Anti-fatigue effect from Ginseng Radix et Rhizoma: a suggestive and promising treatment for long COVID

Abstract

Two years after the coronavirus disease 2019 (COVID-19) outbreak, an increasing number of patients continue to suffer from long COVID (LC), persistent symptoms, and/or delayed or long-term complications beyond the initial 4weeks from the onset of symptoms. Constant fatigue is one of the most common LC symptoms, leading to severely reduced quality of life among patients.Ginseng Radix et Rhizoma—known as the King of Herbs in traditional Chinese medicine—has shown clinical anti-fatigue effects. In this review, we summarize the underlying anti-fatigue mechanisms of Ginseng Radix et Rhizoma extracts and their bioactive compounds, with a special focus on anti-viral, immune remodeling, endocrine system regulation, and metabolism, suggesting that Ginseng Radix et Rhizoma is a potentially promising treatment for LC, especially regarding targeting fatigue.

Keywords

Fatigue / Ginseng Radix et Rhizoma / Long COVID / SARS-CoV-2

References

[[1]] Nabavi N.Long covid: how to define it and how to manage it. BMJ 2020;370:m3489.

[[2]] Marshall M.The lasting misery of coronavirus long-haulers. Nature 2020;585(7825):339-341.

[[3]] Soriano V, Ganado-Pinilla P, Sánchez-Santos M, et al.Unveiling long COVID-19 disease. AIDS Rev 2020;22(4):227-228.

[[4]] Raveendran AV.Long COVID-19: challenges in the diagnosis and proposed diagnostic criteria. Diabetes Metab Syndr 2021;15(1):145-146.

[[5]] Nalbandian A, Sehgal K, Gupta A, et al.Post-acute COVID-19 syndrome. Nat Med 2021;27(4):601-615.

[[6]] Garg P, Arora U, Kumar A, et al.The “post-COVID” syndrome: how deep is the damage? J Med Virol 2021;93(2):673-674.

[[7]] Mahase E.Covid-19: what do we know about “long covid”? BMJ 2020;370:m2815.

[[8]] Greenhalgh T, Knight M, A'Court CM, et al. Management of postacute covid-19 in primary care. BMJ 2020;370:m3026.

[[9]] Callard F, Perego E.How and why patients made long covid. Soc Sci Med 2021;268:113426.

[[10]] Crook H, Raza S, Nowell J, et al.Long covid-mechanisms, risk factors, and management. BMJ 2021;374:n1648.

[[11]] Townsend L, Dyer AH, Jones K, et al.Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. Plos One 2020;15(11):e0240784.

[[12]] Kang S, Min H.Ginseng, the ‘immunity boost': the effects of Panax ginseng on immune system. J Ginseng Res 2012;36(4):354-368.

[[13]] Lu Y, Ma YM.Pharmacology of Chinese Materia Medica. 2nd edBeijing: People's Health Publishing House; 2016;277-310.

[[14]] Arring NM, Millstine D, Marks LA, et al.Ginseng as a treatment for fatigue: a systematic review. J Altern Complement Med 2018;24(7):624-633.

[[15]] Yang J, Shin KM, Abu Dabrh AM, et al. Ginseng for the treatment of chronic fatigue syndrome: a systematic review of clinical studies. Glob Adv Health Med 2022;11. 2164957X221079790.

[[16]] Choi JY, Woo TS, Yoon SY, et al.Red ginseng supplementation more effectively alleviates psychological than physical fatigue. J Ginseng Res 2011;35(3):331-338.

[[17]] Sadeghian M, Rahmani S, Zendehdel M, et al.Ginseng and cancer-related fatigue: a systematic review of clinical trials. Nutr Cancer 2021;73(8):1270-1281.

[[18]] Barton DL, Liu H, Dakhil SR, et al.Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst 2013;105(16):1230-1238.

[[19]] Yennurajalingam S, Reddy A, Tannir NM, et al.High-dose Asian Ginseng (Panax ginseng) for cancer-related fatigue: a preliminary report. Integr Cancer Ther 2015;14(5):419-427.

[[20]] Lee HW, Choi J, Lee Y, et al.Ginseng for managing menopausal woman's health: a systematic review of double-blind, randomized, placebo-controlled trials. Medicine (Baltimore) 2016;95(38):e4914.

[[21]] Jason LA, Gaglio CL, Furst J, et al.Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Chronic Illn 2022;17423953221101606.

[[22]] Clayton EW.Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA 2015;313(11):1101-1102.

[[23]] Poenaru S, Abdallah SJ, Corrales-Medina V, et al.COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review. Ther Adv Infect Dis 2021;8: 20499361211009385.

[[24]] Wong TL, Weitzer DJ.Long COVID and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS)—a systemic review and comparison of clinical presentation and symptomatology. Medicina (Kaunas) 2021;57(5):418.

[[25]] Ratan ZA, Rabbi Mashrur F, Runa NJ, et al.Ginseng, a promising choice for SARS-COV-2: a mini review. J Ginseng Res 2022;46(2):183-187.

[[26]] Lee JS, Ko EJ, Hwang HS, et al.Antiviral activity of ginseng extract against respiratory syncytial virus infection. Int J Mol Med 2014;34(1):183-190.

[[27]] Yi YS.Ameliorative effects of ginseng and ginsenosides on rheumatic diseases. J Ginseng Res 2019;43(3):335-341.

[[28]] Kang Z, Zhonga Y, Wu T, et al.Ginsenoside from ginseng: a promising treatment for inflammatory bowel disease. Pharmacol Rep 2021;73(3):700-711.

[[29]] Lee JM, Hah JO, Kim HS.The effect of red ginseng extract on inflammatory cytokines after chemotherapy in children. J Ginseng Res 2012;36(4):383-390.

[[30]] Lazear HM, Schoggins JW, Diamond MS.Shared and distinct functions of type I and type III interferons. Immunity 2019;50(4):907-923.

[[31]] Liu FX, Lin ZX, Zhang HL, et al.Study of the mechanism of action and potential targets of ginseng anti-fatigue. Chin J Chin Mater Med 2019;44(24):5479-5487.

[[32]] Li C, Li TG, Wang HM, et al.

[Effect of moxibustion on IL-6/ STAT3 signaling in frontal cortex of fatigue rats].Zhen Ci Yan Jiu 2020;45(6):468-472.

[[33]] Zhang X, Chen WN, Song N, et al.Based on molecular interaction network, the mechanism of Danpu tablets in the prevention and treatment of non-alcoholic fatty liver disease in the PI3K/AKT/NF-kB/TNF pathway was discussed. Chin J Immunol 2021;1-20.

[[34]] Pan XB, Li XY, Wang ZX, et al.Research progress on the NLRP3-(Caspase-1)/IL-1b signaling pathway. China Med Herald 2019;16(1):41-44.

[[35]] Li XT, Meng Y, Wei L, et al.Effect of ginsenoside CK on cognitive dysfunction and hippocampal NLRP3 inflammasome in mice with Alzheimer's disease induced by Ab. Chinese Herbal Med 2021;(8):1952-1955.

[[36]] Yuan HJ.Effect of acupuncture on the killing activity of NK cells in rats with chronic fatigue syndrome and its regulatory mechanism of miR-34a-5p/ERK/pERK. Chengdu: Chengdu University of Traditional Chinese Medicine; 2018.

[[37]] Yunhee L, Arum P, YoungJun P, et al. Ginsenoside 20(R)-Rg3 enhances natural killer cell activity by increasing activating receptor expression through the MAPK/ERK signaling pathway. J Int Immunopharmacol 2022;107.

[[38]] Hahm KS, Chase AS, Dwyer B, et al.Indoor human localization and gait analysis using machine learning for in-home health monitoring. Annu Int Conf IEEE Eng Med Biol Soc 2021; 2021:6859-6862.

[[39]] Yu XN, Feng XG, Zhang JM, et al.New progress in the study of chemical composition and pharmacological effects of ginseng. Ginseng Res 2019;31(1):47-51.

[[40]] Lan L, Xu D, Ye G, et al.Positive RT-PCR test results in patients recovered from COVID-19. JAMA 2020;323(15):1502-1503.

[[41]] Biehl M, Sese D. Post-intensive care syndrome and COVID-19— implications post pandemic. Cleve Clin J Med 2020;On-line ahead of print.

[[42]] Cho YK, Kim JE, Woo JH.Genetic defects in the nef gene are associated with Korean Red Ginseng intake: monitoring of nef sequence polymorphisms over 20years. J Ginseng Res 2017;41(2):144-150.

[[43]] Cho YK, Sung H, Lee HJ, et al.Long-term intake of Korean red ginseng in HIV-1-infected patients: development of resistance mutation to zidovudine is delayed. Int Immunopharmacol 2001;1(7):1295-1305.

[[44]] Kim BR, Kim JE, Sung H, et al.Long-term follow up of HIV-1- infected Korean haemophiliacs, after infection from a common source of virus. Haemophilia 2015;21(1):e1-e11.

[[45]] Cho YK, Kim JE.Effect of Korean Red Ginseng intake on the survival duration of human immunodeficiency virus type 1 patients. J Ginseng Res 2017;41(2):222-226.

[[46]] Park EH, Yum J, Ku KB, et al.Red Ginseng-containing diet helps to protect mice and ferrets from the lethal infection by highly pathogenic H5N1 influenza virus. J Ginseng Res 2014;38(1):40-46.

[[47]] Quan FS, Compans RW, Cho YK, et al.Ginseng and Salviae herbs play a role as immune activators and modulate immune responses during influenza virus infection. Vaccine 2007;25(2):272-282.

[[48]] Lee MH, Lee BH, Lee S, et al.Reduction of hepatitis A virus on FRhK-4 cells treated with Korean red ginseng extract and ginsenosides. J Food Sci 2013;78(9):M1412-M1415.

[[49]] Kang LJ, Choi YJ, Lee SG.Stimulation of TRAF6/TAK1 degradation and inhibition of JNK/AP-1 signalling by ginsenoside Rg3 attenuates hepatitis B virus replication. Int J Biochem Cell Biol 2013;45(11):2612-2621.

[[50]] Aramwit P, Porasuphatana S, Srichana T, et al.Toxicity evaluation of cordycepin and its delivery system for sustained in vitro anti-lung cancer activity. Nanoscale Res Lett 2015;10: 152.

[[51]] Yang L, Liu S, Liu J, et al.COVID-19: immunopathogenesis and immunotherapeutics. Signal Transduct Target Ther 2020;5(1):128.

[[52]] Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell2020;181(5):1036-1045. e9.

[[53]] Phetsouphanh C, Darley DR, Wilson DB, et al.Immunological dysfunction persists for 8months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol 2022;23(2):210-216.

[[54]] Lu G, Liu Z, Wang X, et al.Recent advances in Panax ginseng C. A. Meyer as a herb for anti-fatigue: an effects and mechanisms review. Foods 2021;10(5):1030.

[[55]] Zhou SS, Zhou J, Xu JD, et al.Ginseng ameliorates exerciseinduced fatigue potentially by regulating the gut microbiota. Food Funct 2021;12(9):3954-3964.

[[56]] Wostyn P.COVID-19 and chronic fatigue syndrome: is the worst yet to come? Med Hypotheses 2021;146:110469.

[[57]] Jung SJ, Hwang JH, Park SH, et al.A 12-week, randomized, double-blind study to evaluate the efficacy and safety of liver function after using fermented ginseng powder (GBCK25). Food Nutr Res 2020;64.

[[58]] Klimas NG, Broderick G, Fletcher MA.Biomarkers for chronic fatigue. Brain Behav Immun 2012;26(8):1202-1210.

[[59]] Jin Y, Cui RJ, Zhao LH, et al.Mechanisms of Panax ginseng action as an antidepressant. Cell Prolif 2019;52(6):e12696.

[[60]] Li YB, Wang Y, Tang JP, et al.Neuroprotective effects of ginsenoside Rg1-induced neural stem cell transplantation on hypoxic-ischemic encephalopathy. Neural Regen Res 2015;10(5):753-759.

[[61]] Ye J, Yao JP, Wang X, et al.Neuroprotective effects of ginsenosides on neural progenitor cells against oxidative injury. Mol Med Rep 2016;13(4):3083-3091.

[[62]] Xiang Y, Wang SH, Wang L, et al.Effects of ginsenoside Rg1 regulating Wnt/beta-catenin signaling on neural stem cells to delay brain senescence. Stem Cells Int 2019;2019:5010184.

[[63]] Gao J, Wan F, Tian M, et al.Effects of ginsenosideRg1 on the proliferation and glial-like directed differentiation of embryonic rat cortical neural stem cells in vitro. Mol Med Rep 2017;16(6):8875-8881.

[[64]] Wu J, Pan Z, Cheng M, et al.Ginsenoside Rg1 facilitates neural differentiation of mouse embryonic stem cells via GR-dependent signaling pathway. Neurochem Int 2013;62(1):92-102.

[[65]] Chen QW, Shu QJ, Liu QJ, et al.Protective Effect of Ginsenoside Rg3 on Rats with Oxaliplatin Induced Neurotoxicity. Chongqing: The 1st Youth Integrative Medicine Oncology Academic Forum; 2015.

[[66]] Zheng GQ, Zhou Y.A Study on the Protective Mechanism of Ginsenoside Rg1 on Cerebral Edema After Cerebral Ischemia and Reperfusion in Rats. Nanjing: 2013 National Academic Conference on Alzheimer's and Related Diseases; 2013.

[[67]] Paul BD, Lemle MD, Komaroff AL, et al.Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci 2021;118(34):e2024358118.

[[68]] Codo AC, Davanzo GG, Monteiro L, et al.Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1 alpha/glycolysis-dependent axis. Cell Metabolism 2020;32(3):498-499.

[[69]] Santos CS, Morales CM, álvarez ED, et al.Determinants of COVID-19 disease severity in patients with underlying rheumatic disease. Clin Rheumatol 2020;39(9):2789-2796.

[[70]] Shin IS, Kim DH, Jang EY, et al.Anti-fatigue properties of cultivated wild ginseng distilled extract and its active component panaxydol in rats. J Pharmacopuncture 2019;22(2):68-74.

[[71]] Yu F, Lu S, Yu F, et al.Protective effects of polysaccharide from Euphorbia kansui (Euphorbiaceae) on the swimming exerciseinduced oxidative stress in mice. Can J Physiol Pharmacol 2006;84(10):1071-1079.

[[72]] Oh HA, Kim DE, Choi HJ, et al.Anti-fatigue effects of 20(S)- protopanaxadiol and 20(S)-protopanaxatriol in mice. Biol Pharm Bull 2015;38(9):1415-1419.

[[73]] Tan S, Zhou F, Li N, et al.Anti-fatigue effect of ginsenoside Rb1 on postoperative fatigue syndrome induced by major small intestinal resection in rat. Biol Pharm Bull 2013;36(10):1634-1639.

[[74]] Zhou M, Hong Y, Lin X, et al.Recent pharmaceutical evidence on the compatibility rationality of traditional Chinese medicine. J Ethnopharmacol 2017;206:363-375.

[[75]] Jia W, Gao WY, Yan YQ, et al.The rediscovery of ancient Chinese herbal formulas. Phytother Res 2004;18(8):681-686.

[[76]] Pang W, Yang F, Zhao Y, et al.Qingjin Yiqi granules for post- COVID-19 condition: a randomized clinical trial. J Evid Based Med 2022;15(1):30-38.

[[77]] Paik S, Choe JH, Choi GE, et al.Rg6, a rare ginsenoside, inhibits systemic inflammation through the induction of interleukin-10 and microRNA-146a. Sci Rep 2019;9(1):4342.

[[78]] Zhang W, Zhang Y, Ma X, et al.Effects of acupuncturing Pishu combined with Ginsenoside Rg3 on the immune function of rats with chronic fatigue. Int J Clin Exp Med 2015;8(10):19022-19029.

[[79]] Lin K, Liu T.Effects of moderate-load treadmill exercise and ginsenoside Rg1 on immune function in rats with chronic fatigue syndrome. Shaanxi Tradit Chin Med 2014;35(9):1259-1260.

[[80]] Ren LM, Yang S, Lu SY, et al.Total ginsenosides reduce lipopolysaccharide-induced inflammation and oxidative stress in macrophage RAW264.7 cells. Chin J Hosp Pharm 2022;42(9):896-901.

[[81]] Nie ZF, Sun XY, Zhang TP, et al.Effects of ginsenoside compound K on oxidative stress, inflammatory factors and vasoactive substances in atherosclerotic rats. Hebei Tradit Chin Med 2019;41(7):1042-1047.

[[82]] Liu Y, Perumalsamy H, Kang CH, et al.Intracellular synthesis of gold nanoparticles by Gluconacetobacter liquefaciens for delivery of peptide CopA3 and ginsenoside and anti-inflammatory effect on lipopolysaccharide-activated macrophages. Artif Cells Nanomed Biotechnol 2020;48(1):777-788.

[[83]] Wu LN, Fan XM, Wu S, et al.Ginsenoside Rg1 regulates oxidative stress and inflammatory factor expression and improves peripheral nerve injury in diabetic rats. Chin J Immunol 2021;37(4):486-491.

[[84]] Kang XX.Antidepressant Effect of Ginsenoside Rg1-dependent NLRP3 inflammasome. Chengdu: University of Electronic Science and Technology of China; 2021.

[[85]] Mao JY, Ma X, Zhu J, et al.Ginsenoside Rg1 ameliorates psoriasis-like skin lesions by suppressing proliferation and NLRP3 inflammasomes in keratinocytes. J Food Biochem 2022;46(5):e14053.

[[86]] Cheng WD, Jing JH, Wang Z, et al.Chondroprotective effects of ginsenoside Rg1 in human osteoarthritis chondrocytes and a rat model of anterior cruciate ligament transection. Nutrients 2017;9(3):263.

[[87]] Song P.Ginsenoside Rb1 Protects Against Staphylococcus aureus-induced lung injury by inhibiting inflammation, apoptosis and oxidative stress. Wuhan: Huazhong Agricultural University, 2020.

[[88]] Li DW, Zhou FZ, Sun XC, et al.Ginsenoside Rb1 protects dopaminergic neurons from inflammatory injury induced by intranigral lipopolysaccharide injection. Neural Regen Res 2019;14(10):1814-1822.

[[89]] Wu Y, Yu Y, Szabo A, et al.Central inflammation and leptin resistance are attenuated by ginsenoside Rb1 treatment in obese mice fed a high-fat diet. PLoS One 2014;9(3):e92618.

[[90]] Sun MM, Ji YT, Li Z, et al.Ginsenoside Rb3 Reduces the Inflammatory Response Caused by LPS of Porphyromonas gingivalis by Inhibiting the MAPK/AKT/NF-kB Signaling Pathway. Shanghai: 2020,the 10th National Oral Biomedical Academic Annual Meeting of the Oral Biomedical Professional Committee of the Chinese Stomatological Association and the 6th National Oral Outstanding Youth Forum; 2020.

[[91]] Lin Y, Hu Y, Hu X, et al.Ginsenoside Rb2 improves insulin resistance by inhibiting adipocyte pyroptosis. Adipocyte 2020;9(1):302-312.

[[92]] Xue Y, Fu W, Liu Y, et al.Ginsenoside Rb2 alleviates myocardial ischemia/reperfusion injury in rats through SIRT1 activation. J Food Sci 2020;85(11):4039-4049.

[[93]] Huang Q, Wang T, Wang HY.Ginsenoside Rb2 enhances the anti-inflammatory effect of omega-3 fatty acid in LPS-stimulated RAW264.7 macrophages by upregulating GPR120 expression. Acta Pharmacol Sin 2017;38(2):192-200.

[[94]] Wang L, Zhang Y, Wang Z, et al.Inhibitory effect of ginsenoside- Rd on carrageenan-induced inflammation in rats. Can J Physiol Pharmacol 2012;90(2):229-236.

[[95]] Xue Y, Yu X, Zhang X, et al.Protective effects of ginsenoside Rc against acute cold exposure-induced myocardial injury in rats. J Food Sci 2021;86(7):3252-3264.

[[96]] Li Q, Zhai CM, Wang GD, et al.Ginsenoside Rh1 attenuates ovalbumin-induced asthma by regulating Th1/Th2 cytokines balance. Biosci Biotechnol Biochem 2021;85(8):1809-1817.

[[97]] Qin XY.A Preliminary Study of Ginsenoside Rf targeting the BDNF-TrkB-CREB signaling pathway to alleviate pain and inflammatory response in rat models of endometriosis. Ji'nan: Shandong University; 2019.

[[98]] Ma R, Tian JH, Jiang J, et al.Inhibitory effect of ginsenosides on NLRP3 inflammatory body activation. J China Pharmaceut Univ 2016;47(5):614-618.

[[99]] Zhang QC, Li ZY, Lou YJ, et al.Inhibitory Effect of Ginsenoside Rh2 on Inflammatory Signaling Inducing Proliferation of PROST Cancer Cells PC3. Nanchang: The 1st Men's Health TCM and Western Medicine Collaborative Innovation Forum and the 3rd National Andrology Youth Academic Forum of Integrative TCM and Western Medicine; 2019.

[[100]] Bai X, Fu R, Duan Z, et al.Ginsenoside Rk3 alleviates gut microbiota dysbiosis and colonic inflammation in antibiotictreated mice. Food Res Int 2021;146:110465.

[[101]] Li Z, Zhao L, Chen J, et al.Ginsenoside Rk1 alleviates LPSinduced depression-like behavior in mice by promoting BDNF and suppressing the neuroinflammatory response. Biochem Biophys Res Commun 2020;530(4):658-664.

[[102]] Zhu Y, Zhu C, Yang H, et al.Protective effect of ginsenoside Rg5 against kidney injury via inhibition of NLRP3 inflammasome activation and the MAPK signaling pathway in high-fat diet/ streptozotocin-induced diabetic mice. Pharm Res 2020;155: 104746.

[[103]] Lee YY, Park JS, Jung JS, et al.Anti-inflammatory effect of ginsenoside Rg5 in lipopolysaccharide-stimulated BV2 microglial cells. Int J Mol Sci 2013;14(5):9820-9833.

[[104]] Li W, Yan MH, Liu Y, et al.Ginsenoside Rg5 ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of inflammation, oxidative stress, and apoptosis. Nutrients 2016;8(9):566.

[[105]] Reyes AW, Simborio HL, Hop HT, et al.Inhibitory effect of red ginseng acidic polysaccharide from Korean red ginseng on phagocytic activity and intracellular replication of Brucella abortus in RAW 264.7 cells. J Vet Sci 2016;17(3):315-321.

[[106]] Tong T, Dong WQ, Liang XY, et al.Experimental study on the immunomodulatory effect of ginseng polysaccharides. Beijing Tradit Chin Med 2016;35(1):41-45.

[[107]] Wang DD, Shao S, Zhang YQ, et al.Insight into polysaccharides from Panax ginseng C. A. Meyer in improving intestinal inflammation: modulating intestinal microbiota and autophagy. Front Immunol 2021;12:683911.

[[108]] Zuo X.Research on anti-inflammatory activity of essential oil from Ginseng. Changchun: Jilin University, 2021.