Friday Hope: Quercetin Reloaded: Inhibiting Extracellular Matrix (ECM) Production, TGF-β Signaling, and Migration Within the ECM

As we look deeper, we discover more ways by which key therapeutics protecting/treating the endothelium (SPED) also treat/protect the ECM from the Spike’s deleterious effects.

(A) TGF-βRII expression was significantly up regulated in HCFs following lactate stimulation (p < 0.05) and down regulated in HKCs following Quercetin stimulation (p < 0.05), (B) TGF-β2 expression was significantly up regulated in HKCs following Lactate stimulation (p < 0.05) where HCFs showed no differences. Quercetin stimulation led to significant down regulation of TGF-β2 expression in both HCFs and HKCs. All gels have been run under the same experimental conditions. n = 3, error bars represent SEM.

Absolutely. Fascinating.

The more deeply I investigate natural therapeutics which have shown great benefit in preventing/treating Spike Protein Endothelial Disease (SPED), the more I discover that these very same therapeutics also protect/treat the ECM from the effects of the Spike Protein. Last week we reviewed how Vitamin D is beneficial in treating the ECM. This week we will review Quercetin. And it is a mighty ally.

First, let’s look at some of the pathological effects of the Spike on the ECM.

The Spike Protein causes extracellular matrix reorganization and TGF-β signaling. It also interacts with Integrins, as discussed previously this week.

We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19.

SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling
https://www.nature.com/articles/s41467-022-34910-5

The Spike Protein also induces increased levels of Lactate.

The present research goes beyond receptor recognition to explore Spike's influence on cellular metabolism. AP-MS interactome analysis revealed an interaction between the Spike S1 domain and lactate dehydrogenase B (LDHB), which was further confirmed by co-immunoprecipitation and immunofluorescence, indicating colocalisation in cells expressing the S1 domain. The study showed that Spike inhibits the catalytic activity of LDHB, leading to increased lactate levels in HEK-293T cells overexpressing the S1 subunit. In the hypothesised mechanism, Spike deprives LDHB of NAD+, facilitating a metabolic switch from aerobic to anaerobic energy production during infection. The Spike-NAD+ interacting region was characterised and mainly involves the W436 within the RDB domain. This novel hypothesis suggests that the Spike protein may play a broader role in altering host cell metabolism, thereby contributing to the pathophysiology of viral infection.

SARS-CoV-2 uses Spike glycoprotein to control the host's anaerobic metabolism by inhibiting LDHB
https://www.sciencedirect.com/science/article/pii/S0141813024054436

Why are these effects important to ameliorate? Because the ECM is a “launching pad” for fibrosis and cancer, among other diseases. If you wish to dive deeper into the ECM and its relation to fibrosis and cancer, here are two excellent articles:

The extracellular matrix: an active or passive player in fibrosis?
https://pmc.ncbi.nlm.nih.gov/articles/PMC3233785/

The Functional Role of Extracellular Matrix Proteins in Cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC8750014/

Enter our Hero: Quercetin. This brilliant flavonoid has been proven effective in treating both effects discussed above,

LACTATE LEVELS

In this study, we have identified Quercetin as a potent inhibitor of lactate-induced fibrosis in KC. Using a variety of established techniques, we have shown that Quercetin attenuates collagen secretion and terminal differentiation to the fibrotic phenotype observed in HKCs. Considering its antioxidant properties, as previously reported in the retina58,59, we hypothesized that Quercetin may target cellular metabolism in both HCFs and HKCs. Our data is in agreement with our previous observation17 that HKCs have altered cellular metabolism, including elevated lactate production compared to HCFs. Furthermore, the results shown here suggest that Quercetin modulates fibrotic signaling in HKCs by altering cellular metabolism and reducing lactate production.

TGF-β SIGNALING

We have shown in this study that Quercetin down regulates expression of both TGF-βRII and TGF-β2, which provides evidence of direct inhibition by Quercetin of pro-fibrotic markers promoted by TGF-β signaling. Collectively, our data show that Quercetin is a potent inhibitor of key fibrotic markers and a strong metabolic regulator in KC and highlight its potential as a therapeutic in the treatment of corneal scarring associated with KC.

Quercetin Attenuates Lactate Production and Extracellular Matrix Secretion in Keratoconus
https://pmc.ncbi.nlm.nih.gov/articles/PMC4355637/

An added benefit? Quercetin also reduces the migration of cancer cells through the ECM.

A significant reduction of the migration of both myometrial and leiomyoma cells in response to quercetin was observed (P < 0.05) and I3C (P < 0.05 for myometrial and P < 0.01 for leiomyoma cells) treatment. Both quercetin and I3C significantly reduced myometrial cell proliferation (P < 0.05).

Quercetin and indole-3-carbinol inhibit extracellular matrix expression in human primary uterine leiomyoma cells
https://www.sciencedirect.com/science/article/abs/pii/S1472648320300249

It is going to be a very cold and snowy weekend here in northern Vermont. A good, hearty beef stew with plenty of onions and broccoli comes to mind for a natural Quercetin boost combined with midwinter comfort.

Thank you, as always, for your dialogue, readership and support. I am, also as always, insatiably curious as to what other therapeutics we have discovered may be providing far more benefits and protection than we currently realize. I will continue to discover. Please have a blessed and beautiful Valentine’s Day and President’s Day weekend.