Herbs and Nutrients That May Assist

Andrographis
Andrographis paniculata, herb top dry
Green Tea
Camellia sinensis (standardised for epigallocatechin-3-0-gallate [EGCG]), leaf)
Vitamin C
Calcium ascorbate dihydrate
Vitamin D3
Colecalciferol
Zinc
Zinc amino acid chelate (Meta Zn® - Zinc bisglycinate)

Actions

• Viral control
• Inflammatory regulation
• Immune modulation

Clinical Applications

• Reduction in the severity and duration of ARTIs

NK Cell Regulation

Background Information

Acute respiratory tract infections (ARTIs), including colds, influenza, and coronaviruses, are highly contagious, cause mild to severe illness, and may have lasting consequences.^[1],[2] Localised and systemic inflammation is responsible for the symptoms associated with the common cold, including sore throat, nasal congestion, headaches, chills, fever, cough, nasal discharge, sneezing and malaise.^[3] Influenza generally presents with greater severity, characterised by the onset of fever, headache, cough, sore throat, myalgia, nasal congestion, weakness and a loss of appetite.^[4] COVID-19 presents with variable symptoms, most commonly fever, cough, sore throat, shortness of breath and fatigue. Other symptoms may include muscle or joint pain, diarrhoea, headache and loss of taste or smell. Severe symptoms include difficulty breathing, chest pain or loss of speech and movement.^[5]

(Figure 1).^[6-9] Further, epigallocatechin-gallate (EGCG) from green tea dramatically enhances cellular uptake of zinc to increase its antiviral activity.^[10] These herbs and nutrients are also shown to regulate viral inflammasome activation and support antioxidant protection, to reduce symptoms and assist recovery.^[11-15] During the COVID-19 pandemic, metabolic and inflammatory risk factors have been identified to increase the severity if disease. Andrographis, zinc and vitamin D may be protective for patients at risk of severe consequences from infection.^[16-18]

Figure 1: Actions of herbs and nutrients that reduce frequency, severity and duration of ARTIs [6-9].

Key: EGCG-ZnO - epigallocatechin-gallate - zinc oxide; IL-1b - interleukin 1 beta.

Clinical Actions

Viral Control

Andrographis is traditionally used in Ayurvedic and Chinese medicine to relieve the severity and duration of colds and flu.^[19] These effects arise from the bitter diterpenoid lactones, collectively called andrographolides, including andrographolide (AP1), 14-deoxy-11,12-didehydroandrographolide (AP3) and neoandrographolide (AP4), which have demonstrated antiviral and immune modulating properties.^[6],[20] Both in vitro and in vivo models have shown that andrographolides can reduce the infectivity of influenza A viruses (H5N1, H9N2 and H1N1 strains) by binding to viral hemagglutinin and blocking entry to host cells.^[21]

The direct antiviral actions of zinc include the inactivation of extracellular free virus, as well as inhibiting intracellular viral uncoating, genome transcription and activity, including protein translation.^[22] Zinc is also required for interferon (IFN) release, natural killer (NK) cell activity and macrophage phagocytic capacity.^[22-24] The demand for zinc increases during infection, and requirements may further increase with the severity of infection.^[25]

Cellular uptake of zinc is dramatically enhanced upon binding with certain flavonoids and forming compounds called zinc ionophores.^[26],[27] In vitro studies show that cell membranes uptake zinc ionophores via endocytosis, which then disassociate to increase cellular zinc concentrations. The formation of ionophores with epigallocatechin-gallate (EGCG) from green tea and zinc (EGCG-ZnO) (Figure 2) has been shown to double intracellular levels of free zinc ions.^[7] Increased intracellular zinc concentrations, via zinc ionophores, is shown to effectively inhibit the replication of a wide range of RNA viruses, including rhinoviruses, influenza, and coronaviruses.^[28]

Green tea catechins, including EGCG are also shown to bind to the hemagglutinin molecule of influenza virus, thereby inhibiting cellular uptake and blocking virus assembly or maturation.^[29]

Figure 2: EGCG binds to zinc to form zinc ionophores, which increase cellular uptake of zinc.^[27]

Key: EGCG - epigallocatechin-gallate; Zn2⁺ - zinc ion; EGCG-ZnO – EGCG-zinc ionophore.

Vitamin C is required for the antimicrobial efficiency of neutrophils, macrophages, and NK cells.^[8],[23] These innate immune cells actively accumulate vitamin C, reaching 50 to 100 times plasma concentrations. Upon microbial infection, stored vitamin C generates a lethal anti-pathogenic oxidative burst, whilst maintaining redox balance to protect host tissues from excessive reactive oxygen species (ROS).^[8] Vitamin C also regenerates other protective antioxidant pathways, including glutathione and vitamin E.^[12] Upon the resolution of infection, vitamin C is required by macrophages for the clearance of spent neutrophils from sites of infection.^[30]

Vitamin D is crucial for respiratory tract defence, and its deficiency correlates with increased rates of infection.^[12] In response to respiratory pathogens, both localised immune cells and lung epithelium are stimulated to convert 25-hydroxyvitamin D to active 1,25-hydroxyvitamin D for the synthesis of antimicrobial peptides and the efficiency of adaptive immunity.^[9],[31] Additionally, neutrophils and macrophages require vitamin D for their differentiation and phagocytic functions.^[12]

Inflammation Regulation

Viral infections rapidly incite inflammatory defences to inhibit viral replication. For example, SARS-CoV-2 directly activates NLRP3 inflammasome assembly, but also down-regulates IFN release. It appears that patients with compromised immunity may tend towards dysregulated NLRP3 activity that can escalate the severity of COVID-19 illness, associated with tissue damage and a cytokine storm.^[13] Cytokine storms are generally observed in hospitalised patients, where every attempt is made to support recovery and reduce widespread tissue damage causing lasting consequences of severe viral infection.^[32-34]

Andrographis supports antiviral immunity, with potent anti-inflammatory and antioxidant properties.^[6],[20] Recent studies show that andrographis extracts restrict inflammasome activation and interleukin 1 beta (IL-1b) concentrations in tissues, whilst up-regulating the expression of nuclear factor erythroid 2–related factor 2 (Nrf2), thereby inducing protective intracellular antioxidant pathways.^[35] Andrographolides are also shown to beneficially regulate proinflammatory cytokines IL-2, IL-4 and interferon‐gamma (IFN-y).^[36],[14]

The anti-inflammatory and antioxidant effects of green tea are also associated with reduced inflammasome activation and subsequent IL-1b expression.^[15]

Vitamins C, vitamin D, and zinc play various roles in the inflammatory response, including the maintenance of homeostasis, and regulation of inflammasome activity and IL-1b expression.^{[12],[37],[38]} Furthermore, zinc deficiency is independently associated with NLRP3 inflammasome activation and IL-1β expression.^[39]Additionally, zinc is required for the expression of antiviral type-I IFN, which is typically inhibited by the SARS-CoV-2 virus in COVID-19 patients.^[25]

These co-ordinated antiviral, anti-inflammatory and antioxidant effects help to explain how these compounds act to lower the frequency, severity and duration of ARTIs, and may offer prophylaxis against the consequences of severe influenza and COVID-19, including cytokine storm.^[13]

Immune Modulation

The immune modulating properties of andrographis include increasing the antiviral activity of cytotoxic T cells, NK cells, phagocytosis and antibody-dependant cell-mediated immunity. These properties combine to restrain viral replication and virus-induced pathogenesis.^[40]

The vitamins C and D, and zinc are essential micronutrients in immunity, being required for the differentiation, proliferation and antimicrobial functions of innate and adaptive immune cells. These nutrients are also utilised in the recovery and repair of tissues after infection.^[12]

Evidence is accumulating for vitamin D and zinc deficiencies increasing COVID-19 severity. For instance, COVID-19 prognosis is poorer in patients with conditions associated with vitamin D and zinc deficiency, such as advanced age, obesity, hypertension and metabolic disease.^[17],[18] Patients with zinc deficiency were over five times more likely to develop COVID-19 complications, and the degree of their deficiency positively correlated to prolonged hospital stays and mortality risk.^[18]

Clinical Applications

Reduction in the Severity and Duration of ARTI

A meta-analysis of 33 randomised controlled trials, including 7,175 patients, evaluated the efficacy of andrographis for reducing symptoms and duration of ARTIs. Data included trials using variable daily doses from 15.75 mg to 1,200 mg of andrographis extract which, when used alone or alongside other interventions, significantly reduced cold and influenza symptoms and shortened illness by one to three days, compared to placebo and other herbal therapies.[19]

Summary of ingredients

Safety Information

Disclaimer: In the interest of supporting Healthcare Practitioners, all safety information provided at the time of publishing is in accordance with Natural Medicine Database (NATMED PRO), renowned for its professional monographs which include a thorough assessment of safety, warnings, and adverse effects.

For further information on specific interactions with medications, please contact Clinical Support on 1800 777 648, or via email, anz_clinicalsupport@metagenics.com

Pregnancy and Lactation

• Possibly unsafe; avoid using.[44]

Contraindications

• Green tea is contraindicated with Ephedrine, Atorvastatin Lipitor) and Nadolol (Corgard); avoid this combination.[44]

References

[1] WebMD. Understanding the common cold. Updated 2021. Accessed January 5, 2021. https://www.webmd.com/cold-and-flu/cold-guide/understanding-common-cold-basics#1

[2] Greenberg SB. Update on human rhinovirus and coronavirus infections. Semin Respir Crit Care Med. 2016;37(4):555-71. doi:10.1055/s-0036-1584797

[3] Poolsup N, Suthisisang C, Prathanturarug S, Asawamekin A, Chanchareon U. Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials. J Clin Pharm Ther. 2004;29(1):37-45. doi: 10.1046/j.1365-2710.2003

[4] Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis. 2005;5(11):718-25. doi:10.1016/S1473-3099(05)70270-X

[5] World Health Organization. Coronavirus disease (COVID-19). Updated October, 202. Accessed January 14, 2021. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-and-answers-hub/q-a-detail/coronavirus-disease-covid-19#:~:text=symptoms

[6] Sun W, Leng L, Yin Q, Xu M, Huang M, Xu Z, et al. The genome of the medicinal plant Andrographis paniculata provides insight into the biosynthesis of the bioactive diterpenoid neoandrographolide. Plant J. 2019;97(5):841-857. doi:10.1111/tpj.14162

[7] Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O'Sullivan CK, Fernández-Larrea JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem. 2014;62(32):8085-93. doi:10.1021/jf5014633

[8] Carr AC, Maggini S. Vitamin C and immune function. Nutrients. 20173;9(11):1211. doi:10.3390/nu9111211

[9] Jolliffe DA, Griffiths CJ, Martineau AR. Vitamin D in the prevention of acute respiratory infection: systematic review of clinical studies. J Steroid Biochem Mol Biol. 2013;136:321-9. doi: 10.1016/j.jsbmb.2012.11.017

[10] Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O'Sullivan CK, Fernández-Larrea JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem. 2014;62(32):8085-93. doi:10.1021/jf5014633

[11] Pal A, Squitti R, Picozza M, Pawar A, Rongioletti M, Dutta AK, et al. Zinc and COVID-19: basis of current clinical trials. Biol Trace Elem Res. 2020;1–11. doi:10.1007/s12011-020-02437-9

[12] Gombart AF, Pierre A, Maggini S. A review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients. 2020;12(1):236. doi:10.3390/nu12010236

[13] van den Berg DF, Te Velde AA. Severe COVID-19: NLRP3 inflammasome dysregulated. Front Immunol. 2020;11:1580. doi:10.3389/fimmu.2020.01580

[14] Burgos RA, Seguel K, Perez M, Meneses A, Ortega M, Guarda MI, et al. Andrographolide inhibits IFN-gamma and IL-2 cytokine production and protects against cell apoptosis. Planta Med. 2005;71(5):429-34. doi:10.1055/s-2005-864138

[15] Wu J, Xu X, Li Y, Kou J, Huang F, Liu B, et al. Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol. 2014;745:59-68. doi:10.1016/j.ejphar.2014.09.046

[16] Enmozhi SK, Raja K, Sebastine I, Joseph J. Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach. J Biomol Struct Dyn. 2020;1-7. doi:10.1080/07391102.2020.1760136

[17] Rhodes JM, Subramanian S, Laird E, Griffin G, Kenny RA. Perspective: vitamin D deficiency and COVID-19 severity - plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med. 2021;289(1):97-115. doi:10.1111/joim.13149

[18] Jothimani D, Kailasam E, Danielraj S, Nallathambi B, Ramachandran H, Sekar P, et al. COVID-19: poor outcomes in patients with zinc deficiency. Int J Infect Dis. 2020;100:343-349. doi:10.1016/j.ijid.2020.09.014

[19] Hu XY, Wu RH, Logue M, Blondel C, Lai LYW, Stuart B, et al. Andrographis paniculata (Chuān Xīn Lián) for symptomatic relief of acute respiratory tract infections in adults and children: A systematic review and meta-analysis. PLoS One. 2017;12(8):e0181780. doi:10.1371/journal.pone.0181780

[20] Okoye TC, Uzor PF, Onyeto CA, Okereke EK. Safe African medicinal plants for clinical studies. In: Kuete V. Toxicological Survey of African Medicinal Plants [Internet]. London United Kingdom: Elsevier; 2014. [cited 2021 Jan 14]. p. 535-555. doi:10.1016/B978-0-12-800018-2.00018-2

[21] Chen JX, Xue HJ, Ye WC, Fang BH, Liu YH, Yuan SH, et al. Activity of andrographolide and its derivatives against influenza virus in vivo and in vitro. Biol Pharm Bull. 2009;32(8):1385-91. doi:10.1248/bpb.32.1385

[22] Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The role of zinc in antiviral immunity. Adv Nutr. 2019;10(4):696-710. doi:10.1093/advances/nmz013

[23] Maggini S, Pierre A, Calder PC. Immune function and micronutrient requirements change over the life course. Nutrients. 2018;10(10):1531. doi:10.3390/nu10101531

[24] Wu D, Lewis ED, Pae M, Meydani SN. Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance. Front Immunol. 2019;9:3160. doi:10.3389/fimmu.2018.03160

[25] Pal A, Squitti R, Picozza M, Pawar A, Rongioletti M, Dutta AK, et al. Zinc and COVID-19: basis of current clinical trials. Biol Trace Elem Res. 2020;22:1–11. doi:10.1007/s12011-020-02437-9

[26] Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O'Sullivan CK, Fernández-Larrea JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem. 2014;62(32):8085-93. doi:10.1021/jf5014633

[27] Samutprasert P, Chiablaem K, Teeraseranee C, Phaiyarin P, Pukfukdee P, Pienpinijtham P, et al. Epigallocatechin gallate-zinc oxide co-crystalline nanoparticles as an anticancer drug that is non-toxic to normal cells. RSC Advances. 2018;8(14):7369-76. doi:10.1039/C7RA10997K

[28] Hoang BX, Han B. A possible application of hinokitiol as a natural zinc ionophore and anti-infective agent for the prevention and treatment of COVID-19 and viral infections. Med Hypotheses. 2020;145:110333. doi:10.1016/j.mehy.2020.110333

[29] Matsumoto K, Yamada H, Takuma N, Niino H, Sagesaka YM. Effects of green tea catechins and theanine on preventing influenza infection among healthcare workers: a randomized controlled trial. BMC Complement Altern Med. 2011;11:15. doi:10.1186/1472-6882-11-15

[30] Bozonet SM, Carr AC. The role of physiological vitamin C concentrations on key functions of neutrophils isolated from healthy individuals. Nutrients. 2019;11(6):1363. doi:10.3390/nu11061363

[31] Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012;71(1):50-61. doi:10.1017/S0029665111001650

[32] Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 cytokine storm; what we know so far. Front Immunol. 2020;11:1446. doi:10.3389/fimmu.2020.01446

[33] Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13(1):3-10. doi:10.1038/cmi.2015.74

[34] Herold S, Becker C, Ridge KM, Budinger GR. Influenza virus-induced lung injury: pathogenesis and implications for treatment. Eur Respir J. 2015;45(5):1463-78. doi:10.1183/09031936.00186214

[35] Liu YT, Chen HW, Lii CK, Jhuang JH, Huang CS, Li ML, et al. A diterpenoid, 14-Deoxy-11, 12-Didehydroandrographolide, in Andrographis paniculata reduces steatohepatitis and liver injury in mice fed a high-fat and high-cholesterol diet. Nutrients. 2020;12(2):523. doi:10.3390/nu12020523

[36] Yu B, Dai CQ, Jiang ZY, Li EQ, Chen C, Wu XL, et al. Andrographolide as an anti-H1N1 drug and the mechanism related to retinoic acid-inducible gene-I-like receptors signaling pathway. Chin J Integr Med. 2014l;20(7):540-5. doi:10.1007/s11655-014-1860-0

[37] Choe JY, Kim SK. Quercetin and ascorbic acid suppress fructose-induced NLRP3 inflammasome activation by blocking intracellular shuttling of TXNIP in human macrophage cell lines. Inflammation. 2017;40(3):980-994. doi:10.1007/s10753-017-0542-4

[38] Rao Z, Chen X, Wu J, Xiao M, Zhang J, Wang B, et al. Vitamin D receptor inhibits NLRP3 activation by impeding its BRCC3-mediated deubiquitination. Front Immunol. 2019;10:2783. doi:10.3389/fimmu.2019.02783

[39] Summersgill H, England H, Lopez-Castejon G, Lawrence CB, Luheshi NM, Pahle J, et al. Zinc depletion regulates the processing and secretion of IL-1β. Cell Death Dis. 2014;5(1):e1040. doi:10.1038/cddis.2013.547

[40] Gupta S, Mishra KP, Ganju L. Broad-spectrum antiviral properties of andrographolide. Arch Virol. 2017;162(3):611-623. doi:10.1007/s00705-016-3166-3

[41] Cáceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK. Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. a randomized double blind-placebo study. Phytomedicine. 1999;6(4):217-23. doi:10.1016/S0944-7113(99)80012-9

[42] Saxena RC, Singh R, Kumar P, Yadav SC, Negi MP, Saxena VS, et al. A randomized double blind placebo controlled clinical evaluation of extract of Andrographis paniculata (KalmCold) in patients with uncomplicated upper respiratory tract infection. Phytomedicine. 2010;17(3-4):178-85. Doi:10.1016/j.phymed.2009.12.001

[43] Hemilä H. Vitamin C and infections. Nutrients. 2017;9(4):339. doi:10.3390/nu9040339

[44] Natural Medicines Database. AusDi; 2024. Accessed September 20, 2024. https://ausdi.hcn.com.au/