Friday Hope: Andrographolide: Attacking Smoldering Macrophage Syndrome from Both Directions

This “King of Bitters” appears to target both viral stimulus and downstream macrophage dysfunction.

When researching the literature for a natural therapeutic which may be useful in treating my proposed Smoldering Macrophage Syndrome, I found one that stands out. It seems almost custom-tailored to treat the disease. It is Andrographolide (Andro) and, it is known colloquially as the “King of Bitters” for the highly concentrated bitter taste of the Andrographis paniculata plant. It is also a staple of Traditional Chinese Medicine.

Andrographolide is a diterpene lactone compound extracted from Andrographis paniculata (Burm. F) Nees. Andrographis paniculata is also known as lanhelian, yijianxi, zhanshecao, kucao, kudancao, etc. Since this product originates in India, it is also known as Indian grass. This product is dry ground part of Jupiteraceae plant Andrographis paniculata (conus) may originate in South Asia. It is commonly cultivated in China such as in Fujian, Guangdong, Hainan, Guangxi, and Yunnan and also in Australia and was also introduced in Jiangsu and Shaanxi.

Andrographis paniculata is commonly used in traditional Chinese medicine. Its ability of relieving “snake venom, and internal injuries cough” was recorded in “Lingnan herbal medicine records.” “Quanzhou Materia Medica” described it as “heat-clearing and detoxifying, anti-inflammatory, detumescence and inhibition throat inflammation, dysentery and high fever.”

Andrographolide
https://pmc.ncbi.nlm.nih.gov/articles/PMC7122281/

Why it caught my attention is that it shows properties of being theoretically able to bind Spike Protein, prevent Foam Cell formation and quell cytokine release from activated macrophages. All three of these actions would ameliorate Smoldering Macrophage Syndrome.

First, let’s look at how Andro can potentially bind Spike, preventing it from entering cells.

In this study, we used docking and molecular dynamics simulations to understand the binding effect of andrographolide on the SARS-CoV-2 spike protein. During docking, a strong binding affinity was observed between the ligand and the target receptor protein. MD results demonstrated higher conformational fluctuations in the ligand-free protein compared to the bound form. Several residues in the active sites make conformational rearrangements for the S protein to interact with the ligand. While RBD experiences conformational transition to gain more stability upon binding with the ligand. This binding is strengthened via several non-covalent interactions that make the complex structure more stable with higher binding affinity. Overall findings of the study may shed some valuable insights concerning the development of potential therapeutics in the strategies for COVID-19 prevention.

Investigating the binding affinity of andrographolide against human SARS-CoV-2 spike receptor-binding domain through docking and molecular dynamics simulations
https://pubmed.ncbi.nlm.nih.gov/36764825/

Next, Andro has demonstrated abilities to prevent the formation of foam cells, which we have previously discussed as an action the Spike Protein is able to induce.

In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.

Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages
https://pubmed.ncbi.nlm.nih.gov/29298513/

The remaining property of Andro I would like to discuss today is its ability to reduce the expression of cytokines in macrophages. Specifically, the expression of cytokines the Spike is particularly fond of increasing.

Macrophages have remarkable heterogeneity and plasticity that allows them to efficiently respond to exogenous and endogenous signals by changing their functional phenotype11, 14. In this study, thioglycollate-elicited mouse peritoneal macrophage (F4/80+ population)26 have been used to investigate the immunomodulatory activities of andrographolide on the innate immune response in vitro. Our results indicated that andrographolide showed potent immunoregulatory properties in murine macrophages. Andrographolide reduced expression of inflammatory cytokines (TNF-α, IL-12, IL-1β, IL-18, and IL-6) in LPS activated macrophages, which is consistent with a previous report that andrographolide decreased TNF-α and IL-12 mRNA expression and cytokine production in murine peritoneal macrophages, although they did not detect IL-1β, IL-18, and IL-627.

Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response
https://pmc.ncbi.nlm.nih.gov/articles/PMC4002847/

Now it is clear why andrographolide captured my attention: Because it appears to address both sides of the SMS equation.

If Smoldering Macrophage Syndrome is driven by persistent viral stimulation together with macrophages that remain trapped in a chronic inflammatory state, then the ideal therapeutic would do more than simply suppress inflammation. It would reduce the viral stimulus while helping restore normal macrophage biology.

Andrographolide appears to move in exactly those directions.

We examined studies which suggest antiviral activity against SARS-CoV-2. Other studies demonstrated that it limits pathological cytokine production by activated macrophages. Still others show that it prevents macrophages from transforming into foam cells by restoring cholesterol homeostasis.

Taken together, these actions make andrographolide one of the most intriguing natural compounds I have encountered in the context of my Smoldering Macrophage Syndrome hypothesis.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Also, a great thank you to the three new paid subscribers who have joined us since Monday. Please have a blessed weekend.

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