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Source: COVID-19 And Cytokine Storms  Aug 04, 2021  6 months ago
Must Read! Canadian Researchers Discover That The Protein Galectin-9 Is Responsible For Cytokine Storms In COVID-19 Patients
Must Read! Canadian Researchers Discover That The Protein Galectin-9 Is Responsible For Cytokine Storms In COVID-19 Patients
Source: COVID-19 And Cytokine Storms  Aug 04, 2021  6 months ago
A new study by researchers from University of Alberta, Edmonton-Canada have discovered that a little known protein called Galectin-9 is responsible for the destructive and often lethal cytokine storms in COVID-19 patients.

 
Galectin-9 (Gal-9) is an abundant protein in many immune and nonimmune cells. Galectin-9 is a beta-galactoside lectin protein that has important cytoplasmic, intracellular functions and controls AMPK (5' AMP-activated protein kinase) in response to lysosomal damage that can occur upon exposure to endogenous and exogenous membrane damaging agents such as crystalline silica, cholesterol  crystals, microbial toxins, proteopathic aggregates such as tau fibrils and amyloids, and signaling pathways inducing lysosomal permeabilization such as those initiated by TRAIL (TNF-related apoptosis-inducing ligand).
 
To date, clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients.
 
The study team observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, they found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor β (TGF-β) in COVID-19 patients.
 
The study findings found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro.

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Also, the study team observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibits an activated phenotype.
 
Furthermore, it was observed that there was a significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs.
 
The team’s further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may serve as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biom arker in COVID-19 patients.
 
The study findings showed that Gal-9 detection assay can differentiate SARS-CoV-2-infected from non-infected individuals with a specificity/sensitivity of 95%.
 
The study findings were published in the peer reviewed journal: mBIO (A journal of the American Society for Microbiology) https://journals.asm.org/doi/10.1128/mBio.00384-21
 
The study team found that COVID-19 patients have significantly elevated levels of a protein called galectin-9 in their blood plasma. Perhaps more importantly, they also found a positive correlation between the levels of galectin-9 and pro-inflammatory cytokines released in the blood, which can lead to a cytokine storm.
 
The study was led by Dr Shokrollah Elahi, associate professor in the School of Dentistry's Division of Foundational Sciences, University of Alberta.
 
Furthering on his prior work with HIV, AIDS and cancer patients, Dr Elahi and his team analyzed the blood plasma of 120 patients with COVID-19.
 
Interestingly they found that levels of galectin-9 were substantially higher in those patients than in individuals with HIV and cancer.
 
Dr Elahi, who is also a member of the Women and Children's Health Research Institute and Cancer Research Institute of Northern Alberta told Thailand Medical News, "We have reported in the past that galectin-9 levels go up in HIV infection and with some cancers. However, when we compared the levels of galectin-9 in the COVID-19 patients to HIV and cancer patients, we could easily distinguish the COVID patients based on the galectin-9 levels."
 
The study findings suggest that galectin-9 levels in the body could be used as a biomarker to diagnose COVID-19 using a patient's blood, potentially providing another non-invasive tool for COVID-19 testing.
 
The galaectin-9 levels could also be used to indicate the severity of the disease, though further study on that aspect is required, Dr Elahi said.

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This new discovery of elevated galectin-9 levels in COVID-19 patients is important because of the positive correlation between the protein and a wide range of pro-inflammatory cytokines.

The massive elevation of plasma Gal-9 discriminates COVID-19 patients from healthy subjects. (A) Detected concentrations of Gal-9 in the plasma specimens of COVID-19-infected individuals compared to healthy controls (HCs) as measured by ELISA. (B) Detected plasma levels of Gal-9 in COVID-19 patients with mild/moderate or severe disease versus HCs. (C and D) Comparing the plasma levels of Gal-9 in total COVID-19-infected females versus males (C) and those with mild/moderate versus severe disease (D). (E) Graph showing the plasma Gal-9 levels in two COVID-19 patients with moderate and two with severe disease 1 day posthospitalization up to 21 days later. (F) The receiver operating characteristic (ROC) curve of comparison between plasma Gal-9 levels in COVID-19 patients (n = 120) and HCs (n = 57). (G) The ROC curve of comparison of plasma Gal-9 levels in COVID-19 patients (n = 120) versus HCs + cancer patients + HIV-infected individuals (n = 161). (H) The ROC curve of comparison of plasma Gal-9 levels in COVID-19 patients (n = 120) versus cancer patients + HIV-infected individuals (n = 103). (I and J) Detected concentration of Gal-9 in culture supernatants of PBMCs (I) and neutrophils (J) from COVID-19 patients or HCs after 6 h of incubation at 37°C as quantified by ELISA. Each point represents data from a patient. Bar, mean ± 1 standard error. AUC, area under curve; ns, not significant. Credit: DOI: 10.1128/mBio.00384-21

Dr Elahi further added, "Cytokines as small cell-signaling proteins are involved in checks and balances in the immune system; they can turn on or turn off some cells to regulate the immune system. In the context of COVID, the problem is that there is a dysregulation of cytokine production ie they are released very quickly in elevated levels. That's what we call a 'cytokine storm.'”
 
Dr Elahi found that galectin-9 is responsible for instructing immune cells to release the pro-inflammatory cytokines quickly in response to COVID-19 infection by binding to immune cells and forcing them to produce the cytokines.
 
Further, as tissues are damaged as a result of inflammation, more galectin-9 is released from the cells, which activates more immune cells and releases more cytokines in a vicious cycle. The resulting cytokine storm damages tissue and organs, causes severe inflammation and can lead to death, Dr Elahi said.
 
Even if patients survive the storm, the dysregulation of the immune system can have ongoing consequences and could be associated with the condition known as post-COVID-19 syndrome or long COVID.
 
Dr Elahi stressed that the next step was to develop treatments that block or inhibit the protein. While there are compounds available that could potentially be used, such as lactose or anti-galectin-9 antibodies, currently there are no treatments on the market specifically for blocking galectin-9 in humans.
 
Dr Elahi said, "We are now looking at expanding our study to a larger cohort of patients, and then working on a proof of concept in animal models. What is killing COVID patients is not the virus; it's the cytokine storm. Therefore, if we can reduce the cytokine storm damage by inhibiting galectin-9, then we can reduce complications, reduce hospitalizations and prevent mortality."
 
Thailand Medical News would like to add that the phytochemicals Apigenin, 7-Isopenthenyloxycoumarin, Arctigenin, Hesperidin, Sulforaphane, 10-Gingerol and Curcumin which are all found in our Therapeutic Teas have all been shown to inhibit galectin-9.
 
https://dalspace.library.dal.ca/bitstream/handle/10222/73604/Hickey_Megan_MSc_MICI_August_2012.pdf?sequence=5&isAllowed=y
 
https://journals.sagepub.com/doi/pdf/10.1177/1559325818796014
 
https://pubs.acs.org/doi/abs/10.1021/acs.jafc.7b00095
 
https://assets.researchsquare.com/files/rs-431391/v1/a6e1d516-a5bc-4633-a5a8-74f86cb8c996.pdf?c=1620415720
 
Read: https://www.thailandmedical.news/news/new-therapeutic-teas-
 
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For more about Galectin-9 and COVID-19, keep on logging to Thailand Medical News.
 
 
 

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