Sohag University Sohag Medical Journal Faculty of Medicine

Saussurea costus may help in the treatment of COVID-19 Mahmoud Saif-Al-Islam Tropical Medicine and Gastroenterology Department, Sohag University Hospital, Faculty of Medicine, Egypt.

Abstract Coronavirus disease 2019 (COVID-19) is an emerging disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causing an ongoing pandemic and is considered as a national public health emergency. The signs and symptoms of COVID-19 vary from mild symptoms to a fulminating disease with acute respiratory distress syndrome (ARDS) and multi-organ failure, which may culminate into death with no available vaccines or specific antiviral treatments. God provides us with important medicinal plants. Here I shall shed the light on one of these plants that may help in the treatment of COVID-19 or may even cure it. Saussurea costus (S. costus) is a popular plant with medical importance, the roots of which are widely used for healing purposes throughout human history with great safety and effectiveness. Previous studies revealed the presence of many bioactive phytochemical molecules that has antiseptic, antibacterial, antifungal, antiviral, anti- inflammatory, antioxidant, anti-lipid peroxidation, immunostimulant, immunom- odulating, analgesic, bronchodilor, hepatoprotective and antihepatotoxic properties. S. Costus has immunomodulatory effects on cytokine release and has complement- inhibitor substances helpful in the treatment of some diseases related to marked activation of the complement system, like respiratory distress. Keywords: Saussurea costus, COVID-19, respiratory distress.

Background: S. costus (synonymous with widely investigated6. Various compo- Saussurea lappa), belongs to family unds isolated from the plant have Asteraceae, widely distributed in diff- medicinal properties including terp- erent regions in the world; however, enes, alkaloids, anthraquinones, and numerous species are found in India1, favonoids. The plant has many terpe- in Pakistan, and some parts of nes with anti-inflammatory and antitu- Himalayas2. The plant is well-known mor properties, such as costunolide, about 2500 years ago. It is used in dihydrocostunolide, 12-methoxydihy- different ancient systems of medicine drocostunolide, dehydrocostus lactone, such as Ayurveda, Unani, and Siddha3. dihydrocostus lactone7,α-hydroxydeh- S. costus is well Known in Islamic ydrocostus lactone, β-hydroxydehy- medicine, which enlisted in the Holy drocostus lactone, lappadilactone8, Ahadith said by Prophet Muhammad betulinic acid, betulinic acid methyl (Peace be upon him). It is known in ester, mokko lactone9, reynosin, Arab countries as Al-Kost Al-Hindi4, santamarine, cynar-opicrin10, saussur- Al-Kust, and Al-Qust5, and used by eamines A-C11, alantolactone, isoalan- traditional healers since the era of tolactone, α-cycloco-stunolide12, β- Islamic civilization4. cyclocostunolide, isodihydro- In scientific literature, the biological costunolide13, 1β-hydroxy arbusculin activities of the roots of S. costus are A9, arbusculin B6. Also, it contains

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SOHAG MEDICAL JOURNAL Saussurea costus may help in the treatment of COVID-19 Vol. 24 No. 3 July 2020 Mahmoud Saif-Al-Islam pregnenolone, β-sitosterol, daucosterol, ensin converting enzyme (ACE) 12-octadecadienoic acid14, costic acid, inhibitor (myrcene15), diuretic myrcene, p-cymene, tannin, caryophy- (friedelin15), antiedemic(caryophylline llene-oxide, octanoic acid, stigma- oxide, lupeol, taraxasterol15), antirhe- asterol, lupeol,botulin, caryophyllene, umatic (lupeol15), antidermatitis (cary- palmitic acid, oleic acid, inulin, camp- ophyllene15), anticancer3,13,24,27,39,47,51-55 hene, alphaphellandrene, hexanoic (caryophyllene oxide, caryophyllene, acid, saussurine, acetic acid, beta- costunolide, lupeol, tannin, betulin15), ionone, friedelin, taraxasterol15, and sedating16, and anticonvulsant many other constituents14,15. properties3,23,27,28,56 (myrcene15). S.costus has antiseptic16, antibacterial S. costus is used to treat, fever, head- 17,18(costicacid,dehydrocotuslactone,m ache, pain, cough, bronchial asth- yrcene,pcymene, tannin15), antif- ma16,28,57-59, bacterial infections17, dia- ungal19,20 (caryophylleneoxide, myrc- rrhea23, cholera57,59, typhoid23,24, tube- ene, octanoicacid,pcymene15), antiv- rculosis, leprosy23,24,27, vomiting, dysp- iral3,17,21-25(p-cymene,stigmasterol, epsia23,28, hiccups27, gastric tannin15), antiflu (lupeol, p-cymene15), ulcer3,23,43,44,60,61, abdominal pain23,28, anti-Epstein-barr virus(lupeol, diarrhea23, tenesmus23, arthritis3,24, rhe- betulin15), antinematodal23,26, anthe- umatoid arthritis, systemic lupus ery- lmintic23,27,28 (tannin15), anti-trypan0- themaatosus, respiratory distress41, osoma6,anti-malarial23,27 (lupeol15), chronic skin diseases57,59, itching28, anti-leishmanic (caryophyllene15), scabies, ringworm, bruises, cuts28,62,63, antiinflammatory23,29-35, antioxidant36,37 and diabetes mellitus50. (myrcene, palmitic acid, stigmasterol, tannin15), anti-lipid peroxidation37, COVID-19 antileukotriene-D4 (oleic acid15), COVID-19 has emerged as a pandemic immunostimulant37,38 (inulin15), and a public health crisis. The immunomodulating23,39-41, causative agent was named SARS- analgesic27,28,35 (myrcene, p-cymene15), CoV-2 and was detected from throat antipyretic(beta-sitosterol15), swab samples64. It enters the cells by bronchodilating16 (caryophyllene15), endocytosis after attachment to the expectorant (camphene, inulin, alpha- angiotensin-converting enzyme-2 phellandrene, caryophyllene, hexanoic (ACE2) receptors on cells in the lung, acid15), gastic cytoprotective42-45 gastrointestinal tract, blood vessels, (caryophyllene15), antiulcer (tannin15), heart, and kidney65. Many countries try choleretic (oleic acid15), cholagogic46, to find a cure or vaccine to this disease. carminative16,28,antispasmodic23,47 Clinical features of COVID-19 include (myrcene,saussurine15), tiredness, fever, dry cough, shortness antidiarrheal23,48(tannin15),antibacillary of breath, myalgia, aches, nasal (p-cymene, acetic acid, alpha-phellan- congestion, sore throat, nausea, drene, beta-ionone, beta-sitosterol, vomiting, and diarrhea66-68. About 2- caryophyllene15) astringent16, 10% of COVID-19 infected patients hepatoprotective1,3,23,24,28 (tannin, p- have diarrhea, and the RNA of the cymene15), antihepatotoxic49 (tannin15), virus could be detected in stool and hypoglycaemic23 (inulin15), anti- blood samples69. Some cases are hyperglycemic(lupeol15), asymptomatic or lacking the typical hypolipidemic50(beta-sitosterol15), symptoms of fever, dry cough and, hypocholesterolemic(inulin, oleic acid, fatigue, and the diagnosis is based on stigmasterol, beta-sitosterol15), angiot- detection of the viral RNA in throat

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SOHAG MEDICAL JOURNAL Saussurea costus may help in the treatment of COVID-19 Vol. 24 No. 3 July 2020 Mahmoud Saif-Al-Islam swab samples70. In the majority of ARDS, pulmonary edema, septic cases, the course of infection remains shock, and organ failure can occur66. mild71,72, and the patients resolve In some patients with SARS-CoV-2, spontaneously66. The patients can there is overexpression of inflam- develop bacterial and fungal infections matory mediators which is known as as the disease progresses. Therefore, cytokine storm syndrome (CSS) which antibiotic or antifungal treatment may also occurs in other inflammatory con- be given as appropriate73. Individuals ditions such as sepsis. It is unknown with multiple comorbid conditions are who will develop the cytokine storm. prone to severe infection67. CRP, serum ferritin, and IL-6 are early Fever can be treated with antipyretic biomarkers that may predict the drugs such as paracetamol, and patients evolution of CSS. These patients have with non-productive cough can be a much higher incidence of a rapid given expectorants such as guaife- deterioration of health and death81. The nesin74. Empirical early antibiotics cytokine storm is triggered by an were given for possible bacterial pneu- imbalanced response of type 1 and type monia75. 2 T helper cells67,82. Liver injury with various degrees Covid-19 patients had a thrombosis in may occur in patients with COVID-19 the small vessels of multiple organs. and the infection may be caused SARS-CoV-2 facilitates endotheliitis directly by the virus72,76. The incidence that may precipitate thrombosis83. of liver injury ranged from 14.8-53%, Respiratory failure in COVID-19 is not detected mainly by abnormal alanine caused by ARDS alone84, but micro- aminotransferase (ALT)/ aspartate vascular thrombosis may play a role as aminotransferase (AST) levels and well. This has important diagnostic and mild elevation of bilirubin levels67. therapeutic implications85. Whether the Gamma-glutamyl transferase and thrombotic process is directly caused alkaline phosphatase were elevated in by the virus or by the local or systemic 54% and 18% of cases77. The inflammation is not completely under- incidence of liver injury in severe stood86. COVID-19 patients was higher than Hypertensive, diabetic, older patients that in mild cases67,78 and signs of and those with coronary heart disease hepatic dysfunction may occur in were at higher risk of mortality71,72. critically ill patients72. One study Patients with myocardial injury are reported that serum ALT and AST older and have a higher prevalence of levels increased up to 7590 U/L and coronary artery disease, hypertension, 1445 U/L, respectively, in a severe heart failure, and diabetes mellitus than COVID-19 patient. Also, reduced those with normal levels of troponin I albumin levels may be detected in (TnI) or troponin T (TnT). Also, they severe cases66. Postmortem biopsies have evidence of more severe systemic showed moderate microvascular stea- inflammation87,88. Patients with risk tosis and mild lobular and portal factors for atherosclerotic cardio- activity, indicating that the injury may vascular disease have a higher risk of be due to either SARS-CoV-2 infection developing acute coronary syndrome or drug-induced liver injury79, which during acute infections which have might be caused by lopinavir/ritonavir, been shown previously in clinical and that were used as antiviral therapy80. epidemiologic studies of influenza89-91, In COVID-19, various fatal compli- and other acute inflammatory condi- cations including severe pneumonia, tions92. Such acute coronary events

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SOHAG MEDICAL JOURNAL Saussurea costus may help in the treatment of COVID-19 Vol. 24 No. 3 July 2020 Mahmoud Saif-Al-Islam could result from the severe increase in supplemental oxygen105. The use of myocardial demand triggered by convalescent plasma may contribute to infections that precipitate myocardial recovery106. Anti-cytokine therapy, as injury or infarction, or respiratory anti-IL-1 and anti-IL-6 may mitigate dysfunction and hypoxemia caused by the hyper-inflammation that may dev- COVID-19. Alternatively, cytokines elop in conjunction with ARDS102,107. released during severe inflammation Recent recommendations suggest that could lead to atherosclerotic plaque all hospitalized COVID-19 patients instability and rupture93. should receive thromboprophylaxis, or The mortality among all infected full therapeutic-intensity anticoagul- patients is about 0.5-4%94, among ation if needed108. In the absence of patients who require hospitalization is shock, intravenous fluids should be about 5-15%, and for those who carefully administered when needed109. become critically ill is about 22- Patients with a severe respiratory inf- 62%72,74. ection, respiratory distress, hypoxemia, At present, there is no effective or shock require immediate oxygen antiviral treatment or vaccine for therapy110. About 5-10 % of patients COVID-19. Several drugs were tried95. require intensive care unit admission Early initiation of antiviral treatment is and mechanical ventilation94. known to decrease the severity of the disease96. Oseltamivir, a neuraminidase Possible rule of S. costus in inhibitor, is currently being tried. Rem- treatment of COVID-19 desivir acts as an adenosine-analog that S. costus by its myrcene content that induces RNA chain termination, it acts on ACE receptors15 may interfere inhibited SARS-CoV-2 in vitro97,98 and with viral entry into the cells. S. costus decreased the severity of MERS-CoV- is used to treat fever, headache, cough, infection in a non-human primate and bronchial asthma16,28,57-59. Oleic model in vivo99. Several reports have acid acts as antileukotriene-D415 suggested it's clinical efficacy in therefore acts as a bronchodilator. S. patients with COVID-19100,101. costus is traditionally used as a Ritonavir-boosted lopinavir has an bronchodilator16 and as an anal- antiviral effect on SARS-CoV2 in vitro gesic27,28,35. Myrcene and p-cymene but not in vivo study102. Hydroxy- have analgesic properties while camph- chloroquine or chloroquine phosphate ene, inulin, alpha-phellandrene, caryo- has antiviral efficacy against SARS- phyllene, hexanoic acid act as CoV-2 in vitro by interference with the expectorant15. S. costus has antimi- ACE2-receptor-mediated endocytosis crobial17,18,23 and antibacterial prop- and is used as monotherapy or in erties17,18 (costic acid, dehydrocotus combination with azithromycin98,103,104. lactone, myrcene, p-cymene, tannin15). It is not recommended to use syste- It is traditionally used as antiseptic16 matic corticosteroids for respiratory and has a wide spectrum antimicrobial failure without ARDS in COVID-19, activity against some human patho- however, it may be used for patients gens. It exhibited a significant level of with ARDS105. Glucocorticoids may be antibacterial activity against many considered for patients with severe Gram-positive and Gram-negative immune reactions73,74. Treatment with pathogenic bacteria, including staphyl- methyl prednisolone, 1-2 mg/kg/d for ococcus aureus, pseudomonas aerug- 5-7 days, is associated with a reduction inosa, acinetobacter baumanii, esche- in duration of fever and the need for richia coli, and klebsiella pneumonia17.

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SOHAG MEDICAL JOURNAL Saussurea costus may help in the treatment of COVID-19 Vol. 24 No. 3 July 2020 Mahmoud Saif-Al-Islam

Also, it has antifungal activity19,20 (car- neutrophil chemotactic factor induc- yophyllene oxide, myrcene, octanoic tion30. Costunolide has antiinfl- acid, p-cymene15). The decoction of ammatory activity33. S. costus decrea- the plant increases the endogenous ses pain and inflammation by motilin release and accelerates gastric inhibition of cyclooxygenase (COX) emptying42, and improves gastric enzyme35. S. costus is used for treatm- cytoprotection43,44. It amplified the ent of chronic inflammation of the mucus discharge and was proved to be lungs, chest congestion, lung inflam- an antiulcer agent3,23,43,44,60,61. Caryo- mation29, and respiratory distresss41. phyllene15 and increased intracellular Chlorogenic acid in the roots of S. glutathione are responsible for costus exhibited antioxidant activity36. protection against gastric cell injury36. Myrcene, palmitic acid, stigmasterol, Besides, S. costus showed the ability to and tannin have antioxidant inhibit several strains of helicobacter properties15. S. costus extract caused a pylori111 and it is carminative16,28. dose-dependent protection against lipid Oleic acid has choleretic effect15 and peroxidation37. S. costus possesses costunolide has cholagogic effect46. S. immunostimulant effect37,38 (tannin15). costus has significant antidiarrheal It increased the leukocytic count, activity23,48 (tannin15), antiseptic and phagocytosis and antibody-secreating astringent agent16. It is widely utilized cells40. It inhibited the oxidation of in different medical systems all around reduced glutathione (GSH) in a dose- the world for treating a variety of dependent manner37. The importance ailments such as vomiting, dyspepsia, of thiols, especially of cysteine and inflammation, diarrhea, tenesmus, and glutathione, for lymph-ocyte function, abdominal pain23,28. S. costus roots has been known for many years. GSH have hepatoprotective1,3,23,24,28 (tannin, is a non-enzymic mode of defense p-cymene15) and antihepatotoxic against free radicals112. Glutathione is effects49 (tannin15). an important constituent of S. costus roots have antiviral intracellular protective mechanisms activity3,17,21-25. The studies that against several noxious stimuli, demonstrated its antiviral activity were including oxidative stress113. S. costus done on the hepatitis B virus (HBV) roots have immunomodulator and showed its considerable activity activity23,39-41. Cynaropicrin has immu- against the virus and its ability to nomodulatory effects on cytokine inhibit hepatitis B surface antigen release39. S. costus has ― complement- (HBsAg) expression22,25. Constunolide inhibitor’’ substances helpful in the and dehydrocostus lactone showed an treatment of some diseases related to inhibitory effect on the expression of marked activation of the complement HBsAg by Hep3B cells. They system, like rheumatoid arthritis, resp- suppressed HBsAg gene expression at iratory distress, and systemic lupus the mRNA level. Costunolide and erythematosus41. Its roots are used in dehydrocostus lactone are candidates the treatment of rheumatic dise- to be developed as potent anti HBV ases3,24,41. Lupeol has antirheumatic drugs22. P-cymene, stigmasterol, effect15. S. costus has hypoglycaemic tannin, lupeol, and botulin have activity23 (inulin15), and it was found to antiviral effects15. S. costus has anti- be effective for obese diabetic patie- inflammatory activity23,29-35. It is freq- nts50. It showed a significant hypoli- uently used for inflammatory diseases. pidaemic effect in rabbits. Reduction in It inhibited the cytokine-induced serum triglycerides and cholesterol

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SOHAG MEDICAL JOURNAL Saussurea costus may help in the treatment of COVID-19 Vol. 24 No. 3 July 2020 Mahmoud Saif-Al-Islam were also found to be significant50. 4- Ahmad M, Khan MA, Marwat SK, et al. Beta-sitosterol has hypolipidemic and Useful medicinal flora enlisted in Holy hypocholesterolemic effects, inulin, Quran and Ahadith. American-Eurasian oleic acid, and stigmasterol have J Agric Environ Sci 2009; 5(1): 126- hypocholesterolemic effects15. S. 140. 5-Saussurea costus wikipidia costus roots have spasmolytic active- ity23. Myrcene and saussurine have 6- Julianti T, Hata Y, Zimmermann S, et antispasmodic actions15. S. cotus is al. Antitrypanosomal sesquiterpene known to suppress contractions in the lactones from Saussurea costus. Fitoterapia 2011; 82(7): 955-959. guniea-pig aorta. Sesquiterpenes are recognized to stimulate the soluble 7- Yang H, Xie JL, Sun HD. Resarch guanylyl cyclase (sGC) which stim- progress on the medicinal plant ulates extrusion of K+ ions and thereby Saussurea lappa. Nat Prod Res Dev 1998; 10(2): 90-98. reduces intrinsic Ca++ ions through activation of protein kinase G (PKG) 8- Sun CM, Syu WJ, Don MJ, et al. pathway and cyclic guanosine mono- Cytotoxic sesquiterpene lactones from phosphate (cGMP), leading to smooth the root of Saussurea lappa. J Nat Prod 47 2003; 66(9): 1175-1180. muscles relaxation . 9- Choi EM, Kim GH, Lee YS. Protective Conclusion and recommendation: effects of dehydrocostus lactone Medicinal plants provide us with against hydrogen peroxide-induced important drugs that could be used to dysfunction and oxidative stress in treat different diseases. Research insti- osteoblastic MC3T3-E1 cells. Toxicol In Vitro 2009; 23: 862-867. tutes should evaluate the therapeutic potential of S. costus in the treatment 10- Cho JY, Park J, Yoo ES, et al. of COVID-19 and the patients should Inhibitory effect of sesquiterpene be asked to participate in clinical trials. lactones from Saussurea lappa on It is worthy to separate the bioactive tumor necrosis factor-alpha production compounds from the roots of S. costus in murine macrophage-like cells. Planta Med 1998; 64(7): 594-597. to get new natural and effective drugs. 11- Yoshikawa M, Hatakeyama S, Inoue References Y, et al. Saussureamines A, B, C, D, and E, new antiulcer principles from 1- Pandey MM, Rastogi S, Rawat AK. Chinese Saussureae Radix. Chem Saussurea costus: Botanical, chemical, Pharm Bull (Tokyo) 1993; 41(1): 214- and pharmacological review of an ayur- 216. vedic medicinal plant. J Ethnopharmacol 2007; 110(3): 379- 12- Zhao F, Xu H, He EQ, et al. Inhibitory 390. effects of sesquiterpenes from Saussurea lappa on the overproduction 2- Shah R. Nature’s medicinal plants of of nitric oxide and TNF-alpha release Uttaranchal: (Herbs, Grasses and in LPS-activated macrophages. J Asian Ferns). Vol. I and II. Gyanodaya Nat Prod Res 2008; 10(11-12): 1045- Prakashan, Kanpur, Nanital, 1053. Uttarakhand. India 2006.

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