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v. Quercetin - As discussed above, the antiviral roles of 2. Natural Killer (NK) cell support
zinc are well documented. However, protection of a. Radix astragali (Astragalus) - One of the top prescribed
cells against viral appropriation of cellular metabolism botanicals in TCM preparations for SARS-CoV-1 was
to replicate viral RNA requires adequate intracellular Radix astragali, with numerous published clinical trials
zinc. Ionophores play a critical role in facilitating demonstrating significant efficacy for both prevention
transport of zinc into cells. The commonly available and treatment. In SARS-CoV-2, astragalus continues
flavonoid quercetin is a zinc ionophore and has been to be the most common botanical in TCM prevention
shown to facilitate transport of zinc across lipid formulas prescribed in China. 247
membranes. This is particularly relevant as b. Andrographis paniculata (Andrographis) - The
chloroquine is also a zinc ionophore, which has been antiviral properties of andrographis have been
postulated as a possible mechanism for its apparent proposed as leads for pharmaceuticals in the antiviral
efficacy against SARS-CoV-v2. 240,241 drug discovery literature. 248-251 Andrographis has been
Quercetin is also important as one of multiple shown in human randomized controlled trials to be
flavonoids shown in vitro to block the activity of effective in upper respiratory tract infection 252,253 and
MERS-CoV 3CLpro, a critical enzyme for coronavirus pharyngotonsillitis. Andrographis has been shown
254
replication. Animal studies are limited at this time but to promote natural killer cell activity 255,256 and also
support efficacy. 242 reduce the levels of inflammatory cytokines. 257
In a molecular docking study looking for agents c. Ganoderma lucidum (Reishi mushroom) -
that could bind to the SARS-CoV-2 Viral Spike Ganoderma has been used in traditional Chinese
Protein and thus have potential to inhibit its infectivity, medicine (TCM) for thousands of years. The antiviral
researchers found quercetin to be the fifth most properties of ganoderma have been studied in
effective. However, quercetin has low bioavailability dengue, 258,259 HIV, HPV, enterovirus 71,262 and
261
260
243
and therefor requires special formulations to achieve herpes. Reishi activates NK cells 264-268 and Th1
263
clinically effective blood levels. A trial with a cells 269,270 and downregulates inflammatory cytokines
phytosomal quercetin formulation has been started in in human alveolar epithelial cells. 271,272
Italy on 660 hospitalized COVID-19 patients (private
communication with study PI). 3. Th1 cell support
a. Berberine-containing Botanical Medicines
vi. Fish Oil - The role of fish oil in reducing inflammation (Hyrastis canadensis, Coptidis Chinensis) -
is long established. However, in an acute care setting, Berberine has been shown to have activity across a
the time scale involved in addressing acute broad range of viruses. 273-280 Berberine has activity
inflammation may preclude the use of fish oil as a against RSV via upregulation of type 1 interferons.
281
strategy for influencing the body’s inflammatory Type 1 interferons are key activators of NK cells and
equilibrium. Nonetheless, it is worth mentioning the play a central role in antiviral immunity. 282,283 The
potential role that specialized pro-resolving lipid anti-inflammatory, 284-286 cardioprotective, 285,287 and
mediators (SPMs) may play in influencing the biology antifungal effects of berberine have also been
of risk, in those for whom care is occurring in the reviewed. One mechanism by which berberine
288
Prevention Phase. downregulates inflammation is through activation of
SPMs are downstream products of the metabolism AMP kinase (AMPK). AMPK is a known activator
289
of EPA and DHA, the primary active constituents of of SIRT2, a known inhibitor of NLRP3
290
fish oil. EPA is the precursor for the E series resolvins, inflammasome assembly. Other mechanisms of
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and DHA is the precursor for the D series resolvins, berberine inhibition of NLRP3 have also been
neuroprotectins, and maresins. 244,245 These lipid described.291-293 Berberine-induced AMPK inhibits
mediators play a key role in the resolution phase of IL-6-induced inflammation in human liver cells by
the inflammatory process. 9 inhibiting STAT3, the signal transduction factor
SPMs can inhibit priming and activation of required for Th17 cell differentiation.294 Berberine
macrophage NLRP3 inflammasome (in vivo and promotes the Th1 cytokines IL-12 and IFNγ and
in vitro). SPMs, specifically D2, suppressed IL-1β inhibits the Th2 cytokine IL-4. 295-297
246
production and secretion in LPS- and ATP-challenged Berberine also has potential advantages in
macrophages, and reduced inflammasome assembly impacting clotting. Hypoxia inducible factor 1 alpha
and caspase-1 activity. D2 also deactivated the (HIF1α) has been described as a promoter of
inflammasome in a mouse peritonitis model, as thrombosis. 298-300 As the name implies, HIF1α is
shown by reduced IL-1β release and increased M2 upregulated by tissue hypoxia. With poor oxygenation,
markers of inflammation resolution. higher HIF1α levels will drive more thrombus
formation. As described before, neutrophil NETs
offer an additional base material for clot formation.
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Yanuck—Immuno-physiological Approach to COVID-19 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print 21