhodiola rosea L. and its marker compounds. Food Chem Toxicol. 2017; https://doi.org/10.1016/j.fct.2017.02.009.
- 132.Song B, Huang G, Xiong Y, Liu J, Xu L, Wang Z, et al. Inhibitory effects of salidroside on nitric oxide and prostaglandin E2 production in lipopolysaccharide-stimulated RAW 264.7 macrophages. J Med Food. 2013;16:997–1003. https://doi.org/10.1089/jmf.2012.2473.
- 133.Li D, Fu Y, Zhang W, Su G, Liu B, Guo M, et al. Salidroside attenuates inflammatory responses by suppressing nuclear factor-κB and mitogen activated protein kinases activation in lipopolysaccharide-induced mastitis in mice. Inflamm Res. 2013;62:9–15. https://doi.org/10.1007/s00011-012-0545-4.
- 134.Wang Y, Xu CF, Liu YJ, Mao YF, Lv Z, Li SY, et al. Salidroside attenuates ventilation induced lung injury via SIRT1-dependent inhibition of NLRP3 Inflammasome. Cell Physiol Biochem. 2017;42:34–43. https://doi.org/10.1159/000477112.
- 135.Qi Z, Qi S, Ling L, Lv J, Feng Z. Salidroside attenuates inflammatory response via suppressing JAK2-STAT3 pathway activation and preventing STAT3 transfer into nucleus. Int Immunopharmacol. 2016;35:265–71. https://doi.org/10.1016/j.intimp.2016.04.004.
- 136.Chang YW, Yao HT, Hsieh SH, Lu TJ, Yeh TK. Quantitative determination of salidroside in rat plasma by on-line solid-phase extraction integrated with high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;857:164–9.CrossRefPubMedGoogle Scholar
- 137.Han F, Li YT, Mao XJ, Zhang XS, Guan J, Song AH, et al. Metabolic profile of salidroside in rats using high-performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry. Anal Bioanal Chem. 2016;408:1975–81. https://doi.org/10.1007/s00216-015-9080-9.
- 139.Yu S, Liu L, Wen T, Liu Y, Wang D, He Y, et al. Development and validation of a liquid chromatographic/electrospray ionization mass spectrometric method for the determination of salidroside in rat plasma: application to the pharmacokinetics study. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;861:10–5.CrossRefPubMedGoogle Scholar
- 140.•• Guo N, Zhu M, Han X, Sui D, Wang Y, Yang Q. The metabolism of salidroside to its aglycone p-tyrosol in rats following the administration of salidroside. PLoS One. 2014;9:e103648. https://doi.org/10.1371/journal.pone.0103648. Salidroside is extensively processed through various biological activities, and mainly its metabolites can be seen distributed to various organs.
- 141.Zhang Y, Li L, Lin L, Liu J, Zhang Z, Xu D, et al. Pharmacokinetics, tissue distribution, and excretion of salidroside in rats. Planta Med. 2013;79:1429–33. https://doi.org/10.1055/s-0033-1350807.
- 142.• Wang M, Luo L, Yao L, Wang C, Jiang K, Liu X, et al. Salidroside improves glucose homeostasis in obese mice by repressing inflammation in white adipose tissues and improving leptin sensitivity in hypothalamus. Sci Rep. 2016;6:25399. https://doi.org/10.1038/srep25399. Salidroside is a versatile compound found in Rhodiola rosea, and one effective use may be antidiabetic.