1. Introduction
The β coronavirus pandemic, named severe acute respiratory syndrome coronavirus 2 infection (COVID-19), has led to calls to identify effective drugs to treat the disease [1]. The COVID-19 strategy for treating severe diseases is inextricably linked to the development of registered medicines for this new therapeutic indication [2,3].
Most COVID-19 patients have a mild to moderate condition, while some have progressed to a critical condition. SARS-CoV-2 virus mainly affects the lungs, causing respiratory failure and secondary hypoxemia in one-fifth of hospitalised patients [4,5]. Severe illnesses may be associated with cardiovascular complications, thrombus formation, septic shock or acute kidney injury [6,7,8]. SARS-CoV-2 exacerbates disease progression and organ damage due to an uncontrolled immune response in a “cytokine storm” [9,10,11]. Autopsy studies have shown that SARS-CoV-2 RNA has been detected in cells from the lung, trachea, kidney, liver, brain, intestine, testis and blood tissues, indicating SARS-CoV-2 multiorgantropism [12,13,14]. Pathological changes were in arterioles/venules, capillaries and medium-sized blood vessels of the affected organs, mainly due to the accumulation of lymphocytes, plasma cells and macrophages around the endothelial cells: endotheliitis leads to cell apoptosis, tissue edema, thrombotic microcirculatory pathology, vasoconstriction and ischemia [7,14].
The meta-analysis of published global cases (analysed 107 reports from around the world) shows that men and women are at equal risk of SARS-CoV-2 infection. Men have a higher risk of severe COVID-19 are three times more likely to be treated in an intensive care unit [15]. Male mortality is elevated in all age groups and most pronounced in middle age [16,17]. A study of 17 million adults confirms a significant association between male sex and the risk of death from COVID-19 [18,19,20,21].
The median viral RNA content of nasopharyngeal swabs and saliva was higher in men than women [22]. Sex-specific immune reactions are thought to determine the progress of COVID-19 [23]. Sex-driven differences are based on a women’s more effective early adaptive immune response [24,25,26,27]. Sex-related disparities in disease progression may be due to estrogen-induced reduced expression of the angiotensin-converting enzyme 2 (ACE2) receptor [28,29], which serves as a gateway for SARS-CoV-2 to enter the target cell [30,31,32].
The novel bioinformatic approach includes a wider range of clinically approved drugs so that more possibilities are allowed for them to repurpose against COVID-19 [33]. One such drug is valproic acid (2-n-propyl-pentanoic acid; VPA) [34]. VPA is a histone deacetylases (HDACs) inhibitor [35]. VPA is a commonly prescribed antiepileptic drug [36], which is also used to treat bipolar disorder [37], schizophrenia and various forms of headache [38,39,40]; it is an investigational anti-cancer preparation as an immune modulator [33,41]. VPA has an extensive research history in treating various viral infections [33,42]. VPA has been used in clinical practice for six decades, and has a well-known safety profile, as well as therapeutic serum concentrations that make it an attractive drug for adjunctive therapy in off-label settings.
Research of sex-specific features may lead to a new approach to the COVID-19 treatment. This review aims to evaluate VPA as a potential medicine for the treatment of COVID-19 and to elucidate the possible biological sex-related mechanisms of pharmacology, to review VPA as a potential drug to prevent the progression of COVID-19 and to provide personalised treatment of the disease.
2. VPA Metabolism and Sex
VPA is completely absorbed; bioavailability is ≥80% [43]. VPA molecules are 87–95% bound to plasma proteins, resulting in low drug clearance [44]. The free form of VPA crosses the cell membrane [43]. VPA peak time in plasma is 4 h; the half-life is 11–20 h, and depends on the drug formulation [45]. With continuous oral administration, the plasma concentration of VPA is 280–700 μmol/l [43]. In adult humans, the main metabolic pathways of VPA are 50% glucuronidation, 40% mitochondrial β-oxidation and a small fraction by cytochrome P450-mediated oxidation [44]. Urinary excretion of intact VPA is <3% [43].
The G protein system (MRP) is involved in the intracellular transport of VPA; drug transport via G protein substrates is higher in females than in males of experimental animals and humans [46,47], as testosterone down-regulates the drug transport [48]. Hepatobiliary transport of VPA, bypassing hepatic metabolism and subsequent reabsorption from the duodenum after biliary excretion, is stronger in females. The proportion of the bioavailable dose of VPA reabsorbed was 2.1-fold lower in males than in females, indicating a significant difference in hepatobiliary drug transport [49]. In males, due to lower expression of efflux pumps, a saturation of hepatobiliary transport results in longer retention of VPA in the hepatocyte, leading to expantion in VPA clearance [50]. In women using hormonal contraception, the pharmacokinetic parameters of VPA were similar to those in men [49].
3. SARS-CoV-2 Virus and VPA
The docking, binding energy calculation determines that VPA metabolite 4-ene-VPA-CoA creates a stable interaction with nsP12 of SARS-CoV2 RNA polymerase and VPA-CoA could specifically inhibit the target. SARS-CoV-2 RNA polymerase is an enzyme playing in viral RNA replication and the virus’s survival in a host [51,52]. The SARS-CoV-2 virus x-ray crystal structure of a critical protein in the virus’s life cycle is the central protease (Mpro, 3CLpro) [53,54,55]. The Mpro importance recognises Mpro as a target for antiviral drugs, designed as a virus 3CLpro inhibitor, for COVID-19 therapy [56,57]. HDACs’ inhibitors are tightly bound into the active site of the crystallographic virus Mpro structure [58]. The SARS-CoV-2 protease NSP5 interacts with the HDAC2. Researchers predict that NSP5 may inhibit the transportation of HDAC2 into a nucleus, and could affect the HDAC2 strength to interfere with the interferon response and inflammation [59,60]. Experimental studies show that the binding of HDAC2 to the promoters was lower in females than in males [61]. The HDAC2 activity can not only be modulated by VPA binding to the catalytic center, but the HDAC2 protein level is susceptible to selective regulation by VPA [62]. VPA blocks the zinc-containing catalytic domain of HDACs [63]. VPA treatment reduced HDAC2 level in male rats’ brain frontal cortex tissue, but no VPA effect was for HDAC2 protein in females [64].
4. Sex-Related AEC2 Expression and VPA Effect
The SARS-CoV-2 virus connects to the cell membrane-bound ACE2, a functional receptor for SARS-CoV-2, to mediate virus entry into human cells [65,66]. The binding capacity of the virus S protein to the ACE2 receptor was 10–20-fold higher than that of other SARS-CoV [67]. ACE2 is a single-pass type I membrane protein with an active domain exposed on the cell surface in the lung, kidney, arteries, heart and intestine tissue [68,69,70]. The ACE2 gene is encoded in the X chromosome [34,71]; this may counteract X-inactivation in women [72]. Male cells always hold an X chromosome, and display a single ACE2 allele. The female X chromosomes mosaicism is related to the heterogenic ACE2 allele given among cells. A potentially more efficient form of ACE2 receptor would have half all cells in females; therefore, some alleles of this gene may code for the receptors with different efficiency of binding SARS-CoV-2 virus, providing them a partial resistance to the COVID-19 infection [73]. A lower ACE2 tissue expression was observed in women than men [32,74,75]. ACE2 activity is lower in older women than in young ones, while the same does not happen in males [75,76]. ACE2 protein expression in the lung was higher in adult non-smoking males than women [32]. In male smokers, it was more increased than in female smokers, and there was a notably elevated ACE2 level in nasal and bronchial airways cells of male smokers [77,78,79]. Testosterone increases ACE2 levels, whereas estrogens maintain suppressed expression of ACE2 [29,80,81]. Pharmacologic intervention with an androgen receptor antagonist significantly suppressed ACE2 expression in male mice’s lungs [77]. VPA down-regulates ACE2 gene expression [82]. The treatment of human umbilical vein and human coronary artery endothelial cells with VPA in vitro significantly reduced ACE2 expression [82].
5. Virus Entry into Cell and VPA
Co-expression of ACE2 and the transmembrane serine protease 2 (TMPRSS2) receptor is required for SARS-CoV-2 infection of cells [68]. Human lung tissue, type I and II alveolar epithelial cells, arterial and venous endothelial cells, cardiomyocytes, arterial smooth muscle cells expressing ACE2 are targets for the SARS-CoV-2 virus [70]. VPA can reduce ACE2 in endothelial cells [77,83]. TMPRSS2 is highly expressed in lung tissue cells, and makes the respiratory system susceptible to the virus [84]. The cell-surface TMPRSS2 is operated for virus-S protein priming and the activation of membrane fusion processes for the SARS-CoV-2 [68,85]. TMPRSS2 is potentially the most promising target for COVID-19 therapy, as its specific expression in the alveolar cells [86]. VPA reduces the expression of TMPRSS2 [86]. TMPRSS2 is upregulated by androgens [87], and could appear linked to the increased risk of COVID-19 infection in men [8]. There was no sex-related difference in TMPRSS2 expression in humans or mice’s lungs [77]. TMPRSS2 inhibitors are effective against the SARS-CoV-2 [68]. VPA reduced TMPRSS2 expression in prostate cancer cells [88]. After the virus is connected to ACE2, the ACE2 extracellular domain controlling the catalytic effect is cleaved by ADAM-17 (a disintegrin and metalloproteinase-17), enabling viral transport to the cytoplasm [89]. TMPRSS2 competes with the ADAM17 for ACE2 processing [85]. The enhanced activity of ADAM17 in males was reported [90]. ADAM-17 cleaves ACE2 bearing membrane and releases soluble ACE2 (sACE2) into the circulation [91]. The sACE2 retains activity, and can partially block SARS-CoV-2 binding to ACE2 of the target cell membrane; sACE2 could reduce viral replication [92]. Cigarette smoking causes decreased sACE2 blood levels [93].
6. Sex-Related COVID-19 Infection Progression Mechanisms and VPA
Due to the high viral infection load, membrane ACE2 and its mRNA expression are significantly diminished in COVID-19 patients [69,94,95,96]. At a later COVID-19 infection stage, down-regulated ACE2 in tissues may worsen the imbalance in the renin-angiotensin system (RAS). ACE2 has a protective effect through RAS regulation [97], and protects against RAS-mediated activations of harmful effects [69,98]. Depleting ACE2 in tissue cells leads to an increase in angiotensin II (Ang II) blood serum level and the activation of the AT1 receptors, which would activate ADAM17 more. The ACE2 expression is transcriptionally suppressed due to AT1 activation [99]. Increased Ang II levels act as a vasoconstrictor and a pro-inflammatory molecule through AT1 [100]. ACE2 knockout results in pathology similar to the acute respiratory distress syndrome in mice [101]. The ACE2 molecule reduces RAS activity by converting Ang II into Ang 1–7 [102,103,104], decreasing Ang II level and the AT1 activation, which manages reduced pathological inflammation effects in tissues [69,105,106]. Sex distinctions of the RAS in response to stimulation and inhibition of the system have been reviewed [81,107,108]. Higher levels of ANG (1–7) in women may inhibit the harmful effects of ANG II and its activation [109]. Compared with female rats, males have higher AT1 receptor RNA, higher AT1 protein levels, higher receptor density in kidneys and ∼40% higher specific AT1 binding in the glomeruli than females. These differences are 17β-estradiol (E2) dependent [81,108,110]. Activation of AT1 mediates ANG II’s biological functions, such as sodium reabsorption, vasoconstriction, increased oxidative stress and inflammation [111,112]. VPA, inhibiting HDAC1 and HDAC2, down-regulates Ang II and AT1 activity [113,114]. VPA reverses the ANG II-induced increment of HDAC2 RNA and protein levels in cardiomyocytes [115]. Anti-hypertensive action of VPA is mediated by the inhibition of HDAC1 via acetylation processes [113,116].
7. Pre-Clinical Research of VPA Efficiency on Inflammation Mechanisms
7.1. VPA Effectiveness by Experimental Models In Vivo
As a multifunctional regulator of innate and adaptive immune cells, VPA reduces macrophage infiltration in various models of inflammation (Table 1). VPA attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen and the infiltration of macrophages into the kidney [117]. VPA significantly reduced cigarette-smoke-induced neutrophil influx in the female Balb/c mice lung inflammation model, working as the endopeptidase (PE) inhibitor and potentially serving as therapeutic in inflammatory lung disorders, causing a decline in neutrophil infiltration in the bronchoalveolar fluid in a chronic lung inflammation model in female A/J and Balb/c mice [118]. VPA impaired M1 macrophage proliferation while promoting the accumulation of M2 macrophages in the Wistar male rats lung injury model with the lessened inflammation and enhanced tissue repair [119]. VPA can attenuate acute MAP kinase activation in the lung in a sublethal model of hemorrhagic shock reduces pulmonary neutrophil infiltration 20 h after blood loss [120]. In female BALB/c mice LPS-activated dendritic cells (DCs), VPA caused the decreased TNF-α, IL-1α, IL-1β, IL-1RA, IL-6, IL-7, IL-10, IL-12p40, IL-12p70, IFN-γ and TGF-α production. VPA was lowering immune cells’ capacity to induce a pro-inflammatory response may offer new therapeutic options for managing septic shock [121]. VPA attenuated the clinical severity of Coxsackie B3 virus (CVB3) myocarditis, and mortality from CVB3-induced myocarditis of BALB/c male mice, decreased the percentage of splenic Th17, increased the rate of Treg cells, downregulated the IL-17A expression, upregulated IL-10 in serum and heart tissues of CVB3 infected mice, inhibited the differentiation of the Th17 cells and promoted the differentiation and suppressive function of Treg cells [122]. In the mouse NIH3T3/BL6 post-operative inflammation model of conjunctival scarring, VPA repressed the CD45highF4/80low macrophage subset, repressed the CXCL1, IL-5, IL-6 and IL-10, tissue NF-кB2 p100 protein generation in males and females [123]. VPA decreases macrophages infiltration, apoptotic cell death and caspase 3 activation, reduces the lesion volume, improves active recovery after rat male spinal cord injury, improves functional recovery by attenuating the blood-spinal cord barrier after spinal cord injury by inhibition of MMP-9 activity [124]. In the acute colitis model, disease amelioration by VPA was associated with prevention from weight loss, a decrease in histological signs of inflammation, suppression of the pro-inflammatory cytokines IFN-γ and IL-6 [125]. In the female C57BL/6 mouse model, VPA diminished CD4+ T-lymphocyte infiltrates, associating with caspase 3-mediated apoptosis [126]. VPA reduces pro-inflammatory cytokines and reactive oxygen species (ROS) levels and attenuates rat’s multiple organ damages induced by LPS-provoked septic shock due to the recovery of histone H3 acetylation, including: attenuated alanine aminotransferase, aspartate aminotransferase, urine nitrogen, creatinine serum level and decreased TNF-α and myeloperoxidase levels in lung tissue of male rats [127]. VPA treatment improves early survival, lung, liver and brain function in highly lethal poly-trauma and male rat hemorrhagic shock models [127,128]. VPA inhibited by 92% leukocytes migration to the peritoneal cavity in a male rat peritonitis-induced model by decreasing TNF-α and IL-1β, IL-6 levels and ROS generation, and the effect was similar to indomethacin force [129]. In the ischemic kidney/reperfusion injury rat model, VPA-treated male rats show a significant increase in blood IL-10 and TGF-β mRNA levels, a direct correlation between IL-1β and TNF-α mRNA expression and IL-10 with TGF-β levels indicating the anti-inflammatory VPA effect, histopathology showed decreased kidney ischemic changes and the reduced serum creatinine level in VPA-treated animals [130].
7.2. VPA Effectiveness by Experimental Studies In Vitro
VPA drastically inhibited the multiplication of the enveloped viruses (zoonotic lymphocytic choriomeningitis, West Nile viruses). While it did not affect infection by the non-enveloped viruses, VPA abolished West Nile RNA and protein synthesis, indicating that VPA can interfere with the viral cycle at different steps of enveloped virus infection. VPA reduced vesicular stomatitis virus infection [135]. VPA reduces the production of TNF-α, IL-6 in female BALB/c mice bone marrow-derived macrophages [121]. VPA polarises mouse macrophage cell line RAW264.7 and primary mouse bone marrow macrophages (BMMs) of C57BL/6 and BALB/c female mice from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype [137]. VPA inhibited macrophage-mediated T helper 1 (Th1) effector, enhanced Th2 effector cell activation affects the macrophage function, repressed the production of IL-12 and TNF-α by LPS-induced macrophage activation, and promoted IL-10 expression. VPA also affected the costimulatory molecule expression on LPS-stimulated RAW264.7 and BMMs; it downregulated CD40 and CD80 and upregulated CD86 [137]. VPA effect on LPS-induced inflammatory response in mouse RAW 264.7 macrophage-like cells shows that VPA down-regulates LPS-induced NF-κB-dependent transcriptional activity via impaired PI3K/Akt/MDM2 activation and enhanced p53 expression [140]. The VPA-treated fibroblasts resulted in diminished CCL2, VEGF-A, IL-15 levels and in the presence of TNF-α, VPA inhibited the induction of CCL5 and VEGF-A and NF-кB2 p100 level [123]. VPA in human monocyte-derived macrophages (MDMs) infected with Dengue virus (DENV) reduced secretion of IL-8, IL-1b, IL-6, TNF-α and IL-10. Researchers suggest VPA modulates the cytokine storm associated with DENV disease and prevents progression to severe illness [134]. VPA inhibits NF-kappaB activation induced by LPS, inhibited LPS-induced production of TNF-alpha and IL-6 by human monocytic leukemia THP-1 cells [141]. VPA repressed the healthy volunteers’ monocyte differentiation into DCs, and disturbed the DCs differentiation and maturation [142]. VPA-treated healthy blood donors T CD8+ lymphocytes show a decrease in cellular proliferation [139].
8. VPA and Mitochondrial Function of Immune Cells
Mitochondria functions range from supplying energy activation of anti-viral and anti-inflammatory mechanisms [143]. The mitochondria may be affected by the SARS-CoV-2 main protease NSP5. NSP5 interacts with tRNA methyltransferase 1 (TRMT1); its gene is responsible for transferring a methyl group onto a guanine residue in mitochondrial tRNAs [60,144]. The TRMT1 cleaved by NSP5 leads to removing the TRMT1 zinc finger. TRMT1 knockout leads to increased sensitivity to oxidative stress [3,60]. Cells with decreased TRMT1 activity exhibit increased endogenous ROS production [60,144]. In male and female tissues, there was no significant difference in the expression of RNA TRMT1 [145]. VPA decreases oxidative stress by enhancing the enzymatic antioxidant system [146].
VPA metabolites significantly decrease pyruvate-driven oxidative phosphorylation in mitochondria by conflict with pyruvate transport, thus settling mitochondrial energy production [147]. VPA treatment significantly reduced SLC5A8 gene expression in gonad-intact and castrated male rat thymocytes, while in gonad-intact female rat thymocytes, VPA significantly increased gene expression. Higher SLC5A8 gene expression was found in thymocytes of gonad-intact male rats than in corresponding female rats [133]. SLC5A8 has a physiological function transporting short-chain fatty acids into the cell and regulates mitochondrial metabolism [148,149]. SLC5A8 activity has immunomodulatory effects by blocking the development of dendritic cells, making SLC5A8 essential for immune homeostasis through the release of cytokines [150,151]. SLC5A8 induces cell apoptosis by inhibiting pyruvate-dependent HDACs [152]. Inhibition of the SLC5A8 gene is associated with DNA methylation, and treatment with DNA demethylating agents increases SLC5A8 gene expression [153]. VPA can activate SLC5A8 genes regulated by DNA methylation [154,155]. VPA through mitochondria affecting immune cell metabolism, immune-related functions could polarise the pro-inflammatory M1 phenotype of macrophage to the anti-inflammatory M2, which is unable to induce naïve T CD4+ differentiation into a Th1 profile, favouring a Th2 phenotype by changing the kind of respiration from the down TCA cycle to β-oxidation [137,156,157]. Further research needs to examine how VPA-induced sex-specific changes in SLC5A8 capacity influence immune cell function.
9. Sex-Related Differences of Immune Response and COVID-19
Gonad hormones affect the immunological response, with the estrogens being both pro-inflammatory and anti-inflammatory [158,159]. Testosterone has a suppressive impact on immune function [160]. The Y and X chromosomes modulate the immunity in COVID-19 infection [73]. The differentiation and maturation of innate immune cells, like neutrophils, macrophages, dendritic cells, natural killer cells and T cells, are modulated by gonad hormones [161]. The number of innate immune cells, including monocytes and macrophages, is higher in females [162,163]. Males have lower CD4+ and CD3+ cell counts, CD4+/CD8+ cell ratio than females [164,165,166,167]. Females exhibit higher cytotoxic T cell activity and increased expression of antiviral genes [25]. The immune cells Toll-like receptor 7 (TLR7) detects single-stranded RNA viruses. The TLR7 gene is encoded in the X chromosome. Higher expression of TLR7 level in females may serve to escape antiviral genes inactivation [168,169,170]. The 17β-estradiol (E2) regulates various physiological and pathophysiological changes in DNA by epigenetic mechanisms; E2 and VPA mediate immune responses and autoimmunity in women [171,172]. Sex-related differences in the immune response have been reviewed extensively [22,173]. In males over females, innate inflammatory cytokines and chemokines increase throughout the COVID-19 course [22]. COVID-19 severe patients exhibit substantially elevated plasma levels of pro-inflammatory cytokines [174,175], and activation of the release of cytokines may lead to cytokine storm [174,176] and multiple organ failure [177]. Thrombosis is indistinguishable from acute respiratory distress syndrome (ARDS) with micro-and macro-thrombosis [178]. VPA mitigates the inflammation and prevents acute respiratory distress syndrome in a murine model of Escherichia coli pneumonia [131].
10. COVID-19 Thrombotic Complications and VPA
10.1. SARS-CoV-2 and Sex-Related Thrombotic Complications
The pathophysiology of COVID-19 complications is characterised by clinical features of thrombosis and disseminated intravascular coagulopathy in the airways, myocardium, kidneys, brain and other organs [179]. Thrombosis is found in approximately 30% of COVID-19 hospitalised patients [180]. The incidence of thrombosis in COVID-19 is higher in men than in women and explains the higher mortality in men [181]. In an analysis of 29 studies, 70% of all thromboembolic events occurred in men and 30% in women [182]. Viral invasion due to severe vascular endothelial damage triggers the coagulation cascade, impairs fibrinolytic activity, releases von-Willebrand factor [13], increases total cytokine release, activates platelets and the complement system and generates thromboxane [183,184]. SARS-CoV-2 can directly activate coagulation via the viral Mpro; the active site of Mpro is structurally similar to the active site of FXa and thrombin and can therefore activate coagulation [185]. The development of thrombosis has been attributed to the direct effects of the virus by increasing the levels of pro-inflammatory cytokines and pro-inflammatory M1 macrophages, by activation of the complement system and by endothelial dysfunction, leading to disseminated intravascular coagulopathy [186,187,188,189]. Endothelial dysfunction and its association with thrombosis have been implicated in SARS-CoV-2-induced target organ damage [190]. VPA binding to SARS-CoV-2 Mpro is expected to inhibit Mpro pathways [191]. Older men with hypertension, chronic kidney disease, coronary disease, diabetes mellitus and obesity are at increased risk of thrombotic complications [192,193,194]. Changes in plasma levels of D-dimer, von Willibrand factor (vWF), fibrinogen, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 antigen (PAI-1) antigen are associated with poorer outcomes in COVID-19 patients [195,196,197,198].
10.2. VPA Effect on Thrombosis Mechanisms, COVID-19
The VPA effects on thrombogenesis have been explored in pre-clinical studies and during the treatment of patients with VPA (Table 2). HDAC inhibitors have reduced platelet counts and inhibit platelet function [199,200], while other VPA experimental and clinical trials did not find such effects [201,202]. The baseline platelet count was similar in women and men. A causal relationship between prolonged use and rising plasma VPA levels and reduced platelet counts, with reversal of thrombocytopenia after reduction of VPA dosage, was reported: that of thrombocytopenia substantially increased at VPA levels above 100 ug/mL in women and above 130 ug/mL in men; women were significantly more likely to develop thrombocytopenia [203]. There is a significantly higher female overrepresentation in heparin-induced thrombocytopenia, with females at approximately twice the risk of thrombocytopenia than males. However, the underlying mechanism for this sex difference is unclear [204]. VPA may affect several different coagulation factors: decrease in von Willebrand factor:antigen (vWF:Ag) concentration [205,206]; protein C level [205,207], protein S level [207,208], antithrombin III level, decrease prothrombin time [205,206] and increase activated partial thromboplastin time [205,206,207].
SARS-CoV-2 activates the complement system, either directly or through an immune response. Activated complement promotes inflammation [212]. Complement activation is increased and constant in severely ill COVID-19 patients, and complement activation is via the alternative pathway (AP) [213]. The anaphylatoxins C3a and C5a are significant contributors to the cytokine storm syndrome [214]. The healthy adult population is characterised by substantial sex-related differences in complement levels and function: significantly lower AP activity was in females than males. AP revealed lower C3 levels in women [215]. In experimental intestinal ischemia with an acute inflammatory response, complement activity was sex-dependent: female MBL-/- and P-/- mice had significantly less C5a in their serum than males [216]. Experimental results indicate that lysine acetylation by VPA is associated with attenuated C3 gene expression. VPA-associated reductions in circulating complement and clotting factors result from changes in liver-specific gene expression [209]. VPA inhibits intercellular adhesion molecule-1 (ICAM-1) and E-selectin [83,211]. Analysis from patients hospitalised with COVID-19 showed higher circulating VCAM-1 and E-selectin levels in men than women [217]. The endothelial cell adhesion molecules elevated levels promote tissue infiltration of circulating leukocytes and are associated with inflammation and thrombosis, which occur at a higher frequency in males [218]. VPA reduced endothelial cell dysfunction through the mechanisms of action of transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) in a porcine model of ischemia-reperfusion of hemorrhagic shock [219]. Inhibiting TGF-β activity, VPA alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo [132]. Estradiol has been shown to decrease TGF-β1 synthesis [220]. VPA inhibiting IL-12 and TNF-α, reversing macrophage polarisation from pro-inflammatory to the anti-inflammatory type, and reducing macrophage infiltration reduces the risk of thrombosis [117,137].
10.3. VPA and Fibrinolysis
Treatment with VPA in a rat thrombosis model reduced thrombus formation and did not increase bleeding tendency [201]. VPA can selectively manipulate the fibrinolytic system to reduce thrombus formation in blood vessels in vivo. In a murine model of thrombosis induced by intravascular injury, VPA treatment increased t-PA production in blood vessels [201,210,221,222,223] was associated with less fibrin accumulation and fewer thrombi [201,224]. Impaired fibrinolysis, due to reduced t-PA production and depleted storage or increased expression of a significant inhibitor of fibrinolysis PAI-1 [225,226], has been reported in coronary heart disease patients with cardiovascular risk factors, such as hypertension and obesity [227,228,229,230,231]. A clinical trial of VPA treatment showed a significant reduction in PAI-1 and signs of improvement in fibrinolysis, favourably altered the balance between t-PA and PAI-1, and the dose of VPA treatment was significantly lower than the usual dose of VPA for epilepsy [202,223,224]. Thus, VPA could be a potential alternative for preventing thrombotic events based on improved endogenous fibrinolysis [202].
11. Discussion
Sex-related differences in the COVID-19 progression and complications rate suggest that sex biological factors are important in the pathogenesis of COVID-19. Identifying the association of sex-specific factors with associated differences in risk of COVID-19 unfavourable outcome is essential for the development of effective personalised treatment. Detailed knowledge of the mechanisms underlying the differences in immune response between women and men, which may also be related to the risk of thrombotic complications, should lead to new therapeutic strategies.
In this review, we could not provide more detailed information on sex differences in the effects of VPA, as most of the studies involved animals only of one sex or even without specifying the sex of the animal or the cells. In some cases, patients or cells of different sex were combined without addressing sex differences. Regulatory guidelines for pharmaceutical research call for assessing the influence of sex on drug effectiveness, and state that the drug development should provide adequate information on the efficacy of drugs in relationship to sex [232,233]. Clayton points out that female and male cells differ in response to chemicals. Therefore, in pre-clinical and clinical trials, the sex-related effects of investigational drugs cannot be ignored [234,235].
Inflammation alters the ratio of histone acetyltransferases to HDACs and in-vitro or in-vivo data suggest that HDAC inhibitors may be anti-inflammatory agents [236]. VPA exerts organ protection from viruses through multiple anti-inflammatory pathways. Sex differences in the expression of genes related to mitochondrial metabolism may indicate a possible involvement of mitochondria in the susceptibility of infection to VPA treatment. Virus replication and survival depend on the energy produced by the cell’s mitochondria, so antiviral therapies may include drugs that alter the mitochondrial energy mechanisms [237]. The major SARS-CoV-2 protease NSP5 can affect mitochondria by interacting with HDAC2 [3]. VPA, inhibiting HDAC activity [238], causes a decrease in DNA methylation of the SLC5A8 gene [153]. Short-chain fatty acids transported into immune cells via SLC5A8 alter HDAC activity; SLC5A8, participating in the mitochondrial β-oxidation pathway, regulates mitochondrial metabolism [150,151]. VPA treatment had an opposite effect on SLC5A8 RNA gene expression in female and male rat thymocytes [133]. The French Ministry of Health has issued a pharmacovigilance alert that COVID-19 patients should not take Ibuprofen, as the drug may worsen the condition [239]. Ibuprofen is the most potent inhibitor of the SLC5A8 transporter; it is a specific blocker of SLC5A8 [240]. The European Medicines Agency (EMA) responded by saying: “EMA is monitoring the situation closely, and will review any new information that becomes available on this issue” [239]. Thus, the function of the SLC5A8 transporter may be of pharmacological relevance to the study of COVID-19 disease immune response in relation to sex.
Furthermore, pro-inflammatory-immune cells derive most of their energy from aerobic glycolysis to generate more energy and maintain increased activity [239,241]. Rapid growth and proliferation of virus-activated T cells require glucose uptake and glycolysis [242,243,244]. Elevated glucose level favours the progression of SARS-CoV-2 infection [245]. VPA treatment reduces blood glucose levels in animals and humans [246,247].
Data from experimental, epidemiological and clinical studies suggest that VPA has anti-platelet and anti-thrombotic effects. Clinical use of VPA in the treatment of epilepsy is associated with a lower risk of thrombosis, myocardial infarction and stroke [248,249,250,251]. Current anti-thrombotic therapies inhibit the coagulation cascade and platelet function, but dosing is not optimal to prevent bleeding complications [252]. Thus, VPA could be a potential alternative for preventing thrombotic events in COVID-19 patients based on improved endogenous fibrinolysis. The anti-thrombotic effect of VPA may be significantly related to its impact on suppression of the immune response, which may also be sex-related.
VPA treatment decreases serum testosterone levels [253], and in this respect, the relationship of VPA treatment to sex is an important area of research for COVID-19 treatment. Two studies of men undergoing hormonal therapy for prostate cancer show a potential protective effect of androgen suppression on the risk of severe COVID-19 [254,255]. ACE2 level in human alveolar epithelial cells can be downregulated by 5α-reductase inhibitors, suggesting an androgen-driven expression mode [256]. This link could pave the path to novel strategies, including re-purposing approved androgen synthesis inhibitors or androgen receptor antagonists to treat COVID-19. These strategies are the point of the NCT04374279, NCT04475601, NCT04509999 and NCT04397718 clinical trials [257,258]. The development of VPA on COVID-19 therapy is currently being investigated in clinical trials [259,260,261].
12. Conclusions
The anti-inflammatory, anti-thrombotic, immunomodulatory, serum glucose-lowering and testosterone-lowering effects of VPA suggest that it may be a promising investigational medicinal product for the treatment of COVID-19. The pharmacological mechanisms of VPA suggest that VPA could be a drug for the prevention of COVID-19 progression.
The sex-specific differences in the course of COVID-19 and the mechanisms of action of VPA point to the need for prospective, controlled clinical trials to assess the sex-specific efficacy of valproic acid preparations.
Conceptualisation, V.L. and D.S.; methodology, V.L., D.S. and L.K.; validation, V.L. and D.S.; formal analysis, D.S., A.V. (Angelija Valančiūtė), I.B., V.L., T.T., A.V. (Arūnas Vaitkevičius); D.U., V.T., L.K. and K.S.; investigation, all authors; resources, V.L.; data curation, D.S. and L.K.; writing—original draft preparation, D.S., V.L., T.T. and L.K.; writing—review and editing, D.S., L.K., A.V. (Angelija Valančiūtė), I.B., T.T., A.V. (Arūnas Vaitkevičius), E.K., D.G., V.L., D.U., V.T. and K.S.; supervision, V.L.; project administration, V.L., T.T. and D.S.; and funding acquisition, V.L. All authors have read and agreed to the published version of the manuscript.
This research was funded by the Research Council of Lithuania, grant number 13.1.1-LMT-K-718-05-0030.
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No new data were created or analyzed in this study. Data sharing is not applicable to this article.
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Experimental studies of VPA treatment effectiveness on immune-inflammation in vivo and in vitro.
| # | Experimental Model | Animals/Cells | Sex | VPA Treatment Effect | Ref. |
|---|---|---|---|---|---|
| 1. | Lung injury model | Wistar rats | males | ↓ M1 macrophage proliferation and |
[ |
| 2. | Lung inflammation model | Balb/c mice | females | ↓ cigarette-smoke induced neutrophil influx; |
[ |
| 3. | Klebsiella pneumonia sepsis model | BALB/c mice | females | ↓ immune cells capacity to induce a proinflammatory response | [ |
| 4. | Sublethal model of hemorrhagic shock | Wistar Kyoto rats | males | ↓ hemorrhagic shock activated pro-inflammatory MAPK pathways; |
[ |
| 5. | Chronic lung inflammation model | A/J mice | females | ↓ neutrophils infiltration in the bronchoalveolar fluid | [ |
| 6. | Coxsackie B3 virus myocarditis model | BALB/c mice | males | ↓ splenic Th17 and stimulated Treg cells; |
[ |
| 7. | Post-operative inflammation the model of conjunctival scarring; Conjunctival inflammation model | NIH3T3/BL6 mice | males and females | ↓ recruitment of a D45highF4/80low macrophages; |
[ |
| 8. | Spinal cord injury model | BALB/c mice | males | ↓ macrophages infiltration, apoptotic cell death and caspase 3 activation; |
[ |
| 9. | Acute DSS-induced colitis model | C57BL/6J mice | females | disease amelioration was associated with prevention weight loss, |
[ |
| 10. | Experimental autoimmune encephalomyelitis model | C57BL/6 mice | females | ↓ CD4+ T-lymphocyte infiltrates, associating with caspase 3 mediated apoptosis | [ |
| 11. | A model of LPS-provoked septic shock | Sprague-Dawley rats | males | ↓ multiple organ damage caused by LPS induced septic shock | [ |
| 12. | Carrageenan-induced peritonitis model | Wistar rats | males | ↓ by 92% leukocytes migration to the peritoneal cavity in a rat peritonitis; |
[ |
| 13. | Hemorrhagic shock model | Sprague-Dawley rats | males | ↑ early survival, lung, liver and brain function | [ |
| 14. | Kidney ischemic/reperfusion injury model | Wistar rats | males | ↑ blood IL-10 and TGF-β mRNA levels; |
[ |
| 15. | ARDS model | C57BL6 mice | males | ↓ neutrophil influx into the lungs; |
[ |
| 16. | Lung fibrosis model | C57BL/6J mice | males | ↓ TGF-β1 in alveolar epithelial cells; |
[ |
| 17. | Gl. thymus model | Wistar rats | males and |
↑ SLC5A8 gene expression in gonad intact female thymocytes; |
[ |
| Cell model in vitro | |||||
| 18. | BHK-21 cells | Baby hamster kidney fibroblasts | unknown | ↓ replication of enveloped viruses | [ |
| 19. | Vero cells | African green monkey kidney | unknown | ↓ replication of enveloped viruses | [ |
| 20. | RAW264.7 macrophage cells | Mice | unknown | ↓ macrophage-mediated Th1 effector, |
[ |
| 21. | Bone marrow-derived macrophages | BALB/c mice | females | ↓ the production of TNF-α, IL-6 | [ |
| 22. | Bone marrow–derived primary macrophages (BMMs) | C57BL/6 |
females | polarises macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype; |
[ |
| 23. | Alveolar epithelial cell line | A549 | unknown | ↓ TGF-β1-induced EMT in alveolar epithelial cells | [ |
| 24. | PBMCs of healthy subjects | Human | unknown | ↑ apoptosis of normal human CD4+ and CD8+ T cells | [ |
| 25. | Monocytic leukemia THP-1 cells | Human | unknown | ↓ LPS-induced production of TNF-α, IL-6 | [ |
| 26. | Dendritic cells derived from monocytes of healthy blood donors’ | Human | unknown | ↓ monocyte differentiation into DCs; |
[ |
| 27. | Healthy blood donors T CD8+ lymphocytes | Human | males + |
↓ in cellular proliferation | [ |
↓ decreased; ↑ increased.
VPA treatment effect on thrombogenesis.
| # | Thrombogenesis Related Factor | Cells/Animals/Human | Sex | VPA Treatment Effect | Ref. |
|---|---|---|---|---|---|
| 1. | Complement C3 | HepG2 cells | unknown | ↓ C3 gene expression | [ |
| 2. | t-PA | Human umbilical vein endothelial cells | unknown | ↑ t-PA production | [ |
| 3. | ICAM-1 expression | Human umbilical vein ECs and |
unknown | ↓ ICAM-1 expression | [ |
| 4. | Platelets number | C57BL/6 mice | unknown | ↓ platelets count | [ |
| 5. | Vascular t-PA | C57BL/6 mice | males | ↑ endothelial vascular t-PA production; |
[ |
| 6. | E-selectin and ICAM-1 | Sprague–Dawley rats with subarachnoid hemorrhage induced vasospasm | males | ↓ the E-selectin and ICAM-1 level | [ |
| 7. | Platelets number | Epileptic adult patients |
men |
relationship between rising plasma VPA level and reduced platelet counts, with female sex additional risk factor | [ |
| 8. | Arachidonate cascade thromboxane A2 in platelets | Epileptic adult patients |
men | ↓ activity of the arachidonate cascade in platelets; |
[ |
| 9. | Von Willebrand factor:antigen | Epileptic children patients |
male + female |
↓ concentration in blood serum | [ |
| 10. | Protein C | Epileptic children patients |
male + female |
↓ concentration in blood serum | [ |
| 11. | Protein S | Epileptic children patients |
male + female |
↓ concentration in blood serum | [ |
| 12. | Antithrombin III | Epileptic children patients |
male + female |
↓ concentration in blood serum | [ |
| 13. | Prothrombin time | Epileptic children patients |
male + female |
↓ concentration in blood serum | [ |
| 14. | Activated partial thromboplastin time | Epileptic children patients |
male + female |
↓ concentration in blood serum | [ |
↓ decreased; ↑ increased.
References
1. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R. et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med.; 2020; 382, pp. 727-733. [DOI: https://dx.doi.org/10.1056/NEJMoa2001017] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31978945]
2. Dong, L.; Hu, S.; Gao, J. Discovering Drugs to Treat Coronavirus Disease 2019 (COVID-19). Drug Discov. Ther.; 2020; 14, pp. 58-60. [DOI: https://dx.doi.org/10.5582/ddt.2020.01012] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32147628]
3. Gordon, D.E.; Jang, G.M.; Bouhaddou, M.; Xu, J.; Obernier, K.; White, K.M.; O’Meara, M.J.; Rezelj, V.V.; Guo, J.Z.; Swaney, D.L. et al. A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing. Nature; 2020; 583, pp. 459-468. [DOI: https://dx.doi.org/10.1038/s41586-020-2286-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32353859]
4. Richardson, S.; Hirsch, J.S.; Narasimhan, M.; Crawford, J.M.; McGinn, T.; Davidson, K.W. The Northwell COVID-19 Research Consortium Barnaby, D.P.; Becker, L.B.; Chelico, J.D. et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA; 2020; 323, 2052. [DOI: https://dx.doi.org/10.1001/jama.2020.6775]
5. Vincent, J.-L.; Taccone, F.S. Understanding Pathways to Death in Patients with COVID-19. Lancet Respir. Med.; 2020; 8, pp. 430-432. [DOI: https://dx.doi.org/10.1016/S2213-2600(20)30165-X]
6. Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Clinical Predictors of Mortality Due to COVID-19 Based on an Analysis of Data of 150 Patients from Wuhan, China. Intensiv. Care Med.; 2020; 46, pp. 846-848. [DOI: https://dx.doi.org/10.1007/s00134-020-05991-x]
7. Varga, Z.; Flammer, A.J.; Steiger, P.; Haberecker, M.; Andermatt, R.; Zinkernagel, A.S.; Mehra, M.R.; Schuepbach, R.A.; Ruschitzka, F.; Moch, H. Endothelial Cell Infection and Endotheliitis in COVID-19. Lancet; 2020; 395, pp. 1417-1418. [DOI: https://dx.doi.org/10.1016/S0140-6736(20)30937-5]
8. Jin, J.-M.; Bai, P.; He, W.; Wu, F.; Liu, X.-F.; Han, D.-M.; Liu, S.; Yang, J.-K. Gender Differences in Patients With COVID-19: Focus on Severity and Mortality. Front. Public Health; 2020; 8, 152. [DOI: https://dx.doi.org/10.3389/fpubh.2020.00152]
9. Ye, Q.; Wang, B.; Mao, J. The Pathogenesis and Treatment of the ‘Cytokine Storm’ in COVID-19. J. Infect.; 2020; 80, pp. 607-613. [DOI: https://dx.doi.org/10.1016/j.jinf.2020.03.037]
10. Wang, C.; Xie, J.; Zhao, L.; Fei, X.; Zhang, H.; Tan, Y.; Nie, X.; Zhou, L.; Liu, Z.; Ren, Y. et al. Alveolar Macrophage Dysfunction and Cytokine Storm in the Pathogenesis of Two Severe COVID-19 Patients. EBioMedicine; 2020; 57, 102833. [DOI: https://dx.doi.org/10.1016/j.ebiom.2020.102833]
11. Jose, R.J.; Manuel, A. COVID-19 Cytokine Storm: The Interplay between Inflammation and Coagulation. Lancet Respir. Med.; 2020; 8, pp. e46-e47. [DOI: https://dx.doi.org/10.1016/S2213-2600(20)30216-2]
12. Puelles, V.G.; Lütgehetmann, M.; Lindenmeyer, M.T.; Sperhake, J.P.; Wong, M.N.; Allweiss, L.; Chilla, S.; Heinemann, A.; Wanner, N.; Liu, S. et al. Multiorgan and Renal Tropism of SARS-CoV-2. N. Engl. J. Med.; 2020; 383, pp. 590-592. [DOI: https://dx.doi.org/10.1056/NEJMc2011400]
13. Ackermann, M.; Verleden, S.E.; Kuehnel, M.; Haverich, A.; Welte, T.; Laenger, F.; Vanstapel, A.; Werlein, C.; Stark, H.; Tzankov, A. et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N. Engl. J. Med.; 2020; 383, pp. 120-128. [DOI: https://dx.doi.org/10.1056/NEJMoa2015432]
14. Varga, Z. Endotheliitis bei COVID-19. Pathologe; 2020; 41, pp. 99-102. [DOI: https://dx.doi.org/10.1007/s00292-020-00875-9]
15. Peckham, H.; de Gruijter, N.M.; Raine, C.; Radziszewska, A.; Ciurtin, C.; Wedderburn, L.R.; Rosser, E.C.; Webb, K.; Deakin, C.T. Male Sex Identified by Global COVID-19 Meta-Analysis as a Risk Factor for Death and ITU Admission. Nat. Commun.; 2020; 11, 6317. [DOI: https://dx.doi.org/10.1038/s41467-020-19741-6]
16. Gebhard, C.; Regitz-Zagrosek, V.; Neuhauser, H.K.; Morgan, R.; Klein, S.L. Impact of Sex and Gender on COVID-19 Outcomes in Europe. Biol. Sex Differ.; 2020; 11, 29. [DOI: https://dx.doi.org/10.1186/s13293-020-00304-9]
17. Grasselli, G.; Zangrillo, A.; Zanella, A.; Antonelli, M.; Cabrini, L.; Castelli, A.; Cereda, D.; Coluccello, A.; Foti, G.; Fumagalli, R. et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA; 2020; 323, pp. 1574-1581. [DOI: https://dx.doi.org/10.1001/jama.2020.5394]
18. The OpenSAFELY Collaborative Williamson, E.; Walker, A.J.; Bhaskaran, K.; Bacon, S.; Bates, C.; Morton, C.E.; Curtis, H.J.; Mehrkar, A.; Evans, D. et al. OpenSAFELY: Factors Associated with COVID-19-Related Hospital Death in the Linked Electronic Health Records of 17 Million Adult NHS Patients. Nature; 2020; 584, pp. 430-436. [DOI: https://dx.doi.org/10.1038/s41586-020-2521-4]
19. Chen, T.; Wu, D.; Chen, H.; Yan, W.; Yang, D.; Chen, G.; Ma, K.; Xu, D.; Yu, H.; Wang, H. et al. Clinical Characteristics of 113 Deceased Patients with Coronavirus Disease 2019: Retrospective Study. BMJ; 2020; 368, m1091. [DOI: https://dx.doi.org/10.1136/bmj.m1091]
20. Dudley, J.P.; Lee, N.T. Disparities in Age-Specific Morbidity and Mortality From SARS-CoV-2 in China and the Republic of Korea. Clin. Infect. Dis.; 2020; 71, pp. 863-865. [DOI: https://dx.doi.org/10.1093/cid/ciaa354]
21. National Health Service COVID-19 Daily Deaths. Available online: https://web.archive.org/web/20200501094237/https://www.england.nhs.uk/statistics/statistical-work-areas/covid-19-daily-deaths/ (accessed on 14 January 2021).
22. Takahashi, T.; Wong, P.; Ellingson, M.K.; Lucas, C.; Klein, J.; Israelow, B.; Silva, J.; Oh, J.E.; Mao, T.; Tokuyama, M. et al. Sex Differences in Immune Responses That Underlie COVID-19 Disease Outcomes. Nature; 2020; 588, pp. 315-320. [DOI: https://dx.doi.org/10.1038/s41586-020-2700-3]
23. Global Health 5050 Sex, Gender and COVID-19. Available online: https://globalhealth5050.org//the-sex-gender-and-covid-19-project/ (accessed on 14 January 2021).
24. Lee, B.W.; Yap, H.K.; Chew, F.T.; Quah, T.C.; Prabhakaran, K.; Chan, G.S.; Wong, S.C.; Seah, C.C. Age- and Sex-Related Changes in Lymphocyte Subpopulations of Healthy Asian Subjects: From Birth to Adulthood. Cytometry; 1996; 26, pp. 8-15. [DOI: https://dx.doi.org/10.1002/(SICI)1097-0320(19960315)26:1<8::AID-CYTO2>3.0.CO;2-E]
25. Hewagama, A.; Patel, D.; Yarlagadda, S.; Strickland, F.M.; Richardson, B.C. Stronger Inflammatory/Cytotoxic T-Cell Response in Women Identified by Microarray Analysis. Genes Immun.; 2009; 10, pp. 509-516. [DOI: https://dx.doi.org/10.1038/gene.2009.12]
26. Stoica, G.; Macarie, E.; Michiu, V.; Stoica, R.C. Biologic Variation of Human Immunoglobulin Concentration. I. Sex-Age Specific Effects on Serum Levels of IgG, IgA, IgM and IgD. Med. Internet; 1980; 18, pp. 323-332.
27. Abdullah, M.; Chai, P.-S.; Chong, M.-Y.; Tohit, E.R.M.; Ramasamy, R.; Pei, C.P.; Vidyadaran, S. Gender Effect on in Vitro Lymphocyte Subset Levels of Healthy Individuals. Cell Immunol.; 2012; 272, pp. 214-219. [DOI: https://dx.doi.org/10.1016/j.cellimm.2011.10.009]
28. La Vignera, S.; Cannarella, R.; Condorelli, R.A.; Torre, F.; Aversa, A.; Calogero, A.E. Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D. Int. J. Mol. Sci.; 2020; 21, 2948. [DOI: https://dx.doi.org/10.3390/ijms21082948]
29. Bukowska, A.; Spiller, L.; Wolke, C.; Lendeckel, U.; Weinert, S.; Hoffmann, J.; Bornfleth, P.; Kutschka, I.; Gardemann, A.; Isermann, B. et al. Protective Regulation of the ACE2/ACE Gene Expression by Estrogen in Human Atrial Tissue from Elderly Men. Exp. Biol. Med.; 2017; 242, pp. 1412-1423. [DOI: https://dx.doi.org/10.1177/1535370217718808]
30. Wan, Y.; Shang, J.; Graham, R.; Baric, R.S.; Li, F. Receptor Recognition by the Novel Coronavirus from Wuhan: An Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J. Virol.; 2020; 94, e00127-20. [DOI: https://dx.doi.org/10.1128/JVI.00127-20]
31. Cai, G. Bulk and Single-Cell Transcriptomics Identify Tobacco-Use Disparity in Lung Gene Expression of ACE2, the Receptor of 2019-NCov. Infect. Dis.; 2020; [DOI: https://dx.doi.org/10.1101/2020.02.05.20020107]
32. Zhao, Y.; Zhao, Z.; Wang, Y.; Zhou, Y.; Ma, Y.; Zuo, W. Single-Cell RNA Expression Profiling of ACE2, the Receptor of SARS-CoV-2. Am. J. Respir. Crit. Care Med.; 2020; 202, pp. 756-759. [DOI: https://dx.doi.org/10.1164/rccm.202001-0179LE]
33. Naasani, I. COMPARE Analysis, a Bioinformatic Approach to Accelerate Drug Repurposing against Covid-19 and Other Emerging Epidemics. SLAS Discov.; 2021; 26, pp. 345-351. [DOI: https://dx.doi.org/10.1177/2472555220975672] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33267713]
34. Komatsu, T.; Suzuki, Y.; Imai, J.; Sugano, S.; Hida, M.; Tanigami, A.; Muroi, S.; Yamada, Y.; Hanaoka, K. Molecular Cloning, mRNA Expression and Chromosomal Localization of Mouse Angiotensin-Converting Enzyme-Related Carboxypeptidase (MACE2). DNA Seq.; 2002; 13, pp. 217-220. [DOI: https://dx.doi.org/10.1080/1042517021000021608] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12487024]
35. Phiel, C.J.; Zhang, F.; Huang, E.Y.; Guenther, M.G.; Lazar, M.A.; Klein, P.S. Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen. J. Biol. Chem.; 2001; 276, pp. 36734-36741. [DOI: https://dx.doi.org/10.1074/jbc.M101287200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11473107]
36. Perucca, E. Pharmacological and Therapeutic Properties of Valproate: A Summary after 35 Years of Clinical Experience. CNS Drugs; 2002; 16, pp. 695-714. [DOI: https://dx.doi.org/10.2165/00023210-200216100-00004]
37. Goodwin, F.K.; Fireman, B.; Simon, G.E.; Hunkeler, E.M.; Lee, J.; Revicki, D. Suicide Risk in Bipolar Disorder during Treatment with Lithium and Divalproex. JAMA; 2003; 290, pp. 1467-1473. [DOI: https://dx.doi.org/10.1001/jama.290.11.1467]
38. Citrome, L. Schizophrenia and Valproate. Psychopharmacol. Bull.; 2003; 37, (Suppl. S2), pp. 74-88.
39. Belmaker, R.H. Bipolar Disorder. N. Engl. J. Med.; 2004; 351, pp. 476-486. [DOI: https://dx.doi.org/10.1056/NEJMra035354]
40. Frediani, F. Anticonvulsant Drugs in Primary Headaches Prophylaxis. Neurol. Sci.; 2004; 25, (Suppl. S3), pp. S161-S166. [DOI: https://dx.doi.org/10.1007/s10072-004-0278-4]
41. Michaelis, M.; Doerr, H.W.; Cinatl, J. Valproic Acid as Anti-Cancer Drug. Curr. Pharm. Des.; 2007; 13, pp. 3378-3393. [DOI: https://dx.doi.org/10.2174/138161207782360528]
42. Andreu, S.; Ripa, I.; Bello-Morales, R.; López-Guerrero, J.A. Valproic Acid and Its Amidic Derivatives as New Antivirals against Alphaherpesviruses. Viruses; 2020; 12, 1356. [DOI: https://dx.doi.org/10.3390/v12121356]
43. Silva, M.F.B.; Aires, C.C.P.; Luis, P.B.M.; Ruiter, J.P.N.; IJlst, L.; Duran, M.; Wanders, R.J.A.; Tavares de Almeida, I. Valproic Acid Metabolism and Its Effects on Mitochondrial Fatty Acid Oxidation: A Review. J. Inherit. Metab. Dis.; 2008; 31, pp. 205-216. [DOI: https://dx.doi.org/10.1007/s10545-008-0841-x]
44. Ghodke-Puranik, Y.; Thorn, C.F.; Lamba, J.K.; Leeder, J.S.; Song, W.; Birnbaum, A.K.; Altman, R.B.; Klein, T.E. Valproic Acid Pathway: Pharmacokinetics and Pharmacodynamics. Pharm. Genom.; 2013; 23, pp. 236-241. [DOI: https://dx.doi.org/10.1097/FPC.0b013e32835ea0b2]
45. Schobben, F.; van der Kleijn, E.; Gabreëls, F.J. Pharmacokinetics of Di-n-Propylacetate in Epileptic Patients. Eur. J. Clin. Pharm.; 1975; 8, pp. 97-105. [DOI: https://dx.doi.org/10.1007/BF00561557]
46. Rost, D.; Kopplow, K.; Gehrke, S.; Mueller, S.; Friess, H.; Ittrich, C.; Mayer, D.; Stiehl, A. Gender-Specific Expression of Liver Organic Anion Transporters in Rat. Eur. J. Clin. Investig.; 2005; 35, pp. 635-643. [DOI: https://dx.doi.org/10.1111/j.1365-2362.2005.01556.x]
47. Smirnova, O.V. Sex differences in drug action: The role of multidrug-resistance proteins (MRPs). Fiziol. Cheloveka; 2012; 38, pp. 124-136.
48. Suzuki, T.; Zhao, Y.L.; Nadai, M.; Naruhashi, K.; Shimizu, A.; Takagi, K.; Takagi, K.; Hasegawa, T. Gender-Related Differences in Expression and Function of Hepatic P-Glycoprotein and Multidrug Resistance-Associated Protein (Mrp2) in Rats. Life Sci.; 2006; 79, pp. 455-461. [DOI: https://dx.doi.org/10.1016/j.lfs.2006.01.024]
49. Ibarra, M.; Vázquez, M.; Fagiolino, P.; Derendorf, H. Sex Related Differences on Valproic Acid Pharmacokinetics after Oral Single Dose. J. Pharm. Pharm.; 2013; 40, pp. 479-486. [DOI: https://dx.doi.org/10.1007/s10928-013-9323-3]
50. Wong, H.; Xia, B.; Tong, V.; Kumar, S.; Kenny, J.R. Atypical Kinetics of Valproic Acid Glucuronidation In Vitro and In Vivo in Humans. Pharm. Anal. Acta; 2012; 01, 55626283. [DOI: https://dx.doi.org/10.4172/2153-2435.S11-006]
51. Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L. et al. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature; 2020; 579, pp. 270-273. [DOI: https://dx.doi.org/10.1038/s41586-020-2012-7]
52. Bhavesh, N.S.; Patra, A. Virtual Screening and Molecular Dynamics Simulation Suggest Valproic Acid Co-A could Bind to SARS-CoV2 RNA Depended RNA Polymerase. Preprints; 2020; 2020030393. [DOI: https://dx.doi.org/10.20944/preprints202003.0393.v1]
53. Mengist, H.M.; Fan, X.; Jin, T. Designing of Improved Drugs for COVID-19: Crystal Structure of SARS-CoV-2 Main Protease Mpro. Signal Transduct. Target.; 2020; 5, 67. [DOI: https://dx.doi.org/10.1038/s41392-020-0178-y]
54. Elfiky, A.A. Anti-HCV, Nucleotide Inhibitors, Repurposing against COVID-19. Life Sci.; 2020; 248, 117477. [DOI: https://dx.doi.org/10.1016/j.lfs.2020.117477]
55. Elfiky, A.A. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp): A Molecular Docking Study. Life Sci.; 2020; 253, 117592. [DOI: https://dx.doi.org/10.1016/j.lfs.2020.117592]
56. Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C. et al. Structure of Mpro from SARS-CoV-2 and Discovery of Its Inhibitors. Nature; 2020; 582, pp. 289-293. [DOI: https://dx.doi.org/10.1038/s41586-020-2223-y]
57. Pillaiyar, T.; Manickam, M.; Namasivayam, V.; Hayashi, Y.; Jung, S.-H. An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J. Med. Chem.; 2016; 59, pp. 6595-6628. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.5b01461]
58. Mohamed, M.F.A.; Abuo-Rahma, G.E.A.; Hayallah, A.M.; Aziz, A.M.; Nafady, A.; Samir, E. Molecular Docking Study Reveals The Potential Repurposing Of Histone Deacetylase Inhibitors Against COVID-19. Int. J. Pharm. Sci. Res.; 2020; 18, pp. 4261-4270. [DOI: https://dx.doi.org/10.13040/IJPSR.0975-8232.11(9).4261-70]
59. Barnes, P.J. Role of HDAC2 in the Pathophysiology of COPD. Annu. Rev. Physiol.; 2009; 71, pp. 451-464. [DOI: https://dx.doi.org/10.1146/annurev.physiol.010908.163257]
60. Dewe, J.M.; Fuller, B.L.; Lentini, J.M.; Kellner, S.M.; Fu, D. TRMT1-Catalyzed tRNA Modifications Are Required for Redox Homeostasis To Ensure Proper Cellular Proliferation and Oxidative Stress Survival. Mol. Cell. Biol.; 2017; 37, e00214-17. [DOI: https://dx.doi.org/10.1128/MCB.00214-17]
61. Matsuda, K.I.; Mori, H.; Nugent, B.M.; Pfaff, D.W.; McCarthy, M.M.; Kawata, M. Histone Deacetylation during Brain Development Is Essential for Permanent Masculinization of Sexual Behavior. Endocrinology; 2011; 152, pp. 2760-2767. [DOI: https://dx.doi.org/10.1210/en.2011-0193]
62. Krämer, O.H.; Zhu, P.; Ostendorff, H.P.; Golebiewski, M.; Tiefenbach, J.; Paters, M.A.; Brill, B.; Groner, B.; Bach, I.; Heinzel, T. et al. The Histone Deacetylase Inhibitor Valproic Acid Selectively Induces Proteasomal Degradation of HDAC2. EMBO J.; 2003; 22, pp. 3411-3420. [DOI: https://dx.doi.org/10.1093/emboj/cdg315]
63. Dokmanovic, M.; Clarke, C.; Marks, P.A. Histone Deacetylase Inhibitors: Overview and Perspectives. Mol. Cancer Res.; 2007; 5, pp. 981-989. [DOI: https://dx.doi.org/10.1158/1541-7786.MCR-07-0324] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17951399]
64. Tyler, C.R.S.; Smoake, J.J.W.; Solomon, E.R.; Villicana, E.; Caldwell, K.K.; Allan, A.M. Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure. Front. Genet.; 2018; 9, 200. [DOI: https://dx.doi.org/10.3389/fgene.2018.00200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29963072]
65. Jia, H.P.; Look, D.C.; Tan, P.; Shi, L.; Hickey, M.; Gakhar, L.; Chappell, M.C.; Wohlford-Lenane, C.; McCray, P.B. Ectodomain Shedding of Angiotensin Converting Enzyme 2 in Human Airway Epithelia. Am. J. Physiol. Lung Cell. Mol. Physiol.; 2009; 297, pp. L84-L96. [DOI: https://dx.doi.org/10.1152/ajplung.00071.2009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19411314]
66. Wu, J.; Deng, W.; Li, S.; Yang, X. Advances in Research on ACE2 as a Receptor for 2019-NCoV. Cell. Mol. Life Sci.; 2021; 78, pp. 531-544. [DOI: https://dx.doi.org/10.1007/s00018-020-03611-x]
67. Wrapp, D.; Wang, N.; Corbett, K.S.; Goldsmith, J.A.; Hsieh, C.-L.; Abiona, O.; Graham, B.S.; McLellan, J.S. Cryo-EM Structure of the 2019-NCoV Spike in the Prefusion Conformation. Science; 2020; 367, pp. 1260-1263. [DOI: https://dx.doi.org/10.1126/science.abb2507]
68. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell; 2020; 181, pp. 271-280.e8. [DOI: https://dx.doi.org/10.1016/j.cell.2020.02.052]
69. Gheblawi, M.; Wang, K.; Viveiros, A.; Nguyen, Q.; Zhong, J.-C.; Turner, A.J.; Raizada, M.K.; Grant, M.B.; Oudit, G.Y. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ. Res.; 2020; 126, pp. 1456-1474. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.120.317015]
70. Hamming, I.; Timens, W.; Bulthuis, M.L.C.; Lely, A.T.; Navis, G.J.; van Goor, H. Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis. J. Pathol.; 2004; 203, pp. 631-637. [DOI: https://dx.doi.org/10.1002/path.1570]
71. Tipnis, S.R.; Hooper, N.M.; Hyde, R.; Karran, E.; Christie, G.; Turner, A.J. A Human Homolog of Angiotensin-Converting Enzyme. Cloning and Functional Expression as a Captopril-Insensitive Carboxypeptidase. J. Biol. Chem.; 2000; 275, pp. 33238-33243. [DOI: https://dx.doi.org/10.1074/jbc.M002615200]
72. Culebras, E.; Hernández, F. ACE2 Is on the X Chromosome: Could This Explain COVID-19 Gender Differences?. Eur. Heart J.; 2020; 41, 3095. [DOI: https://dx.doi.org/10.1093/eurheartj/ehaa521]
73. Kloc, M.; Ghobrial, R.M.; Kubiak, J.Z. The Role of Genetic Sex and Mitochondria in Response to COVID-19 Infection. Int. Arch. Allergy Immunol.; 2020; 181, pp. 629-634. [DOI: https://dx.doi.org/10.1159/000508560]
74. Patel, S.K.; Velkoska, E.; Burrell, L.M. Emerging Markers in Cardiovascular Disease: Where Does Angiotensin-Converting Enzyme 2 Fit In?. Clin. Exp. Pharm. Physiol.; 2013; 40, pp. 551-559. [DOI: https://dx.doi.org/10.1111/1440-1681.12069]
75. Fernández-Atucha, A.; Izagirre, A.; Fraile-Bermúdez, A.B.; Kortajarena, M.; Larrinaga, G.; Martinez-Lage, P.; Echevarría, E.; Gil, J. Sex Differences in the Aging Pattern of Renin–Angiotensin System Serum Peptidases. Biol. Sex Differ.; 2017; 8, 5. [DOI: https://dx.doi.org/10.1186/s13293-017-0128-8]
76. Hu, Y.; Li, X.; Wu, N.; Wang, N.; Qiu, C.; Li, J. Study on the Correlation among Sex, Age and the Activity of ACE, ACE2 and the Ratio of ACE/ACE2. J. Qiqihar. Med. Coll.; 2018; 39, pp. 884-887. [DOI: https://dx.doi.org/10.3969/j.issn.1002-1256.2018.08.005]
77. Baratchian, M.; McManus, J.M.; Berk, M.P.; Nakamura, F.; Mukhopadhyay, S.; Xu, W.; Erzurum, S.; Drazba, J.; Peterson, J.; Klein, E.A. et al. Androgen Regulation of Pulmonary AR, TMPRSS2 and ACE2 with Implications for Sex-Discordant COVID-19 Outcomes. Sci. Rep.; 2021; 11, 11130. [DOI: https://dx.doi.org/10.1038/s41598-021-90491-1]
78. Saheb Sharif-Askari, N.; Saheb Sharif-Askari, F.; Alabed, M.; Temsah, M.-H.; Al Heialy, S.; Hamid, Q.; Halwani, R. Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower in Children Than Adults and Increases with Smoking and COPD. Mol. Ther. Methods Clin. Dev.; 2020; 18, pp. 1-6. [DOI: https://dx.doi.org/10.1016/j.omtm.2020.05.013]
79. Smith, J.C.; Sausville, E.L.; Girish, V.; Yuan, M.L.; Vasudevan, A.; John, K.M.; Sheltzer, J.M. Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract. Dev. Cell; 2020; 53, pp. 514-529.e3. [DOI: https://dx.doi.org/10.1016/j.devcel.2020.05.012]
80. Dalpiaz, P.L.M.; Lamas, A.Z.; Caliman, I.F.; Ribeiro, R.F.; Abreu, G.R.; Moyses, M.R.; Andrade, T.U.; Gouvea, S.A.; Alves, M.F.; Carmona, A.K. et al. Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats. PLoS ONE; 2015; 10, e0127515. [DOI: https://dx.doi.org/10.1371/journal.pone.0127515]
81. Fischer, M.; Baessler, A.; Schunkert, H. Renin Angiotensin System and Gender Differences in the Cardiovascular System. Cardiovasc. Res.; 2002; 53, pp. 672-677. [DOI: https://dx.doi.org/10.1016/S0008-6363(01)00479-5]
82. Cui, Q.; Cui, C.; Huang, C.; Zhou, W.; Ji, X.; Zhang, F.; Wang, L.; Zhou, Y. AGTR2, One Possible Novel Key Gene for the Entry of 2019-NCoV into Human Cells. IEEE/ACM Trans. Comput. Biol. Bioinform.; 2020; 18, pp. 1230-1233. [DOI: https://dx.doi.org/10.1109/TCBB.2020.3009099]
83. Singh, S.; Singh, K.K. Valproic Acid in Prevention and Treatment of COVID-19. Int. J. Respir. Pulm. Med.; 2020; 7, 138. [DOI: https://dx.doi.org/10.23937/2378-3516/1410138]
84. Vaarala, M.H.; Porvari, K.S.; Kellokumpu, S.; Kyllönen, A.P.; Vihko, P.T. Expression of Transmembrane Serine Protease TMPRSS2 in Mouse and Human Tissues. J. Pathol.; 2001; 193, pp. 134-140. [DOI: https://dx.doi.org/10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T]
85. Heurich, A.; Hofmann-Winkler, H.; Gierer, S.; Liepold, T.; Jahn, O.; Pöhlmann, S. TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein. J. Virol.; 2014; 88, pp. 1293-1307. [DOI: https://dx.doi.org/10.1128/JVI.02202-13]
86. Zarubin, A.; Stepanov, V.; Markov, A.; Kolesnikov, N.; Marusin, A.; Khitrinskaya, I.; Swarovskaya, M.; Litvinov, S.; Ekomasova, N.; Dzhaubermezov, M. et al. Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy. Genes; 2020; 12, 19. [DOI: https://dx.doi.org/10.3390/genes12010019]
87. Lucas, J.M.; Heinlein, C.; Kim, T.; Hernandez, S.A.; Malik, M.S.; True, L.D.; Morrissey, C.; Corey, E.; Montgomery, B.; Mostaghel, E. et al. The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis. Cancer Discov.; 2014; 4, pp. 1310-1325. [DOI: https://dx.doi.org/10.1158/2159-8290.CD-13-1010]
88. Fortson, W.S.; Kayarthodi, S.; Fujimura, Y.; Xu, H.; Matthews, R.; Grizzle, W.E.; Rao, V.N.; Bhat, G.K.; Reddy, E.S.P. Histone Deacetylase Inhibitors, Valproic Acid and Trichostatin-A Induce Apoptosis and Affect Acetylation Status of P53 in ERG-Positive Prostate Cancer Cells. Int. J. Oncol.; 2011; 39, pp. 111-119. [DOI: https://dx.doi.org/10.3892/ijo.2011.1014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21519790]
89. Wang, H.; Yang, P.; Liu, K.; Guo, F.; Zhang, Y.; Zhang, G.; Jiang, C. SARS Coronavirus Entry into Host Cells through a Novel Clathrin- and Caveolae-Independent Endocytic Pathway. Cell Res.; 2008; 18, pp. 290-301. [DOI: https://dx.doi.org/10.1038/cr.2008.15] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18227861]
90. Swärd, P.; Edsfeldt, A.; Reepalu, A.; Jehpsson, L.; Rosengren, B.E.; Karlsson, M.K. Age and Sex Differences in Soluble ACE2 May Give Insights for COVID-19. Crit. Care; 2020; 24, 221. [DOI: https://dx.doi.org/10.1186/s13054-020-02942-2]
91. Lambert, D.W.; Yarski, M.; Warner, F.J.; Thornhill, P.; Parkin, E.T.; Smith, A.I.; Hooper, N.M.; Turner, A.J. Tumor Necrosis Factor-α Convertase (ADAM17) Mediates Regulated Ectodomain Shedding of the Severe-Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Receptor, Angiotensin-Converting Enzyme-2 (ACE2). J. Biol. Chem.; 2005; 280, pp. 30113-30119. [DOI: https://dx.doi.org/10.1074/jbc.M505111200]
92. Li, W.; Moore, M.J.; Vasilieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C. et al. Angiotensin-Converting Enzyme 2 Is a Functional Receptor for the SARS Coronavirus. Nature; 2003; 426, pp. 450-454. [DOI: https://dx.doi.org/10.1038/nature02145]
93. Guan, W.; Ni, Z.; Hu, Y.; Liang, W.; Ou, C.; He, J.; Liu, L.; Shan, H.; Lei, C.; Hui, D.S.C. et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med.; 2020; 382, pp. 1708-1720. [DOI: https://dx.doi.org/10.1056/NEJMoa2002032] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32109013]
94. Kuba, K.; Imai, Y.; Rao, S.; Gao, H.; Guo, F.; Guan, B.; Huan, Y.; Yang, P.; Zhang, Y.; Deng, W. et al. A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury. Nat. Med.; 2005; 11, pp. 875-879. [DOI: https://dx.doi.org/10.1038/nm1267] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16007097]
95. Walls, A.C.; Park, Y.-J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell; 2020; 181, pp. 281-292.e6. [DOI: https://dx.doi.org/10.1016/j.cell.2020.02.058] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32155444]
96. Oudit, G.Y.; Kassiri, Z.; Jiang, C.; Liu, P.P.; Poutanen, S.M.; Penninger, J.M.; Butany, J. SARS-Coronavirus Modulation of Myocardial ACE2 Expression and Inflammation in Patients with SARS. Eur. J. Clin. Investig.; 2009; 39, pp. 618-625. [DOI: https://dx.doi.org/10.1111/j.1365-2362.2009.02153.x]
97. Soler, M.J.; Wysocki, J.; Batlle, D. Angiotensin-Converting Enzyme 2 and the Kidney. Exp. Physiol.; 2008; 93, pp. 549-556. [DOI: https://dx.doi.org/10.1113/expphysiol.2007.041350]
98. Zipeto, D.; da Palmeira, J.F.; Argañaraz, G.A.; Argañaraz, E.R. ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19. Front. Immunol.; 2020; 11, 576745. [DOI: https://dx.doi.org/10.3389/fimmu.2020.576745]
99. Ferrario, C.M.; Jessup, J.; Chappell, M.C.; Averill, D.B.; Brosnihan, K.B.; Tallant, E.A.; Diz, D.I.; Gallagher, P.E. Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2. Circulation; 2005; 111, pp. 2605-2610. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.104.510461]
100. Eguchi, S.; Kawai, T.; Scalia, R.; Rizzo, V. Understanding Angiotensin II Type 1 Receptor Signaling in Vascular Pathophysiology. Hypertension; 2018; 71, pp. 804-810. [DOI: https://dx.doi.org/10.1161/HYPERTENSIONAHA.118.10266]
101. Imai, Y.; Kuba, K.; Rao, S.; Huan, Y.; Guo, F.; Guan, B.; Yang, P.; Sarao, R.; Wada, T.; Leong-Poi, H. et al. Angiotensin-Converting Enzyme 2 Protects from Severe Acute Lung Failure. Nature; 2005; 436, pp. 112-116. [DOI: https://dx.doi.org/10.1038/nature03712]
102. Donoghue, M.; Hsieh, F.; Baronas, E.; Godbout, K.; Gosselin, M.; Stagliano, N.; Donovan, M.; Woolf, B.; Robison, K.; Jeyaseelan, R. et al. A Novel Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9. Circ. Res.; 2000; 87, pp. E1-E9. [DOI: https://dx.doi.org/10.1161/01.RES.87.5.e1]
103. Mascolo, A.; Scavone, C.; Rafaniello, C.; Ferrajolo, C.; Racagni, G.; Berrino, L.; Paolisso, G.; Rossi, F.; Capuano, A. Renin-Angiotensin System and Coronavirus Disease 2019: A Narrative Review. Front. Cardiovasc. Med.; 2020; 7, 143. [DOI: https://dx.doi.org/10.3389/fcvm.2020.00143]
104. Ferrario, C.M.; Chappell, M.C. Novel Angiotensin Peptides. Cell. Mol. Life Sci.; 2004; 61, pp. 2720-2727. [DOI: https://dx.doi.org/10.1007/s00018-004-4243-4]
105. Turner, A.J.; Hiscox, J.A.; Hooper, N.M. ACE2: From Vasopeptidase to SARS Virus Receptor. Trends Pharm. Sci.; 2004; 25, pp. 291-294. [DOI: https://dx.doi.org/10.1016/j.tips.2004.04.001]
106. Vickers, C.; Hales, P.; Kaushik, V.; Dick, L.; Gavin, J.; Tang, J.; Godbout, K.; Parsons, T.; Baronas, E.; Hsieh, F. et al. Hydrolysis of Biological Peptides by Human Angiotensin-Converting Enzyme-Related Carboxypeptidase. J. Biol. Chem.; 2002; 277, pp. 14838-14843. [DOI: https://dx.doi.org/10.1074/jbc.M200581200]
107. McGuire, B.B.; Watson, R.W.G.; Pérez-Barriocanal, F.; Fitzpatrick, J.M.; Docherty, N.G. Gender Differences in the Renin-Angiotensin and Nitric Oxide Systems: Relevance in the Normal and Diseased Kidney. Kidney Blood Press. Res.; 2007; 30, pp. 67-80. [DOI: https://dx.doi.org/10.1159/000099150]
108. Sandberg, K.; Ji, H. Sex and the Renin Angiotensin System: Implications for Gender Differences in the Progression of Kidney Disease. Adv. Ren. Replace; 2003; 10, pp. 15-23. [DOI: https://dx.doi.org/10.1053/jarr.2003.50006]
109. Sullivan, J.C. Sex and the Renin-Angiotensin System: Inequality between the Sexes in Response to RAS Stimulation and Inhibition. Am. J. Physiol.-Regul. Integr. Comp. Physiol.; 2008; 294, pp. R1220-R1226. [DOI: https://dx.doi.org/10.1152/ajpregu.00864.2007]
110. Rogers, J.L.; Mitchell, A.R.; Maric, C.; Sandberg, K.; Myers, A.; Mulroney, S.E. Effect of Sex Hormones on Renal Estrogen and Angiotensin Type 1 Receptors in Female and Male Rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.; 2007; 292, pp. R794-R799. [DOI: https://dx.doi.org/10.1152/ajpregu.00424.2006]
111. Brewster, U.C.; Perazella, M.A. The Renin-Angiotensin-Aldosterone System and the Kidney: Effects on Kidney Disease. Am. J. Med.; 2004; 116, pp. 263-272. [DOI: https://dx.doi.org/10.1016/j.amjmed.2003.09.034]
112. Touyz, R.M.; Schiffrin, E.L. Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells. Pharm. Rev.; 2000; 52, pp. 639-672.
113. Choi, J.; Park, S.; Kwon, T.K.; Sohn, S.I.; Park, K.M.; Kim, J.I. Role of the Histone Deacetylase Inhibitor Valproic Acid in High-Fat Diet-Induced Hypertension via Inhibition of HDAC1/Angiotensin II Axis. Int. J. Obes.; 2017; 41, pp. 1702-1709. [DOI: https://dx.doi.org/10.1038/ijo.2017.166] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28720877]
114. Rajeshwari, T.; Raja, B.; Manivannan, J.; Silambarasan, T.; Dhanalakshmi, T. Valproic Acid Prevents the Deregulation of Lipid Metabolism and Renal Renin-Angiotensin System in L-NAME Induced Nitric Oxide Deficient Hypertensive Rats. Env. Toxicol. Pharm.; 2014; 37, pp. 936-945. [DOI: https://dx.doi.org/10.1016/j.etap.2014.02.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24705342]
115. Lu, Y.; Yang, S. Angiotensin II Induces Cardiomyocyte Hypertrophy Probably through Histone Deacetylases. Tohoku J. Exp. Med.; 2009; 219, pp. 17-23. [DOI: https://dx.doi.org/10.1620/tjem.219.17] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19713680]
116. Struhl, K. Histone Acetylation and Transcriptional Regulatory Mechanisms. Genes Dev.; 1998; 12, pp. 599-606. [DOI: https://dx.doi.org/10.1101/gad.12.5.599]
117. Van Beneden, K.; Geers, C.; Pauwels, M.; Mannaerts, I.; Verbeelen, D.; van Grunsven, L.A.; Van den Branden, C. Valproic Acid Attenuates Proteinuria and Kidney Injury. J. Am. Soc. Nephrol.; 2011; 22, pp. 1863-1875. [DOI: https://dx.doi.org/10.1681/ASN.2010111196]
118. Abdul Roda, M.; Sadik, M.; Gaggar, A.; Hardison, M.T.; Jablonsky, M.J.; Braber, S.; Blalock, J.E.; Redegeld, F.A.; Folkerts, G.; Jackson, P.L. Targeting Prolyl Endopeptidase with Valproic Acid as a Potential Modulator of Neutrophilic Inflammation. PLoS ONE; 2014; 9, e97594. [DOI: https://dx.doi.org/10.1371/journal.pone.0097594]
119. Venosa, A.; Gow, J.G.; Hall, L.; Malaviya, R.; Gow, A.J.; Laskin, J.D.; Laskin, D.L. Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor. Toxicol. Sci.; 2017; 157, pp. 222-234. [DOI: https://dx.doi.org/10.1093/toxsci/kfx032]
120. Kochanek, A.R.; Fukudome, E.Y.; Li, Y.; Smith, E.J.; Liu, B.; Velmahos, G.C.; deMoya, M.; King, D.; Alam, H.B. Histone Deacetylase Inhibitor Treatment Attenuates MAP Kinase Pathway Activation and Pulmonary Inflammation Following Hemorrhagic Shock in a Rodent Model. J. Surg. Res.; 2012; 176, pp. 185-194. [DOI: https://dx.doi.org/10.1016/j.jss.2011.06.007]
121. Roger, T.; Lugrin, J.; Le Roy, D.; Goy, G.; Mombelli, M.; Koessler, T.; Ding, X.C.; Chanson, A.-L.; Reymond, M.K.; Miconnet, I. et al. Histone Deacetylase Inhibitors Impair Innate Immune Responses to Toll-like Receptor Agonists and to Infection. Blood; 2011; 117, pp. 1205-1217. [DOI: https://dx.doi.org/10.1182/blood-2010-05-284711]
122. Jin, H.; Guo, X. Valproic Acid Ameliorates Coxsackievirus-B3-Induced Viral Myocarditis by Modulating Th17/Treg Imbalance. Virol. J.; 2016; 13, 168. [DOI: https://dx.doi.org/10.1186/s12985-016-0626-z]
123. Seet, L.-F.; Toh, L.Z.; Finger, S.N.; Chu, S.W.L.; Wong, T.T. Valproic Acid Exerts Specific Cellular and Molecular Anti-Inflammatory Effects in Post-Operative Conjunctiva. J. Mol. Med.; 2019; 97, pp. 63-75. [DOI: https://dx.doi.org/10.1007/s00109-018-1722-x]
124. Lee, J.Y.; Kim, H.S.; Choi, H.Y.; Oh, T.H.; Ju, B.G.; Yune, T.Y. Valproic Acid Attenuates Blood-Spinal Cord Barrier Disruption by Inhibiting Matrix Metalloprotease-9 Activity and Improves Functional Recovery after Spinal Cord Injury. J. Neurochem.; 2012; 121, pp. 818-829. [DOI: https://dx.doi.org/10.1111/j.1471-4159.2012.07731.x]
125. Glauben, R.; Batra, A.; Fedke, I.; Zeitz, M.; Lehr, H.A.; Leoni, F.; Mascagni, P.; Fantuzzi, G.; Dinarello, C.A.; Siegmund, B. Histone Hyperacetylation Is Associated with Amelioration of Experimental Colitis in Mice. J. Immunol.; 2006; 176, pp. 5015-5022. [DOI: https://dx.doi.org/10.4049/jimmunol.176.8.5015]
126. Lv, J.; Du, C.; Wei, W.; Wu, Z.; Zhao, G.; Li, Z.; Xie, X. The Antiepileptic Drug Valproic Acid Restores T Cell Homeostasis and Ameliorates Pathogenesis of Experimental Autoimmune Encephalomyelitis. J. Biol. Chem.; 2012; 287, pp. 28656-28665. [DOI: https://dx.doi.org/10.1074/jbc.M112.356584]
127. Shang, Y.; Jiang, Y.; Ding, Z.; Shen, A.; Xu, S.; Yuan, S.; Yao, S. Valproic Acid Attenuates the Multiple-Organ Dysfunction in a Rat Model of Septic Shock. Chin. Med. J.; 2010; 123, pp. 2682-2687.
128. Lin, T.; Chen, H.; Koustova, E.; Sailhamer, E.A.; Li, Y.; Shults, C.; Liu, B.; Rhee, P.; Kirkpatrick, J.; Alam, H.B. Histone Deacetylase as Therapeutic Target in a Rodent Model of Hemorrhagic Shock: Effect of Different Resuscitation Strategies on Lung and Liver. Surgery; 2007; 141, pp. 784-794. [DOI: https://dx.doi.org/10.1016/j.surg.2007.01.014]
129. Ximenes, J.C.M.; de Oliveira Gonçalves, D.; Siqueira, R.M.P.; Neves, K.R.T.; Santos Cerqueira, G.; Correia, A.O.; Félix, F.H.C.; Leal, L.K.A.M.; de Castro Brito, G.A.; da Graça Naffah-Mazzacorati, M. et al. Valproic Acid: An Anticonvulsant Drug with Potent Antinociceptive and Anti-Inflammatory Properties. Naunyn-Schmiedeberg’s Arch. Pharm.; 2013; 386, pp. 575-587. [DOI: https://dx.doi.org/10.1007/s00210-013-0853-4]
130. Amirzargar, M.A.; Yaghubi, F.; Hosseinipanah, M.; Jafari, M.; Pourjafar, M.; Rezaeepoor, M.; Rezaei, H.; Roshanaei, G.; Hajilooi, M.; Solgi, G. Anti-Inflammatory Effects of Valproic Acid in a Rat Model of Renal Ischemia/Reperfusion Injury: Alteration in Cytokine Profile. Inflammation; 2017; 40, pp. 1310-1318. [DOI: https://dx.doi.org/10.1007/s10753-017-0574-9]
131. Kasotakis, G.; Galvan, M.; King, E.; Sarkar, B.; Stucchi, A.; Mizgerd, J.P.; Burke, P.A.; Remick, D. Valproic Acid Mitigates the Inflammatory Response and Prevents Acute Respiratory Distress Syndrome in a Murine Model of Escherichia Coli Pneumonia at the Expense of Bacterial Clearance. J. Trauma Acute Care Surg.; 2017; 82, pp. 758-765. [DOI: https://dx.doi.org/10.1097/TA.0000000000001389]
132. Chen, L.; Alam, A.; Pac-Soo, A.; Chen, Q.; Shang, Y.; Zhao, H.; Yao, S.; Ma, D. Pretreatment with Valproic Acid Alleviates Pulmonary Fibrosis through Epithelial–Mesenchymal Transition Inhibition in Vitro and in Vivo. Lab. Investig.; 2021; 101, pp. 1166-1175. [DOI: https://dx.doi.org/10.1038/s41374-021-00617-2]
133. Juknevičienė, M.; Balnytė, I.; Valančiūtė, A.; Stanevičiūtė, J.; Sužiedėlis, K.; Stakišaitis, D. The Effect of Valproic Acid on SLC5A8 Expression in Gonad-Intact and Gonadectomized Rat Thymocytes. Int. J. Immunopathol. Pharm.; 2022; 36, 20587384211051954. [DOI: https://dx.doi.org/10.1177/20587384211051954]
134. Delgado, F.G.; Cárdenas, P.; Castellanos, J.E. Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus. Diseases; 2018; 6, 59. [DOI: https://dx.doi.org/10.3390/diseases6030059]
135. Vázquez-Calvo, A.; Saiz, J.-C.; Sobrino, F.; Martín-Acebes, M.A. Inhibition of Enveloped Virus Infection of Cultured Cells by Valproic Acid. J. Virol.; 2011; 85, pp. 1267-1274. [DOI: https://dx.doi.org/10.1128/JVI.01717-10]
136. Adhya, D.; Dutta, K.; Kundu, K.; Basu, A. Histone Deacetylase Inhibition by Japanese Encephalitis Virus in Monocyte/Macrophages: A Novel Viral Immune Evasion Strategy. Immunobiology; 2013; 218, pp. 1235-1247. [DOI: https://dx.doi.org/10.1016/j.imbio.2013.04.018]
137. Wu, C.; Li, A.; Leng, Y.; Li, Y.; Kang, J. Histone Deacetylase Inhibition by Sodium Valproate Regulates Polarization of Macrophage Subsets. DNA Cell Biol.; 2012; 31, pp. 592-599. [DOI: https://dx.doi.org/10.1089/dna.2011.1401]
138. Frikeche, J.; Simon, T.; Brissot, E.; Grégoire, M.; Gaugler, B.; Mohty, M. Impact of Valproic Acid on Dendritic Cells Function. Immunobiology; 2012; 217, pp. 704-710. [DOI: https://dx.doi.org/10.1016/j.imbio.2011.11.010]
139. Ersvaer, E.; Brenner, A.K.; Vetås, K.; Reikvam, H.; Bruserud, Ø. Effects of Cytarabine on Activation of Human T Cells—Cytarabine Has Concentration-Dependent Effects That Are Modulated Both by Valproic Acid and All-Trans Retinoic Acid. BMC Pharm. Toxicol.; 2015; 16, 12. [DOI: https://dx.doi.org/10.1186/s40360-015-0012-2]
140. Jambalganiin, U.; Tsolmongyn, B.; Koide, N.; Odkhuu, E.; Naiki, Y.; Komatsu, T.; Yoshida, T.; Yokochi, T. A Novel Mechanism for Inhibition of Lipopolysaccharide-Induced Proinflammatory Cytokine Production by Valproic Acid. Int. Immunopharmacol.; 2014; 20, pp. 181-187. [DOI: https://dx.doi.org/10.1016/j.intimp.2014.02.032]
141. Ichiyama, T.; Okada, K.; Lipton, J.M.; Matsubara, T.; Hayashi, T.; Furukawa, S. Sodium Valproate Inhibits Production of TNF-Alpha and IL-6 and Activation of NF-KappaB. Brain Res.; 2000; 857, pp. 246-251. [DOI: https://dx.doi.org/10.1016/S0006-8993(99)02439-7]
142. Nencioni, A.; Beck, J.; Werth, D.; Grünebach, F.; Patrone, F.; Ballestrero, A.; Brossart, P. Histone Deacetylase Inhibitors Affect Dendritic Cell Differentiation and Immunogenicity. Clin. Cancer Res.; 2007; 13, pp. 3933-3941. [DOI: https://dx.doi.org/10.1158/1078-0432.CCR-06-2903]
143. Nunn, A.V.W.; Guy, G.W.; Brysch, W.; Botchway, S.W.; Frasch, W.; Calabrese, E.J.; Bell, J.D. SARS-CoV-2 and Mitochondrial Health: Implications of Lifestyle and Ageing. Immun. Ageing; 2020; 17, 33. [DOI: https://dx.doi.org/10.1186/s12979-020-00204-x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33292333]
144. Liu, J.; Strâby, K.B. The Human TRNA(m(2)(2)G(26))Dimethyltransferase: Functional Expression and Characterization of a Cloned HTRM1 Gene. Nucleic Acids Res.; 2000; 28, pp. 3445-3451. [DOI: https://dx.doi.org/10.1093/nar/28.18.3445] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10982862]
145. Harikrishnan, K.N.; Okabe, J.; Mathiyalagan, P.; Khan, A.W.; Jadaan, S.A.; Sarila, G.; Ziemann, M.; Khurana, I.; Maxwell, S.S.; Du, X.-J. et al. Sex-Based Mhrt Methylation Chromatinizes MeCP2 in the Heart. iScience; 2019; 17, pp. 288-301. [DOI: https://dx.doi.org/10.1016/j.isci.2019.06.031]
146. Rajeshwari, T.; Raja, B.; Manivannan, J.; Silambarasan, T. Valproic Acid Attenuates Blood Pressure, Vascular Remodeling and Modulates ET-1 Expression in L-NAME Induced Hypertensive Rats. Biomed. Prev. Nutr.; 2014; 4, pp. 195-202. [DOI: https://dx.doi.org/10.1016/j.bionut.2013.09.002]
147. Silva, M.F.; Ruiter, J.P.; Illst, L.; Jakobs, C.; Duran, M.; de Almeida, I.T.; Wanders, R.J. Valproate Inhibits the Mitochondrial Pyruvate-Driven Oxidative Phosphorylation in Vitro. J. Inherit. Metab. Dis.; 1997; 20, pp. 397-400. [DOI: https://dx.doi.org/10.1023/A:1005398516208]
148. Thangaraju, M.; Ananth, S.; Martin, P.M.; Roon, P.; Smith, S.B.; Sterneck, E.; Prasad, P.D.; Ganapathy, V. C/Ebpdelta Null Mouse as a Model for the Double Knock-out of Slc5a8 and Slc5a12 in Kidney. J. Biol. Chem.; 2006; 281, pp. 26769-26773. [DOI: https://dx.doi.org/10.1074/jbc.C600189200]
149. Frank, H.; Gröger, N.; Diener, M.; Becker, C.; Braun, T.; Boettger, T. Lactaturia and Loss of Sodium-Dependent Lactate Uptake in the Colon of SLC5A8-Deficient Mice. J. Biol. Chem.; 2008; 283, pp. 24729-24737. [DOI: https://dx.doi.org/10.1074/jbc.M802681200]
150. Singh, N.; Thangaraju, M.; Prasad, P.D.; Martin, P.M.; Lambert, N.A.; Boettger, T.; Offermanns, S.; Ganapathy, V. Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-Dependent Inhibition of Histone Deacetylases. J. Biol. Chem.; 2010; 285, pp. 27601-27608. [DOI: https://dx.doi.org/10.1074/jbc.M110.102947]
151. Zimmerman, M.A.; Singh, N.; Martin, P.M.; Thangaraju, M.; Ganapathy, V.; Waller, J.L.; Shi, H.; Robertson, K.D.; Munn, D.H.; Liu, K. Butyrate Suppresses Colonic Inflammation through HDAC1-Dependent Fas Upregulation and Fas-Mediated Apoptosis of T Cells. Am. J. Physiol. Gastrointest. Liver Physiol.; 2012; 302, pp. G1405-G1415. [DOI: https://dx.doi.org/10.1152/ajpgi.00543.2011]
152. Thangaraju, M.; Carswell, K.N.; Prasad, P.D.; Ganapathy, V. Colon Cancer Cells Maintain Low Levels of Pyruvate to Avoid Cell Death Caused by Inhibition of HDAC1/HDAC3. Biochem. J.; 2009; 417, pp. 379-389. [DOI: https://dx.doi.org/10.1042/BJ20081132]
153. Babu, E.; Ramachandran, S.; CoothanKandaswamy, V.; Elangovan, S.; Prasad, P.D.; Ganapathy, V.; Thangaraju, M. Role of SLC5A8, a Plasma Membrane Transporter and a Tumor Suppressor, in the Antitumor Activity of Dichloroacetate. Oncogene; 2011; 30, pp. 4026-4037. [DOI: https://dx.doi.org/10.1038/onc.2011.113]
154. Milutinovic, S.; D’Alessio, A.C.; Detich, N.; Szyf, M. Valproate Induces Widespread Epigenetic Reprogramming Which Involves Demethylation of Specific Genes. Carcinogenesis; 2007; 28, pp. 560-571. [DOI: https://dx.doi.org/10.1093/carcin/bgl167]
155. Veronezi, G.M.; Felisbino, M.B.; Gatti, M.S.V.; Mello, M.L.S.; Vidal, B.D.C. DNA Methylation Changes in Valproic Acid-Treated HeLa Cells as Assessed by Image Analysis, Immunofluorescence and Vibrational Microspectroscopy. PLoS ONE; 2017; 12, e0170740. [DOI: https://dx.doi.org/10.1371/journal.pone.0170740]
156. Angajala, A.; Lim, S.; Phillips, J.B.; Kim, J.-H.; Yates, C.; You, Z.; Tan, M. Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism. Front. Immunol.; 2018; 9, 1605. [DOI: https://dx.doi.org/10.3389/fimmu.2018.01605]
157. Weinberg, S.E.; Sena, L.A.; Chandel, N.S. Mitochondria in the Regulation of Innate and Adaptive Immunity. Immunity; 2015; 42, pp. 406-417. [DOI: https://dx.doi.org/10.1016/j.immuni.2015.02.002]
158. Klein, S.L.; Flanagan, K.L. Sex Differences in Immune Responses. Nat. Rev. Immunol.; 2016; 16, pp. 626-638. [DOI: https://dx.doi.org/10.1038/nri.2016.90]
159. Vemuri, R.; Sylvia, K.E.; Klein, S.L.; Forster, S.C.; Plebanski, M.; Eri, R.; Flanagan, K.L. The Microgenderome Revealed: Sex Differences in Bidirectional Interactions between the Microbiota, Hormones, Immunity and Disease Susceptibility. Semin. Immunopathol.; 2019; 41, pp. 265-275. [DOI: https://dx.doi.org/10.1007/s00281-018-0716-7]
160. Bartz, D.; Chitnis, T.; Kaiser, U.B.; Rich-Edwards, J.W.; Rexrode, K.M.; Pennell, P.B.; Goldstein, J.M.; O’Neal, M.A.; LeBoff, M.; Behn, M. et al. Clinical Advances in Sex- and Gender-Informed Medicine to Improve the Health of All: A Review. JAMA Intern. Med.; 2020; 180, 574. [DOI: https://dx.doi.org/10.1001/jamainternmed.2019.7194]
161. Jaillon, S.; Berthenet, K.; Garlanda, C. Sexual Dimorphism in Innate Immunity. Clin. Rev. Allerg. Immunol.; 2019; 56, pp. 308-321. [DOI: https://dx.doi.org/10.1007/s12016-017-8648-x]
162. Xia, H.-J.; Zhang, G.-H.; Wang, R.-R.; Zheng, Y.-T. The Influence of Age and Sex on the Cell Counts of Peripheral Blood Leukocyte Subpopulations in Chinese Rhesus Macaques. Cell. Mol. Immunol.; 2009; 6, pp. 433-440. [DOI: https://dx.doi.org/10.1038/cmi.2009.55]
163. Melgert, B.N.; Oriss, T.B.; Qi, Z.; Dixon-McCarthy, B.; Geerlings, M.; Hylkema, M.N.; Ray, A. Macrophages: Regulators of Sex Differences in Asthma?. Am. J. Respir. Cell Mol. Biol.; 2010; 42, pp. 595-603. [DOI: https://dx.doi.org/10.1165/rcmb.2009-0016OC]
164. Wikby, A.; Månsson, I.A.; Johansson, B.; Strindhall, J.; Nilsson, S.E. The Immune Risk Profile Is Associated with Age and Gender: Findings from Three Swedish Population Studies of Individuals 20–100 Years of Age. Biogerontology; 2008; 9, pp. 299-308. [DOI: https://dx.doi.org/10.1007/s10522-008-9138-6]
165. Villacres, M.C.; Longmate, J.; Auge, C.; Diamond, D.J. Predominant Type 1 CMV-Specific Memory T-Helper Response in Humans: Evidence for Gender Differences in Cytokine Secretion. Hum. Immunol.; 2004; 65, pp. 476-485. [DOI: https://dx.doi.org/10.1016/j.humimm.2004.02.021]
166. Amadori, A.; Zamarchi, R.; De Silvestro, G.; Forza, G.; Cavatton, G.; Danieli, G.A.; Clementi, M.; Chieco-Bianchi, L. Genetic Control of the CD4/CD8 T-Cell Ratio in Humans. Nat. Med.; 1995; 1, pp. 1279-1283. [DOI: https://dx.doi.org/10.1038/nm1295-1279]
167. Das, B.R.; Bhanushali, A.A.; Khadapkar, R.; Jeswani, K.D.; Bhavsar, M.; Dasgupta, A. Reference Ranges for Lymphocyte Subsets in Adults from Western India: Influence of Sex, Age and Method of Enumeration. Indian J. Med. Sci.; 2008; 62, pp. 397-406. [DOI: https://dx.doi.org/10.4103/0019-5359.42725]
168. Pisitkun, P.; Deane, J.A.; Difilippantonio, M.J.; Tarasenko, T.; Satterthwaite, A.B.; Bolland, S. Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication. Science; 2006; 312, pp. 1669-1672. [DOI: https://dx.doi.org/10.1126/science.1124978]
169. Fink, A.L.; Engle, K.; Ursin, R.L.; Tang, W.-Y.; Klein, S.L. Biological Sex Affects Vaccine Efficacy and Protection against Influenza in Mice. Proc. Natl. Acad. Sci. USA; 2018; 115, pp. 12477-12482. [DOI: https://dx.doi.org/10.1073/pnas.1805268115]
170. Souyris, M.; Cenac, C.; Azar, P.; Daviaud, D.; Canivet, A.; Grunenwald, S.; Pienkowski, C.; Chaumeil, J.; Mejía, J.E.; Guéry, J.-C. TLR7 Escapes X Chromosome Inactivation in Immune Cells. Sci. Immunol.; 2018; 3, eaap8855. [DOI: https://dx.doi.org/10.1126/sciimmunol.aap8855]
171. Kovács, T.; Szabó-Meleg, E.; Ábrahám, I.M. Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression. Int. J. Mol. Sci.; 2020; 21, 3177. [DOI: https://dx.doi.org/10.3390/ijms21093177]
172. Casali, P.; Shen, T.; Xu, Y.; Qiu, Z.; Chupp, D.P.; Im, J.; Xu, Z.; Zan, H. Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of MiR-26a. Front. Immunol.; 2020; 11, 491. [DOI: https://dx.doi.org/10.3389/fimmu.2020.00491]
173. Bechmann, N.; Barthel, A.; Schedl, A.; Herzig, S.; Varga, Z.; Gebhard, C.; Mayr, M.; Hantel, C.; Beuschlein, F.; Wolfrum, C. et al. Sexual Dimorphism in COVID-19: Potential Clinical and Public Health Implications. Lancet Diabetes Endocrinol.; 2022; 10, pp. 221-230. [DOI: https://dx.doi.org/10.1016/S2213-8587(21)00346-6]
174. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X. et al. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. Lancet; 2020; 395, pp. 497-506. [DOI: https://dx.doi.org/10.1016/S0140-6736(20)30183-5]
175. Tan, M.; Liu, Y.; Zhou, R.; Deng, X.; Li, F.; Liang, K.; Shi, Y. Immunopathological Characteristics of Coronavirus Disease 2019 Cases in Guangzhou, China. Immunology; 2020; 160, pp. 261-268. [DOI: https://dx.doi.org/10.1111/imm.13223] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32460357]
176. Shi, Y.; Wang, Y.; Shao, C.; Huang, J.; Gan, J.; Huang, X.; Bucci, E.; Piacentini, M.; Ippolito, G.; Melino, G. COVID-19 Infection: The Perspectives on Immune Responses. Cell Death Differ.; 2020; 27, pp. 1451-1454. [DOI: https://dx.doi.org/10.1038/s41418-020-0530-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32205856]
177. Barnes, B.J.; Adrover, J.M.; Baxter-Stoltzfus, A.; Borczuk, A.; Cools-Lartigue, J.; Crawford, J.M.; Daßler-Plenker, J.; Guerci, P.; Huynh, C.; Knight, J.S. et al. Targeting Potential Drivers of COVID-19: Neutrophil Extracellular Traps. J. Exp. Med.; 2020; 217, e20200652. [DOI: https://dx.doi.org/10.1084/jem.20200652] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32302401]
178. Greene, R.; Lind, S.; Jantsch, H.; Wilson, R.; Lynch, K.; Jones, R.; Carvalho, A.; Reid, L.; Waltman, A.C.; Zapol, W. Pulmonary Vascular Obstruction in Severe ARDS: Angiographic Alterations after i.v. Fibrinolytic Therapy. AJR Am. J. Roentgenol.; 1987; 148, pp. 501-508. [DOI: https://dx.doi.org/10.2214/ajr.148.3.501]
179. Giannis, D.; Ziogas, I.A.; Gianni, P. Coagulation Disorders in Coronavirus Infected Patients: COVID-19, SARS-CoV-1, MERS-CoV and Lessons from the Past. J. Clin. Virol.; 2020; 127, 104362. [DOI: https://dx.doi.org/10.1016/j.jcv.2020.104362]
180. Klok, F.A.; Kruip, M.J.H.A.; Van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.A.M.P.J.; Kant, K.M.; Endeman, H. Incidence of Thrombotic Complications in Critically Ill ICU Patients with COVID-19. Thromb. Res.; 2020; 191, pp. 145-147. [DOI: https://dx.doi.org/10.1016/j.thromres.2020.04.013]
181. Cohen, K.R.; Anderson, D.; Ren, S.; Cook, D.J. Contribution of the Elevated Thrombosis Risk of Males to the Excess Male Mortality Observed in COVID-19: An Observational Study. BMJ Open; 2022; 12, e051624. [DOI: https://dx.doi.org/10.1136/bmjopen-2021-051624]
182. Malas, M.B.; Naazie, I.N.; Elsayed, N.; Mathlouthi, A.; Marmor, R.; Clary, B. Thromboembolism Risk of COVID-19 Is High and Associated with a Higher Risk of Mortality: A Systematic Review and Meta-Analysis. EClinicalMedicine; 2020; 29, 100639. [DOI: https://dx.doi.org/10.1016/j.eclinm.2020.100639]
183. Magro, C.; Mulvey, J.J.; Berlin, D.; Nuovo, G.; Salvatore, S.; Harp, J.; Baxter-Stoltzfus, A.; Laurence, J. Complement Associated Microvascular Injury and Thrombosis in the Pathogenesis of Severe COVID-19 Infection: A Report of Five Cases. Transl. Res.; 2020; 220, pp. 1-13. [DOI: https://dx.doi.org/10.1016/j.trsl.2020.04.007]
184. Manne, B.K.; Denorme, F.; Middleton, E.A.; Portier, I.; Rowley, J.W.; Stubben, C.; Petrey, A.C.; Tolley, N.D.; Guo, L.; Cody, M. et al. Platelet Gene Expression and Function in Patients with COVID-19. Blood; 2020; 136, pp. 1317-1329. [DOI: https://dx.doi.org/10.1182/blood.2020007214]
185. Biembengut, Í.V.; de Souza, T.D.A.C.B. Coagulation Modifiers Targeting SARS-CoV-2 Main Protease Mpro for COVID-19 Treatment: An in Silico Approach. Mem. Inst. Oswaldo Cruz; 2020; 115, e200179. [DOI: https://dx.doi.org/10.1590/0074-02760200179]
186. Campbell, C.M.; Kahwash, R. Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis?. Circulation; 2020; 141, pp. 1739-1741. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.120.047419]
187. Li, T.; Lu, H.; Zhang, W. Clinical Observation and Management of COVID-19 Patients. Emerg. Microbes Infect.; 2020; 9, pp. 687-690. [DOI: https://dx.doi.org/10.1080/22221751.2020.1741327]
188. Uthman, I.W.; Gharavi, A.E. Viral Infections and Antiphospholipid Antibodies. Semin. Arthritis Rheum.; 2002; 31, pp. 256-263. [DOI: https://dx.doi.org/10.1053/sarh.2002.28303]
189. Zhang, Y.; Xiao, M.; Zhang, S.; Xia, P.; Cao, W.; Jiang, W.; Chen, H.; Ding, X.; Zhao, H.; Zhang, H. et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N. Engl. J. Med.; 2020; 382, e38. [DOI: https://dx.doi.org/10.1056/NEJMc2007575]
190. Bikdeli, B.; Madhavan, M.V.; Jimenez, D.; Chuich, T.; Dreyfus, I.; Driggin, E.; Nigoghossian, C.D.; Ageno, W.; Madjid, M.; Guo, Y. et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J. Am. Coll. Cardiol.; 2020; 75, pp. 2950-2973. [DOI: https://dx.doi.org/10.1016/j.jacc.2020.04.031]
191. Yang, H.; Xie, W.; Xue, X.; Yang, K.; Ma, J.; Liang, W.; Zhao, Q.; Zhou, Z.; Pei, D.; Ziebuhr, J. et al. Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases. PLoS Biol.; 2005; 3, e324. [DOI: https://dx.doi.org/10.1371/journal.pbio.0030324]
192. Bilaloglu, S.; Aphinyanaphongs, Y.; Jones, S.; Iturrate, E.; Hochman, J.; Berger, J.S. Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System. JAMA; 2020; 324, pp. 799-801. [DOI: https://dx.doi.org/10.1001/jama.2020.13372]
193. Zhang, L.; Feng, X.; Zhang, D.; Jiang, C.; Mei, H.; Wang, J.; Zhang, C.; Li, H.; Xia, X.; Kong, S. et al. Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome. Circulation; 2020; 142, pp. 114-128. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.120.046702]
194. Gerotziafas, G.T.; Catalano, M.; Colgan, M.-P.; Pecsvarady, Z.; Wautrecht, J.C.; Fazeli, B.; Olinic, D.-M.; Farkas, K.; Elalamy, I.; Falanga, A. et al. Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine. Thromb. Haemost.; 2020; 120, pp. 1597-1628. [DOI: https://dx.doi.org/10.1055/s-0040-1715798]
195. Panigada, M.; Bottino, N.; Tagliabue, P.; Grasselli, G.; Novembrino, C.; Chantarangkul, V.; Pesenti, A.; Peyvandi, F.; Tripodi, A. Hypercoagulability of COVID-19 Patients in Intensive Care Unit: A Report of Thromboelastography Findings and Other Parameters of Hemostasis. J. Thromb. Haemost.; 2020; 18, pp. 1738-1742. [DOI: https://dx.doi.org/10.1111/jth.14850]
196. Goshua, G.; Pine, A.B.; Meizlish, M.L.; Chang, C.-H.; Zhang, H.; Bahel, P.; Baluha, A.; Bar, N.; Bona, R.D.; Burns, A.J. et al. Endotheliopathy in COVID-19-Associated Coagulopathy: Evidence from a Single-Centre, Cross-Sectional Study. Lancet Haematol.; 2020; 7, pp. e575-e582. [DOI: https://dx.doi.org/10.1016/S2352-3026(20)30216-7]
197. Wang, F.; Hou, H.; Luo, Y.; Tang, G.; Wu, S.; Huang, M.; Liu, W.; Zhu, Y.; Lin, Q.; Mao, L. et al. The Laboratory Tests and Host Immunity of COVID-19 Patients with Different Severity of Illness. JCI Insight; 2020; 5, 137799. [DOI: https://dx.doi.org/10.1172/jci.insight.137799] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32324595]
198. Andrianto,; Al-Farabi, M.J.; Nugraha, R.A.; Marsudi, B.A.; Azmi, Y. Biomarkers of Endothelial Dysfunction and Outcomes in Coronavirus Disease 2019 (COVID-19) Patients: A Systematic Review and Meta-Analysis. Microvasc. Res.; 2021; 138, 104224. [DOI: https://dx.doi.org/10.1016/j.mvr.2021.104224] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34273359]
199. Kis, B.; Szupera, Z.; Mezei, Z.; Gecse, A.; Telegdy, G.; Vecsei, L. Valproate Treatment and Platelet Function: The Role of Arachidonate Metabolites. Epilepsia; 1999; 40, pp. 307-310. [DOI: https://dx.doi.org/10.1111/j.1528-1157.1999.tb00709.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10080510]
200. Bishton, M.J.; Harrison, S.J.; Martin, B.P.; McLaughlin, N.; James, C.; Josefsson, E.C.; Henley, K.J.; Kile, B.T.; Prince, H.M.; Johnstone, R.W. Deciphering the Molecular and Biologic Processes That Mediate Histone Deacetylase Inhibitor-Induced Thrombocytopenia. Blood; 2011; 117, pp. 3658-3668. [DOI: https://dx.doi.org/10.1182/blood-2010-11-318055] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21292776]
201. Larsson, P.; Alwis, I.; Niego, B.; Sashindranath, M.; Fogelstrand, P.; Wu, M.C.L.; Glise, L.; Magnusson, M.; Daglas, M.; Bergh, N. et al. Valproic Acid Selectively Increases Vascular Endothelial Tissue-Type Plasminogen Activator Production and Reduces Thrombus Formation in the Mouse. J. Thromb. Haemost.; 2016; 14, pp. 2496-2508. [DOI: https://dx.doi.org/10.1111/jth.13527]
202. Niklas, B.; Idström, J.-P.; Abdoulaye, C.; Hansson, H.; Faijerson-Säljö, J.; Dahlöf, B. A First in Class Treatment for Thrombosis Prevention? A Phase I Study with Cs1, a New Controlled Release Formulation of Sodium Valproate. J. Cardio Vasc. Med.; 2019; 5, pp. 1-12.
203. Nasreddine, W.; Beydoun, A. Valproate-Induced Thrombocytopenia: A Prospective Monotherapy Study. Epilepsia; 2008; 49, pp. 438-445. [DOI: https://dx.doi.org/10.1111/j.1528-1167.2007.01429.x]
204. Warkentin, T.E.; Sheppard, J.-A.I.; Sigouin, C.S.; Kohlmann, T.; Eichler, P.; Greinacher, A. Gender Imbalance and Risk Factor Interactions in Heparin-Induced Thrombocytopenia. Blood; 2006; 108, pp. 2937-2941. [DOI: https://dx.doi.org/10.1182/blood-2005-11-012450]
205. Banerjea, M.C.; Diener, W.; Kutschke, G.; Schneble, H.J.; Korinthenberg, R.; Sutor, A.H. Pro- and Anticoagulatory Factors under Sodium Valproate-Therapy in Children. Neuropediatrics; 2002; 33, pp. 215-220. [DOI: https://dx.doi.org/10.1055/s-2002-34499]
206. Koenig, S.; Gerstner, T.; Keller, A.; Teich, M.; Longin, E.; Dempfle, C.-E. High Incidence of Vaproate-Induced Coagulation Disorders in Children Receiving Valproic Acid: A Prospective Study. Blood Coagul. Fibrinolysis; 2008; 19, pp. 375-382. [DOI: https://dx.doi.org/10.1097/MBC.0b013e3282f3f9ec]
207. Ugras, M.; Yakinci, C. Protein C, Protein S and Other pro- and Anticoagulant Activities among Epileptic Children Using Sodium Valproate. Brain Dev.; 2006; 28, pp. 549-553. [DOI: https://dx.doi.org/10.1016/j.braindev.2006.03.009]
208. Köse, G.; Arhan, E.; Unal, B.; Ozaydin, E.; Guven, A.; Sayli, T.R. Valproate-Associated Coagulopathies in Children during Short-Term Treatment. J. Child Neurol.; 2009; 24, pp. 1493-1498. [DOI: https://dx.doi.org/10.1177/0883073808331084]
209. Felisbino, M.B.; Ziemann, M.; Khurana, I.; Okabe, J.; Al-Hasani, K.; Maxwell, S.; Harikrishnan, K.N.; de Oliveira, C.B.M.; Mello, M.L.S.; El-Osta, A. Valproic Acid Influences the Expression of Genes Implicated with Hyperglycaemia-Induced Complement and Coagulation Pathways. Sci. Rep.; 2021; 11, 2163. [DOI: https://dx.doi.org/10.1038/s41598-021-81794-4]
210. Larsson, P.; Ulfhammer, E.; Magnusson, M.; Bergh, N.; Lunke, S.; El-Osta, A.; Medcalf, R.L.; Svensson, P.-A.; Karlsson, L.; Jern, S. Role of Histone Acetylation in the Stimulatory Effect of Valproic Acid on Vascular Endothelial Tissue-Type Plasminogen Activator Expression. PLoS ONE; 2012; 7, e31573. [DOI: https://dx.doi.org/10.1371/journal.pone.0031573]
211. Bambakidis, T.; Dekker, S.E.; Halaweish, I.; Liu, B.; Nikolian, V.C.; Georgoff, P.E.; Piascik, P.; Li, Y.; Sillesen, M.; Alam, H.B. Valproic Acid Modulates Platelet and Coagulation Function Ex Vivo. Blood Coagul. Fibrinolysis; 2017; 28, pp. 479-484. [DOI: https://dx.doi.org/10.1097/MBC.0000000000000626]
212. Song, W.-C.; FitzGerald, G.A. COVID-19, Microangiopathy, Hemostatic Activation, and Complement. J. Clin. Investig.; 2020; 130, pp. 3950-3953. [DOI: https://dx.doi.org/10.1172/JCI140183]
213. Leatherdale, A.; Stukas, S.; Lei, V.; West, H.E.; Campbell, C.J.; Hoiland, R.L.; Cooper, J.; Wellington, C.L.; Sekhon, M.S.; Pryzdial, E.L.G. et al. Persistently Elevated Complement Alternative Pathway Biomarkers in COVID-19 Correlate with Hypoxemia and Predict in-Hospital Mortality. Med. Microbiol. Immunol.; 2022; 211, pp. 37-48. [DOI: https://dx.doi.org/10.1007/s00430-021-00725-2]
214. Afzali, B.; Noris, M.; Lambrecht, B.N.; Kemper, C. The State of Complement in COVID-19. Nat. Rev. Immunol.; 2022; 22, pp. 77-84. [DOI: https://dx.doi.org/10.1038/s41577-021-00665-1]
215. Gaya da Costa, M.; Poppelaars, F.; van Kooten, C.; Mollnes, T.E.; Tedesco, F.; Würzner, R.; Trouw, L.A.; Truedsson, L.; Daha, M.R.; Roos, A. et al. Age and Sex-Associated Changes of Complement Activity and Complement Levels in a Healthy Caucasian Population. Front. Immunol.; 2018; 9, 2664. [DOI: https://dx.doi.org/10.3389/fimmu.2018.02664]
216. Wu, M.; Rowe, J.M.; Fleming, S.D. Complement Initiation Varies by Sex in Intestinal Ischemia Reperfusion Injury. Front. Immunol.; 2021; 12, 649882. [DOI: https://dx.doi.org/10.3389/fimmu.2021.649882]
217. Kumar, N.; Zuo, Y.; Yalavarthi, S.; Hunker, K.L.; Knight, J.S.; Kanthi, Y.; Obi, A.T.; Ganesh, S.K. SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism. Viruses; 2021; 13, 2209. [DOI: https://dx.doi.org/10.3390/v13112209]
218. Evans, P.C.; Rainger, G.E.; Mason, J.C.; Guzik, T.J.; Osto, E.; Stamataki, Z.; Neil, D.; Hoefer, I.E.; Fragiadaki, M.; Waltenberger, J. et al. Endothelial Dysfunction in COVID-19: A Position Paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc. Res.; 2020; 116, pp. 2177-2184. [DOI: https://dx.doi.org/10.1093/cvr/cvaa230]
219. Causey, M.W.; Salgar, S.; Singh, N.; Martin, M.; Stallings, J.D. Valproic Acid Reversed Pathologic Endothelial Cell Gene Expression Profile Associated with Ischemia-Reperfusion Injury in a Swine Hemorrhagic Shock Model. J. Vasc. Surg.; 2012; 55, pp. 1096-1103.e51. [DOI: https://dx.doi.org/10.1016/j.jvs.2011.08.060]
220. Pastorcic, M.; De, A.; Boyadjieva, N.; Vale, W.; Sarkar, D.K. Reduction in the Expression and Action of Transforming Growth Factor Beta 1 on Lactotropes during Estrogen-Induced Tumorigenesis in the Anterior Pituitary. Cancer Res.; 1995; 55, pp. 4892-4898.
221. Larsson, P.; Bergh, N.; Lu, E.; Ulfhammer, E.; Magnusson, M.; Wåhlander, K.; Karlsson, L.; Jern, S. Histone Deacetylase Inhibitors Stimulate Tissue-Type Plasminogen Activator Production in Vascular Endothelial Cells. J. Thromb. Thrombolysis; 2013; 35, pp. 185-192. [DOI: https://dx.doi.org/10.1007/s11239-012-0831-6]
222. Svennerholm, K.; Bergh, N.; Larsson, P.; Jern, S.; Johansson, G.; Biber, B.; Haney, M. Histone Deacetylase Inhibitor Treatment Increases Coronary T-PA Release in a Porcine Ischemia Model. PLoS ONE; 2014; 9, e97260. [DOI: https://dx.doi.org/10.1371/journal.pone.0097260]
223. Svennerholm, K.; Haney, M.; Biber, B.; Ulfhammer, E.; Saluveer, O.; Larsson, P.; Omerovic, E.; Jern, S.; Bergh, N. Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man. PLoS ONE; 2015; 10, e0121196. [DOI: https://dx.doi.org/10.1371/journal.pone.0121196]
224. Saluveer, O.; Larsson, P.; Ridderstråle, W.; Hrafnkelsdóttir, T.J.; Jern, S.; Bergh, N. Profibrinolytic Effect of the Epigenetic Modifier Valproic Acid in Man. PLoS ONE; 2014; 9, e107582. [DOI: https://dx.doi.org/10.1371/journal.pone.0107582] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25295869]
225. Poli, K.A.; Tofler, G.H.; Larson, M.G.; Evans, J.C.; Sutherland, P.A.; Lipinska, I.; Mittleman, M.A.; Muller, J.E.; D’Agostino, R.B.; Wilson, P.W. et al. Association of Blood Pressure with Fibrinolytic Potential in the Framingham Offspring Population. Circulation; 2000; 101, pp. 264-269. [DOI: https://dx.doi.org/10.1161/01.CIR.101.3.264]
226. Song, C.; Burgess, S.; Eicher, J.D.; O’Donnell, C.J.; Johnson, A.D. Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease. J. Am. Heart Assoc.; 2017; 6, e004918. [DOI: https://dx.doi.org/10.1161/JAHA.116.004918] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28550093]
227. Hrafnkelsdóttir, T.; Ottosson, P.; Gudnason, T.; Samuelsson, O.; Jern, S. Impaired Endothelial Release of Tissue-Type Plasminogen Activator in Patients with Chronic Kidney Disease and Hypertension. Hypertension; 2004; 44, pp. 300-304. [DOI: https://dx.doi.org/10.1161/01.HYP.0000137380.91476.fb] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15249548]
228. Hrafnkelsdóttir, T.; Wall, U.; Jern, C.; Jern, S. Impaired Capacity for Endogenous Fibrinolysis in Essential Hypertension. Lancet; 1998; 352, pp. 1597-1598. [DOI: https://dx.doi.org/10.1016/S0140-6736(05)61044-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9843110]
229. Newby, D.E.; McLeod, A.L.; Uren, N.G.; Flint, L.; Ludlam, C.A.; Webb, D.J.; Fox, K.A.; Boon, N.A. Impaired Coronary Tissue Plasminogen Activator Release Is Associated with Coronary Atherosclerosis and Cigarette Smoking: Direct Link between Endothelial Dysfunction and Atherothrombosis. Circulation; 2001; 103, pp. 1936-1941. [DOI: https://dx.doi.org/10.1161/01.CIR.103.15.1936] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11306520]
230. Osterlund, B.; Jern, S.; Jern, C.; Seeman-Lodding, H.; Ostman, M.; Johansson, G.; Biber, B. Impaired Myocardial T-PA Release in Patients with Coronary Artery Disease. Acta Anaesthesiol. Scand.; 2008; 52, pp. 1375-1384. [DOI: https://dx.doi.org/10.1111/j.1399-6576.2008.01741.x]
231. Van Guilder, G.P.; Hoetzer, G.L.; Smith, D.T.; Irmiger, H.M.; Greiner, J.J.; Stauffer, B.L.; DeSouza, C.A. Endothelial T-PA Release Is Impaired in Overweight and Obese Adults but Can Be Improved with Regular Aerobic Exercise. Am. J. Physiol. Endocrinol. Metab; 2005; 289, pp. E807-E813. [DOI: https://dx.doi.org/10.1152/ajpendo.00072.2005]
232. Cavagnaro, J.A. Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. Nat. Rev. Drug Discov.; 2002; 1, pp. 469-475. [DOI: https://dx.doi.org/10.1038/nrd822]
233. U.S. Food and Drug Administration. Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs; Notice. Fed. Regist.; 1993; 58, pp. 39406-39416.
234. Clayton, J.A.; Collins, F.S. Policy: NIH to Balance Sex in Cell and Animal Studies. Nature; 2014; 509, pp. 282-283. [DOI: https://dx.doi.org/10.1038/509282a]
235. De Vries, S.T.; Starokozhko, V.; Schellens, I.M.M.; Wijnans, L.; Enzmann, H.; Cavaleri, M.; Mol, P.G.M. Attention for Sex in COVID-19 Trials: A Review of Regulatory Dossiers. BMJ Glob. Health; 2022; 7, e008173. [DOI: https://dx.doi.org/10.1136/bmjgh-2021-008173]
236. Adcock, I.M. HDAC Inhibitors as Anti-Inflammatory Agents. Br. J. Pharm.; 2007; 150, pp. 829-831. [DOI: https://dx.doi.org/10.1038/sj.bjp.0707166]
237. El-Bacha, T.; Da Poian, A.T. Virus-Induced Changes in Mitochondrial Bioenergetics as Potential Targets for Therapy. Int. J. Biochem. Cell Biol.; 2013; 45, pp. 41-46. [DOI: https://dx.doi.org/10.1016/j.biocel.2012.09.021]
238. Mihaylova, M.M.; Vasquez, D.S.; Ravnskjaer, K.; Denechaud, P.-D.; Yu, R.T.; Alvarez, J.G.; Downes, M.; Evans, R.M.; Montminy, M.; Shaw, R.J. Class IIa Histone Deacetylases Are Hormone-Activated Regulators of FOXO and Mammalian Glucose Homeostasis. Cell; 2011; 145, pp. 607-621. [DOI: https://dx.doi.org/10.1016/j.cell.2011.03.043]
239. Day, M. Covid-19: Ibuprofen Should Not Be Used for Managing Symptoms, Say Doctors and Scientists. BMJ; 2020; 368, m1086. [DOI: https://dx.doi.org/10.1136/bmj.m1086]
240. Itagaki, S.; Gopal, E.; Zhuang, L.; Fei, Y.-J.; Miyauchi, S.; Prasad, P.D.; Ganapathy, V. Interaction of Ibuprofen and Other Structurally Related NSAIDs with the Sodium-Coupled Monocarboxylate Transporter SMCT1 (SLC5A8). Pharm. Res.; 2006; 23, pp. 1209-1216. [DOI: https://dx.doi.org/10.1007/s11095-006-0023-1]
241. Shyer, J.A.; Flavell, R.A.; Bailis, W. Metabolic Signaling in T Cells. Cell Res.; 2020; 30, pp. 649-659. [DOI: https://dx.doi.org/10.1038/s41422-020-0379-5]
242. Sinclair, L.V.; Rolf, J.; Emslie, E.; Shi, Y.-B.; Taylor, P.M.; Cantrell, D.A. Control of Amino-Acid Transport by Antigen Receptors Coordinates the Metabolic Reprogramming Essential for T Cell Differentiation. Nat. Immunol.; 2013; 14, pp. 500-508. [DOI: https://dx.doi.org/10.1038/ni.2556]
243. Kidani, Y.; Elsaesser, H.; Hock, M.B.; Vergnes, L.; Williams, K.J.; Argus, J.P.; Marbois, B.N.; Komisopoulou, E.; Wilson, E.B.; Osborne, T.F. et al. Sterol Regulatory Element–Binding Proteins Are Essential for the Metabolic Programming of Effector T Cells and Adaptive Immunity. Nat. Immunol.; 2013; 14, pp. 489-499. [DOI: https://dx.doi.org/10.1038/ni.2570] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23563690]
244. Wang, R.; Dillon, C.P.; Shi, L.Z.; Milasta, S.; Carter, R.; Finkelstein, D.; McCormick, L.L.; Fitzgerald, P.; Chi, H.; Munger, J. et al. The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation. Immunity; 2011; 35, pp. 871-882. [DOI: https://dx.doi.org/10.1016/j.immuni.2011.09.021] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22195744]
245. Codo, A.C.; Davanzo, G.G.; de Monteiro, L.B.; de Souza, G.F.; Muraro, S.P.; Virgilio-da-Silva, J.V.; Prodonoff, J.S.; Carregari, V.C.; de Biagi Junior, C.A.O.; Crunfli, F. et al. Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis. Cell Metab.; 2020; 32, pp. 437-446.e5. [DOI: https://dx.doi.org/10.1016/j.cmet.2020.07.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32697943]
246. Khan, S.; Jena, G. Valproic Acid Improves Glucose Homeostasis by Increasing Beta-Cell Proliferation, Function, and Reducing Its Apoptosis through HDAC Inhibition in Juvenile Diabetic Rat. J. Biochem. Mol. Toxicol.; 2016; 30, pp. 438-446. [DOI: https://dx.doi.org/10.1002/jbt.21807]
247. Rakitin, A.; Kõks, S.; Haldre, S. Valproate Modulates Glucose Metabolism in Patients with Epilepsy after First Exposure. Epilepsia; 2015; 56, pp. e172-e175. [DOI: https://dx.doi.org/10.1111/epi.13114]
248. Brookes, R.L.; Crichton, S.; Wolfe, C.D.A.; Yi, Q.; Li, L.; Hankey, G.J.; Rothwell, P.M.; Markus, H.S. Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated with Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack. Stroke; 2018; 49, pp. 54-61. [DOI: https://dx.doi.org/10.1161/STROKEAHA.117.016674]
249. Dregan, A.; Charlton, J.; Wolfe, C.D.A.; Gulliford, M.C.; Markus, H.S. Is Sodium Valproate, an HDAC Inhibitor, Associated with Reduced Risk of Stroke and Myocardial Infarction? A Nested Case-Control Study. Pharm. Drug Saf.; 2014; 23, pp. 759-767. [DOI: https://dx.doi.org/10.1002/pds.3651]
250. Olesen, J.B.; Abildstrøm, S.Z.; Erdal, J.; Gislason, G.H.; Weeke, P.; Andersson, C.; Torp-Pedersen, C.; Hansen, P.R. Effects of Epilepsy and Selected Antiepileptic Drugs on Risk of Myocardial Infarction, Stroke, and Death in Patients with or without Previous Stroke: A Nationwide Cohort Study. Pharm. Drug Saf.; 2011; 20, pp. 964-971. [DOI: https://dx.doi.org/10.1002/pds.2186]
251. Olesen, J.B.; Hansen, P.R.; Abildstrøm, S.Z.; Andersson, C.; Weeke, P.; Schmiegelow, M.; Erdal, J.; Torp-Pedersen, C.; Gislason, G.H. Valproate Attenuates the Risk of Myocardial Infarction in Patients with Epilepsy: A Nationwide Cohort Study. Pharm. Drug Saf.; 2011; 20, pp. 146-153. [DOI: https://dx.doi.org/10.1002/pds.2073]
252. Capodanno, D.; Huber, K.; Mehran, R.; Lip, G.Y.H.; Faxon, D.P.; Granger, C.B.; Vranckx, P.; Lopes, R.D.; Montalescot, G.; Cannon, C.P. et al. Management of Antithrombotic Therapy in Atrial Fibrillation Patients Undergoing PCI: JACC State-of-the-Art Review. J. Am. Coll. Cardiol.; 2019; 74, pp. 83-99. [DOI: https://dx.doi.org/10.1016/j.jacc.2019.05.016]
253. Zhao, S.; Wang, X.; Wang, Y.; Xu, J.; Zhu, G.; Zhao, C.; Teng, W. Effects of Valproate on Reproductive Endocrine Function in Male Patients with Epilepsy: A Systematic Review and Meta-Analysis. Epilepsy Behav.; 2018; 85, pp. 120-128. [DOI: https://dx.doi.org/10.1016/j.yebeh.2018.04.029]
254. Montopoli, M.; Zumerle, S.; Vettor, R.; Rugge, M.; Zorzi, M.; Catapano, C.V.; Carbone, G.M.; Cavalli, A.; Pagano, F.; Ragazzi, E. et al. Androgen-Deprivation Therapies for Prostate Cancer and Risk of Infection by SARS-CoV-2: A Population-Based Study (N = 4532). Ann. Oncol.; 2020; 31, pp. 1040-1045. [DOI: https://dx.doi.org/10.1016/j.annonc.2020.04.479]
255. Klein, E.A.; Li, J.; Milinovich, A.; Schold, J.D.; Sharifi, N.; Kattan, M.W.; Jehi, L. Androgen Deprivation Therapy in Men with Prostate Cancer Does Not Affect Risk of Infection with SARS-CoV-2. J. Urol.; 2021; 205, pp. 441-443. [DOI: https://dx.doi.org/10.1097/JU.0000000000001338]
256. Samuel, R.M.; Majd, H.; Richter, M.N.; Ghazizadeh, Z.; Zekavat, S.M.; Navickas, A.; Ramirez, J.T.; Asgharian, H.; Simoneau, C.R.; Bonser, L.R. et al. Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men. Cell Stem Cell; 2020; 27, pp. 876-889. [DOI: https://dx.doi.org/10.1016/j.stem.2020.11.009]
257. Stopsack, K.H.; Mucci, L.A.; Antonarakis, E.S.; Nelson, P.S.; Kantoff, P.W. TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention?. Cancer Discov.; 2020; 10, pp. 779-782. [DOI: https://dx.doi.org/10.1158/2159-8290.CD-20-0451]
258. Sharifi, N.; Ryan, C.J. Androgen Hazards with COVID-19. Endocr. Relat. Cancer; 2020; 27, pp. E1-E3. [DOI: https://dx.doi.org/10.1530/ERC-20-0133]
259. Musselman, D. A Practical, Pilot, Randomized, Controlled Trial of Valproate Alone or in Combination with Quetiapine for Severe COVID-19 Pneumonia with Agitated Delirium 2021. Available online: https://clinicaltrials.gov/ct2/show/NCT04513314 (accessed on 14 January 2021).
260. Chiquete, E.; Toapanta-Yanchapaxi, L.; Cantú-Brito, C. Methods of An Open-Label Proof-of-Concept Trial of Intravenous Valproic Acid for Severe COVID-19. LAJCSMT; 2020; 2, pp. 44-48. [DOI: https://dx.doi.org/10.34141/LJCS6241818]
261. Collazos, J.; Domingo, P.; Fernández-Araujo, N.; Asensi-Díaz, E.; Vilchez-Rueda, H.; Lalueza, A.; Roy-Vallejo, E.; Blanes, R.; Raya-Cruz, M.; Sanz-Cánovas, J. et al. Exposure to Valproic Acid Is Associated with Less Pulmonary Infiltrates and Improvements in Diverse Clinical Outcomes and Laboratory Parameters in Patients Hospitalized with COVID-19. PLoS ONE; 2022; 17, e0262777. [DOI: https://dx.doi.org/10.1371/journal.pone.0262777]
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Abstract
Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic acid (VPA) is a potential drug that could be adapted to prevent the progression and complications of SARS-CoV-2 infection. VPA has a history of research in the treatment of various viral infections. This article reviews the preclinical data, showing that the pharmacological impact of VPA may apply to COVID-19 pathogenetic mechanisms. VPA inhibits SARS-CoV-2 virus entry, suppresses the pro-inflammatory immune cell and cytokine response to infection, and reduces inflammatory tissue and organ damage by mechanisms that may appear to be sex-related. The antithrombotic, antiplatelet, anti-inflammatory, immunomodulatory, glucose- and testosterone-lowering in blood serum effects of VPA suggest that the drug could be promising for therapy of COVID-19. Sex-related differences in the efficacy of VPA treatment may be significant in developing a personalised treatment strategy for COVID-19.
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Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
; Kapočius, Linas 2 ; Valančiūtė, Angelija 2
; Balnytė, Ingrida 2 ; Tamošuitis, Tomas 3
; Vaitkevičius, Arūnas 4 ; Sužiedėlis, Kęstutis 5 ; Urbonienė, Daiva 6
; Tatarūnas, Vacis 7 ; Kilimaitė, Evelina 2 ; Gečys, Dovydas 7
; Lesauskaitė, Vaiva 7
1 Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania;
2 Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
3 Department of Intensive Care Medicine, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
4 Institute of Clinical Medicine, Faculty of Medicine, Vilnius University Hospital Santaros Klinikos, Vilnius University, 08661 Vilnius, Lithuania;
5 Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania;
6 Department of Laboratory Medicine, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, 50161 Kaunas, Lithuania;
7 Institute of Cardiology, Laboratory of Molecular Cardiology, Lithuanian University of Health Sciences, Sukileliu Ave., 50161 Kaunas, Lithuania;