key: cord-0916129-lxnk5mlm authors: Das, Undurti N. title: Reply to: Bioactive Lipids and Coronavirus (COVID-19)-further Discussion date: 2020-04-15 journal: Arch Med Res DOI: 10.1016/j.arcmed.2020.04.004 sha: 4dac5dd80325abfa1cc650f7889334204f1af52d doc_id: 916129 cord_uid: lxnk5mlm nan I appreciate the interest shown by Sora Yasri, and Viroj Wiwanitkit on my proposal that bioactive lipids can inactivate Coronavirus (COVID- 19) and thus, may be of significant clinical benefit (1) . The following are the likely actions of bioactive lipids with specific reference to Coronavirus . COVID-19 uses angiotensin-converting enzyme 2 (ACE2) and the cellular protease transmembrane protease serine 2 (TMPRSS2) to enter the target cells. The spike glycoprotein (S protein) of COVID-19 is needed to mediate receptor recognition and facilitate membrane fusion. The S protein is cleaved during the COVID-19 infection into S1 and S2 subunits. S1 contains the receptor binding domain (RBD) that binds to the peptidase domain (PD) of ACE2, whereas S2 is needed for membrane fusion. The ectodomain of the SARS-CoV-2 S protein binds to the PD of ACE2 (2) . ACE2 is a type 1 integral membrane glycoprotein that is expressed and active in most tissues and its highest expression is observed in the kidney, the endothelium, the lungs, and in the heart. Arch Med Res E20_435 2 The renin-angiotensin system (RAS) is a modulator of vascular function and is needed for regulation of blood pressure, natriuresis, and blood volume control. RAS is needed for regulating regional renal blood flow. The RAS has a number of different regulatory components and effector peptides to facilitate the dynamic control of vascular function (Figure 1 ). Angiotensin I (Ang I) is metabolized by angiotensin-converting enzyme (ACE) to form angiotensin II (Ang II) that is metabolized by ACE2 to produce angiotensin (2-8) (Ang 1-7), a vasodilator. Though the focus has been on ACE and Ang II, recent studies showed that ACE2 is needed to maintain the balance of the RAS. Acquired or genetic deficiency of ACE2 leads to an increase in tissue and circulating levels of Ang II and reduced levels of Ang 1-7. Thus, ACE2 controls vasoconstriction and blood pressure. Alternatively, reducing ACE activity can lead to a reduction in the circulating levels of Ang II that suppresses the necessity of ACE2. SARS-CoV-2 (COVID-19) leads to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. It is noteworthy that bioactive lipids inhibit the activity of ACE (3) and thus, may indirectly suppress the expression of ACE2 leading to reduction in the availability of ACE receptors to SARS-CoV-1 (COVID-19) to bind to enter the target cell. The other possibility is that bioactive lipids can get incorporated into the cell membrane phospholipids and alter the membrane fluidity that, in turn, changes the expression of receptors both their number and affinity to the respective proteins (4-6). Thus, it is proposed that supplementation of bioactive lipids can possibly, suppress ACE2 expression and decrease the affinity of SARS-CoV (COVID- 19) to ACE2. Bioactive lipids can induce leakage and lysis of microbial cell membranes, disrupt viral protein surrounding tissues to bring about their antimicrobial action (11, 12) . In this context, the work of Juers JA, et al. (12) in noteworthy. It was reported that alveolar macrophages do not kill in vitro unless the microorganisms have been incubated with alveolar lining material before phagocytosis. The factor that enhanced the microbicidal capacity of alveolar macrophages was found to be present in the lipid fraction of the alveolar lining material, which could be one of the bioactive lipids. These results imply that there is a close interaction/crosstalk between alveolar lining material and alveolar macrophages. This is further supported by the observation that activated macrophages release bioactive lipid to kill tumor cells (13) . The ability of various immunocytes (NK cells, cytotoxic tumor lymphocytes: CTL cells, lymphokine activated killer cells, dendritic cells, leukocytes, etc.,) to release cytotoxic molecules such as perforin and granzyme, cytokines IL-6, TNF-α, and IFN-γ is needed to kill tumor and infected cells. It is noteworthy that NK cells and CTLs induce apoptosis of tumor cells even when perforin, granzyme pathway is inactivated and is dependent on the expression of soluble phospholipase A2 (sPLA2) (14) . This suggests that one additional mechanism by which NK cells and Arch Med Res E20_435 4 CTLs, even if do not secrete perforin and granzyme, induce apoptosis of tumor cells and those that harbor intracellular microbes is by activating sPLA2. It is likely that perforin and granzyme may have the ability to activate sPLA2 that needs to be established. But what is certain is the fact that PLD (phospholipase D) activation is necessary in the CD16-triggered signaling cascade that leads to NK cytotoxic granule exocytosis that, in turn, is associated with AA release (15) (16) (17) . In this context, it is interesting to note that lipids are a constitutive component of cytolytic granules of CTL, NK and γδT cells (18) and cytokine activated macrophages release bioactive lipids to induce apoptosis of tumor cells (13, (19) (20) (21) . To exhibit their functions adequately, macrophages need cooperation of tissue-resident memory CD8+ T cells both for pathogen sensing and rapid protection of barrier tissues (22) It is noteworthy that pro-inflammatory TNF-α and IL-6 inhibit the activities of desaturases that are essential for the generation of AA, EPA and DHA from their precursors LA and ALA respectively (36) . Hence, in instances where there is substantial degree of inflammation due to high levels of IL-6 and TNF-α (as it may happen in it may lead to a deficiency of AA, EPA and DHA and decreased generation of LXA4, resolvins, protectins and maresins due to their precursor deficiency. AA, EPA, DHA, LXA4, resolvins, protectins and maresins are potent suppressors of IL-6 and TNF-α formation. Thus, there appears to be a delicate balance maintained between PUFAs and their metabolites and pro-inflammatory cytokines (7) . This suggests that administration of PUFAs and their metabolites LXA4, resolvins, protectins and maresins suppress inappropriate production of IL-6 and TNF-α to resolve inflammation and enhance recovery and also prevent cytokine storm (17) that may occur in COVID-19. AA is the precursor of both prostaglandin E2 (PGE2) and LXA4. In general, it is believed that PGE2 is pro-inflammatory whereas LXA4 is an anti-inflammatory molecule. But, under some very specific conditions PGE2 shows anti-inflammatory actions and is highly beneficial (37, 38) . This antiinflammatory action of PGE2 seems to depend on its ability to enhance LXA4 formation (38) . This suggests that once the inflammation reaches a peak in which PGE2 plays a significant role, the metabolism of AA is redirected to form LXA4 instead of PGE2 indicating a crosstalk between PGE2 and LXA4. This switching of AA metabolism from PGE2 to LXA4 (and probably vice versa, if need be) appears to be a crucial event in the resolution of inflammation in which anti-inflammatory cytokines play a role (39) . In this context, it is interesting to note that 15-PGDH-(15-prostaglandin dehydrogenase, a prostaglandin degrading enzyme) deficient mice showed a twofold increase in PGE2 levels in several tissues including bone marrow, colon, and liver, increased fitness of these tissues with enhanced hematopoietic capacity. These 15-PGDH animals not only had rapid liver regeneration after partial hepatectomy but also showed accelerated recovery of neutrophils, platelets, and erythrocytes (40) . These results are supported by other studies which showed that PGE2 regulates haematopoietic stem cell homeostasis, promotes wound healing and tissue regeneration and modulates stem cell trafficking, events that ultimately promote hematopoiesis (41) (42) (43) (44) . These It has been reported that mortality due to SARS-CoV-1 (COVID-19) infection is higher in those with diabetes mellitus, hypertension and cardiovascular diseases and the elderly. Previously, we showed that plasma levels of AA and other bioactive lipid shave been shown to be low in diabetes mellitus, hypertension and coronary heart disease (45) and plasma LXA4 levels, a potent anti-inflammatory bioactive lipid, fall with age (46) that may explain adverse outcome in them. Furthermore, it has been shown that it is safe to administer GLA and AA intravenously (47) and oral supplementation of AA enhances LXA4 formation with little or no change in PGE2 formation (that shifts the balance more towards anti-inflammatory events) without increasing the severity of underlying condition with no adverse events (48) (49) (50) . Previously, we showed that bioactive lipids (especially AA) have cytoprotective actions against many chemicals, prevents both alloxan and streptozotocin-induced apoptosis of pancreatic β cells and ameliorate development of both type 1 and type 2 diabetes mellitus that is associated with suppression of inflammation and increase in the formation of LXA4 (51) (52) (53) (54) (55) (56) (57) . It is evident from the preceding discussion that bioactive lipids especially AA had many beneficial actions that may be of benefit in the prevention and management of SARS-CoV-1 (COVID- 19) infection and other enveloped viruses. Bioactive lipids are useful in view of their ability not only to Arch Med Res E20_435 8 inactivate enveloped viruses but also several other harmful microbes, enhance macrophage phagocytic capacity, augment wound healing and tissue regeneration, promote hematopoiesis and protect normal cells from both endogenous and exogenous cytotoxic agents with relatively few adverse actions. Hence, efforts need to be made to test their efficacy in SARS-CoV-1 (COVID- 19) infection. It is possible to deliver bioactive lipids orally, parenterally and as nasal drops. Can Bioactive Lipids Inactivate Coronavirus (COVID-19) Structural basis for the recognition of the SARS-CoV-2 by fulllength human ACE2 Effect of cis-unsaturated fatty acids, prostaglandins and free radicals on angiotensin converting enzyme activity in vitro Insulin resistance and hyperinsulinemia: Are they secondary to an alteration in the metabolism of essential fatty acids? GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus Activity of bradykinin B2 receptor is regulated by long-chain polyunsaturated fatty aAcids Arachidonic acid and other unsaturated fatty acids and some of their metabolites function as endogenous antimicrobial molecules: A review Effects of acetate and other short chain fatty acids on sugar and amino acid uptake of Bacillus subtilis Unsaturated fatty acid requirement in Escherichia coli. Mechanism of palmitate-induced inhibition of growth by strain WNl Inhibitory action of a nonmetabolizable fatty acid on the growth of Escherichia coli. Role of metabolism and outer membrane integrity The function of human alveolar macrophages Enhancement of bactericidal capacity of alveolar macrophages by human alveolar lining material Role of macrophage lipids in Arch Med Res E20_435 10 regulating tumoricidal activity Apoptosis inducing factor of a cytotoxic T cell line: involvement of a secretory phospholipase A2 Beta 1 integrin crosslinking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells: role of phospholipase D in CD16-triggered degranulation 20-Hydroxyeicosatetraenoic acid mediates angiotensin ii-induced phospholipase D activation in vascular smooth muscle cells Can bioactive lipid(s) augment anti-cancer action of immunotherapy and prevent cytokine storm Lipids are a constitutive component of cytolytic granules Role of membrane lipids in the immunological killing of tumor cells, II. Effector cell lipids Role of membrane lipids in the immunological killing of tumor cells, I Role of macrophage lipids in regulating tumoricidal activity. II. Internal genetic and external physiologic regulatory factors controlling macrophage tumor cytotoxicity also control characteristic lipid changes associated with tumoricidal cells Salivary gland macrophages and tissue-resident CD8+ T cells cooperate for homeostatic organ surveillance Organ-specific isoform selection of fatty acid-binding proteins in tissue-resident lymphocytes Specific repair by discerning macrophages Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection Resolvin D3 multi level proresolving actions are host protective during infection The protectin PCTR1 is produced by human M2 macrophages and enhances resolution of infectious inflammation Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production Effects of Lipoxin A4 on antimicrobial actions of neutrophils in sepsis Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition HLA-DR expression, cytokines and bioactive lipids in sepsis Current and emerging strategies for the treatment and management of systemic lupus erythematosus based on molecular signatures of acute and chronic inflammation Is sepsis a pro-resolution deficiency disorder? In vitro mimicry of essential fatty acid deficiency in human endothelial cells by TNFα impact of ω-3 versus ω-6 fatty acids Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production Current and emerging strategies for the treatment and management of systemic lupus erythematosus based on molecular signatures of acute and chronic inflammation Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration Apoptotic cells activate the "Phoenix Rising" pathway to 45. promote wound healing and tissue regeneration Differential stem-and progenitor-cell trafficking by prostaglandin E2 Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease Aging is characterized by a profound reduction in anti-inflammatory lipoxin A4 levels n-6 Polyunsaturated Fatty Acids Enhance the Activities of Ceftazidime and Amikacin in Experimental Sepsis Caused by Multidrug-Resistant Pseudomonas aeruginosa Dietary supplementation of arachidonic acid 52. increases arachidonic acid and lipoxin A4 contents in colon but does not affect severity or prostaglandin E2 content in murine colitis model Dietary supplementation with arachidonic acid increases arachidonic acid content in paw but does not affect arthritis severity or prostaglandin E2 content in rat adjuvant-induced arthritis model Supplementation of arachidonic acid-enriched oil increases arachidonic acid contents in plasma phospholipids but does not increase their metabolites and clinical parameters in Japanese healthy elderly individuals: a randomized controlled study Protective action of arachidonic acid against alloxan-induced cytotoxicity Arch Med Res E20_435 16 and diabetes mellitus Long-chain polyunsaturated fatty acids and chemically-induced diabetes mellitus: Effect of ω-6 fatty acids Long-chain polyunsaturated fatty acids and chemically-induced diabetes mellitus: Effect of ω-3 fatty acids Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo Arachidonic acid and lipoxin A4 attenuate streptozotocininduced cytotoxicity to RIN5F cells in vitro and type 1 and type 2 diabetes mellitus in vivo Amelioration of streptozotocin-induced type 2 diabetes mellitus in Wistar rats by arachidonic acid BDNF and lipoxin A4 inhibit chemical-induced cytotoxicity of RIN5F cells in vitro and streptozotocin-induced type 2 diabetes mellitus in vivo. Lipids Health Dis 2019, humoral balance, inflammation, cell proliferation, hypertrophy ACE2 may play a role in regulating cardiovascular and renal functions and fertility ACE catalyzes angiotensin I (AngI) to convert to the potent vasoconstrictor angiotensin II (AngII), whereas ACE2 cleaves Ang I to produce inactive angiotensin 1-9 peptide (Ang 1-9 Ang 1-7 acts on the Mas receptor to exert cardiovascular protection of diastolic blood vessels, anti-inflammatory, anti-proliferation, anti-fibrosis, anti-alveolar epithelial cell apoptosis, and anti-oxidative stress, thereby antagonizing the biological effects of Ang II