BREAKING! COVID-19 Supplements: UCLA And Beijing Researchers Discover That Antioxidant Enzyme Catalase Could Be Used As An Adjuvant Drug For COVID-19
: Medical researchers from University of California-Los Angeles, Beijing University and also Jinan University in Guangdong- China have discovered that a new stabilized nano-capsulized drug based on the antioxidant enzyme catalase could play a vital part in reducing the inflammation associated with progressive and severe COVID-19 disease.
The research findings have been published on a preprint server but are currently undergoing peer review. https://www.biorxiv.org/content/10.1101/2020.07.15.205211v1
In most COVID-19 patients or following treatment with certain drugs, there is a condition characterized by severe multi-organ damage caused by cytokine overproduction or what is termed as cytokine storm syndrome.
The critical management consists of reducing the excessive levels of inflammation and uncontrolled immune response. This involves immunosuppression as with steroids, intravenous immunoglobulin, and specific drugs targeting one or other of the cytokines involved, such as an IL-6 blocker.
This novel research however takes another route by looking at the possibility of intervening at the secondary level, that is, muting the production of reactive oxygen species (ROS) that correlates with inflammation, organ damage due to oxidative injury to membrane lipids, DNA and protein oxidation, inducing cell apoptosis. Higher ROS levels are also linked to higher levels of viral infection and replication.
The study team tested the use of stabilized catalase that can regulate the level of ROS. ROS are oxygen metabolites that are potent oxidants, mostly generated by the electron transport chain in the mitochondria and cytochrome P450, but also via oxidase enzymes found in many cells, especially endothelium and phagocytes.
Typically, the process of ROS generation begins with superoxide anions, which being unstable are rapidly converted to H2O2 or hydrogen peroxide, via superoxide dismutase (SOD3
). This may be converted to oxygen and water through the enzyme catalase, or to HOCl via myeloperoxidase (MPO), or to water through glutathione/glutathione peroxidase complex (GSH/GPX).
Whenever antioxidant enzymes are deficient, or if ROS are produced in excessive amounts, H2O2 may accumulate in the tissues, causing oxidative protein damage and producing more ROS. Thus, it is important to get rid of this chemical when it is present in large amounts.
The ROS is part of the body’s weaponry against infections, and also an essential part of the body’s signaling mechanism. Its generation is essential to recruiting leukocytes to wounds, to modulate the immune response. Thus, it is needful to mitigate the excessive production of ROS rather than suppress them altogether. This could also restore immune function to normal.
The antioxidant catalase is the most abundant and effective enzyme to break down H2O2. It is commonly found in the liver, red cells, and the alveolar cells of the lung. It is able to decompose 107
molecules of H2O2 within a second. However the problem is that this enzyme is highly unstable.
Stabilization of Catalase For Use As A Therapeutic.
In order to be used as a therapeutic, catalase first has to be stabilized. To do this, the study team enclosed catalase in a thin polymer shell via in situ polymerization, using the monomers 2-methacryloyloxyethyl phosphorylcholine (MPC) and N-(3-aminopropyl) methacrylamide hydrochloride (APM), and N,N’-methylenebisacrylamide (BIS) as the crosslinkers.
This polymerization surrounds each individual molecule of catalase, forming nanocapsules or n(CAT). This protective thin shell structure prevents the enzyme from breaking down but allows H2O2 to pass through readily. Thus, the n(CAT) is supplied in a highly active stage, with excellent stability and a longer half-life.
This stabilized catalase nanocapsule or n(CAT) has better thermal stability, retaining 90% of stability after incubation in buffer at 37oC compared to the native enzyme, and 87% after incubation with trypsin, 100% after storage at 4oC or 25oC, and more than 90% after freeze-drying.
The study team wanted to examine the ability of this new stabilized catalase to prevent oxidative injury in lung tissues, using human lung alveolar epithelial cells. They cultured these cells with n(CAT) at different concentrations and found that they remained viable, ruling out any cytotoxicity.
The team then cultured the cells with n(CAT) followed by the addition of H2O2, when 100% viability was observed after 12 hours. This indicates the protective ability against oxidative injury. In the third step, they cultured the cells with H2O2 and then added n(CAT) to the injured cell culture. The viability, which had dropped to 50% improved to 73%, showing its ability to help damaged cells to regenerate.
The subsequent part of the study was aimed at studying the ability of n(CAT) to regulate cytokine production since excessive cytokine secretion by activated leukocytes is instrumental in inducing hyperinflammation in severe COVID-19.
It was observed that when the white cells were cultured with lipopolysaccharide alone, without n(CAT), the production of TNF-a and IL-10 was significantly higher than when they were cultured with n(CAT). In the latter situation, the cytokine levels were similar to those found with non-activated cells. Thus, this enzyme can act as an immunoregulator as well.
It was also noted that when white cells and H2O2-injured alveolar cells were co-cultured, the viability dropped from 85% to 71%. Adding in n(CAT) restored viability in a dose-dependent manner, from 82% to 91% at doses of 8 to 40 μg/mL. When co-cultured with activated leukocytes, the alveolar epithelial cells showed only 67% viability, but this increased with the addition of n(CAT) in a dose-dependent manner, from 78% to 91%. Thus, n(CAT) protects the alveolar cells from injury by activated leukocytes.
The study team also found that n(CAT) persists in circulation for a longer duration than the native enzyme. When administered intratracheally by nebulization, it is retained mainly within the lung.
Interestingly, the team observed that viral load in rhesus monkeys exposed to the virus intranasally fell rapidly after two days, but in one animal, it fell in just one day. The same was seen with intravenous administration of the virus. Thus, n(CAT) was able to suppress viral replication in rhesus monkeys.
Also, it does not cause toxic changes in the liver or kidney unlike conventional drugs currently being used to treat COVID-19.
Numerous advantages are associated with the use of catalase in the therapy of severe COVID-19. It has anti-inflammatory and protective effects on alveolar epithelium cells in animal models. It is noticeably safe. It is already in use as a food additive and dietary supplement. Its manufacture is feasible, as shown by a pilot project.
Dr Yunfeng Lu from Department of Chemical and Molecular Engineering, Microbiology, Immunology and Molecular Genetics, and the David Geffen School of Medicine, University of California, Los Angeles and corresponding author of te study told Thailand Medical News, “In contrast to the current focus on vaccines and antiviral drugs, this may provide an effective therapeutic solution for the pandemic, as well as treatment of hyperinflammation in general.”
It should be noted that stabilized forms of catalase are also available by certain reputable supplement brands and sometimes in combination with SOD3. Life Extension is one such reputable and highly esteem brand of supplements.
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