Estatinas en COVID-19: ¿existe algún fundamento? / Statins in COVID-19: is there any foundation?

El coronavirus tipo 2 del síndrome respiratorio agudo grave (SARS-CoV-2) es el agente causal de la enfermedad por coronavirus 2019 (COVID-19). El síndrome de distress respiratorio agudo constituye la principal causa de muerte por COVID-19 y ocurre por una respuesta inflamatoria exagerada que provoca la liberación de citocinas proinflamatorias como interleucinas y factor de necrosis tumoral alfa (TNF-α). Las estatinas son fármacos hipolipemiantes con efectos pleiotrópicos. Han demostrado beneficio en el manejo de enfermedades inflamatorias y autoinmunes como el lupus eritematoso sistémico, la artritis reumatoide y la esclerosis múltiple. Además, debido a sus propiedades inmunomoduladoras se han utilizado en el tratamiento de diversas enfermedades infecciosas como neumonía adquirida en la comunidad e influenza. En esta revisión analizamos los fundamentos fisiopatológicos que apoyan el uso de estatinas como tratamiento coadyuvante en pacientes con COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19). Acute respiratory distress syndrome is the main cause of death from COVID-19 and occurs due to an exaggerated inflammatory response that causes the release of pro-inflammatory cytokines such as interleukins and tumor necrosis factor-alpha (TNF-α). Statins are lipid lowering drugs with pleiotropic effects. They have shown benefit in the management of inflammatory and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. Furthermore, due to their immunomodulatory properties, they have been used in the treatment of various infectious diseases such as community-acquired pneumonia and influenza. In this review we analyze the pathophysiological foundations that support the use of statins as an adjunctive treatment in patients with COVID-19

Statins in COVID-19: is there any foundation? / Estatinas en COVID-19: ¿existe algún fundamento?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19). Acute respiratory distress syndrome is the main cause of death from COVID-19 and occurs due to an exaggerated inflammatory response that causes the release of pro-inflammatory cytokines such as interleukins and tumor necrosis factor-alpha (TNF-α). Statins are lipid lowering drugs with pleiotropic effects. They have shown benefit in the management of inflammatory and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. Furthermore, due to their immunomodulatory properties, they have been used in the treatment of various infectious diseases such as community-acquired pneumonia and influenza. In this review we analyze the pathophysiological foundations that support the use of statins as an adjunctive treatment in patients with COVID-19.

A Useful Allene for the Stereoselective Synthesis of Protected Quaternary 2-Amino-2-vinyl-1,3-diols.

Treatment of readily available allene 1 with Cy2BH followed by addition of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical since the observed N- to O-Bz transfer during the process prevents later undesired isomerizations in the adducts and keeps all heteroatoms protected.

Complicaciones de la diabetes y su asociación con el estrés oxidativo: un viaje hacia el daño endotelial / Complications of diabetes and its association with oxidative stress: a journey to the endothelial damage

La diabetes es un trastorno metabólico que se ha incrementado en Latinoamérica y Venezuela en la última década. Ejerce una influencia considerable en la morbimortalidad de las enfermedades cardiovasculares debido al desequilibrio hidrocarbon ado y a los pacientes fuera de los objetivos de la Asociación americana de diabetes 2012, con factores de riesgo como hipertensión y dislipidemia. Es, igualmente, un estado de estrés oxidativo en el que hay un desequilibrio entre la formación excesiva y la eliminación insuficiente de moléculas altamente reactivas, como las especies reactivas de oxígeno y las de nitrógeno. El estrés oxidativo desempeña un papel importante en el desarrollo de complicaciones de la diabetes debido a la actividad oxidativa excesiva. La disfunción endotelial se define como alteraciones que afectan la síntesis, liberación, difusión o degradación de los factores sintetizados por el endotelio. El mecanismo intrínseco que impulsa a las células endoteliales para cambiar su fenotipo fisiológico es un estado de activación, conocido erróneamente como disfunción en la capacidad de expresar los sistemas enzimáticos de producción de oxígeno. Los fármacos que modulan la vía de la incretina (GLP-1 y los inhibidores de la DPP-4) se caracterizan por la baja incidencia de su efecto hipoglucemiante, fenómeno que aumenta su seguridad. Estudios recientes con GLP-1 demuestran su capacidad para revertir el estrés oxidativo producido por la hiperglucemia, la hipoglucemia y la transición de esta última y la primera.

Diabetes is a metabolic disorder that has increased in Latin America and Venezuela over the last decade. It exerts an important influence on cardiovascular diseases morbi-mortality because of the hydrocarbonate imbalance and on patients outside ADA's 2012 goals, with risk factors such as hypertension and dyslipidemia. Diabetes is a state of oxidative stress where there is an imbalance between excessive formation and insufficient removal of highly reactive molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Oxidative stress plays an important role in developing diabetes complications because excessive oxidative activity. Endothelial dysfunction is defined as alterations affecting synthesis, liberation, diffusion or degradation of the factors synthesized by the endothelium. The intrinsic mechanism that drives endothelial cells to switch their physiologic phenotype into an activation state mistakenly known as dysfunction is the ability to express O2 production enzymatic systems. Drugs that modulate incretin pathway (GLP-1 and DPP4 inhibitors) are characterized by their low incidence of hypoglycemic effect, which increases their safety. Recent studies with GLP-1 have shown its ability to reverse oxidative stress produced by hyperglycemia, hypoglycemia and the transition from hypo to hyperglycemia.

PPARα activation induces N(ε)-Lys-acetylation of rat liver peroxisomal multifunctional enzyme type 1.

Peroxisomes are ubiquitous subcellular organelles that participate in metabolic and disease processes, with few of its proteins undergoing posttranslational modifications. As the role of lysine-acetylation has expanded into the cellular intermediary metabolism, we used a combination of differential centrifugation, organelle isolation by linear density gradient centrifugation, western blot analysis, and peptide fingerprinting and amino acid sequencing by mass spectrometry to investigate protein acetylation in control and ciprofibrate-treated rat liver peroxisomes. Organelle protein samples isolated by density gradient centrifugation from PPARα-agonist treated rat liver screened with an anti-N(ε)-acetyl lysine antibody revealed a single protein band of 75 kDa. Immunoprecipitation with this antibody resulted in the precipitation of a protein from the protein pool of ciprofibrate-induced peroxisomes, but not from the protein pool of non-induced peroxisomes. Peptide mass fingerprinting analysis identified the protein as the peroxisomal multifunctional enzyme type 1. In addition, mass spectrometry-based amino acid sequencing resulted in the identification of unique peptides containing 4 acetylated-Lys residues (K¹55, K¹7³, K¹9°, and K58³). This is the first report that demonstrates posttranslational acetylation of a peroxisomal enzyme in PPARα-dependent proliferation of peroxisomes in rat liver.

Electrocatalysts of Pt-TiO2 prepared by sol-gel and microwave-assisted polyol method for the oxygen reduction reaction in 0.5 M H2SO4.

Electrocatalysts of Pt-TiO2 were prepared by sol-gel and microwave assisted polyol method for the oxygen reduction reaction in acid media. The prepared electrocatalysts were morphologically and structurally characterized by X-Ray Diffraction, Scanning Electronic Microscopy and EDX analysis. Cyclic voltammetry and rotating disk electrode techniques were employed for electrocatalytic evaluation. It was found that electrocatalysts consisted of crystalline particles with nanometric size, and those obtained at pH = 9 showed an acceptable activity for the oxygen reduction reaction in acid media.

Peroxisomal dysfunction in inflammatory childhood white matter disorders: an unexpected contributor to neuropathology.

The peroxisome, an ubiquitous subcellular organelle, plays an important function in cellular metabolism, and its importance for human health is underscored by the identification of fatal disorders caused by genetic abnormalities. Recent findings indicate that peroxisomal dysfunction is not only restricted to inherited peroxisomal diseases but also to disease processes associated with generation of inflammatory mediators that downregulate cellular peroxisomal homeostasis. Evidence indicates that leukodystrophies (i.e. X-linked adrenoleukodystrophy, globoid cell leukodystrophy, and periventricular leukomalacia) may share common denominators in the development and progression of the inflammatory process and thus in the dysfunctions of peroxisomes. Dysfunctions of peroxisomes may therefore contribute in part to white matter disease and to the mental and physical disabilities that develop in patients affected by these diseases.

Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: attenuation by N-acetyl cysteine.

Cerebral white matter injury during prenatal maternal infection characterized as periventricular leukomalacia is the main substrate for cerebral palsy (CP) in premature infants. Previously, we reported that maternal LPS exposure causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by an antioxidant agent, N-acetyl cysteine (NAC). Herein, we elucidated the role of peroxisomes in LPS-induced neuroinflammation and cerebral white matter injury. Peroxisomes are important for detoxification of reactive oxidative species (ROS) and metabolism of myelin-lipids in OLs. Maternal LPS exposure induced selective depletion of developing OLs in the fetal brain which was associated with ROS generation, glutathione depletion and peroxisomal dysfunction. Likewise, hypomyelination in the postnatal brain was associated with decrease in peroxisomes and OLs after maternal LPS exposure. Conversely, NAC abolished these LPS-induced effects in the developing brain. CP brains imitated these observed changes in peroxisomal/myelin proteins in the postnatal brain after maternal LPS exposure. In vitro studies revealed that pro-inflammatory cytokines cause OL-injury via peroxisomal dysfunction and ROS generation. NAC or WY14643 (peroxisome proliferators activated receptor (PPAR)-alpha agonist) reverses these effects of pro-inflammatory cytokines in the wild-type OLs, but not in PPAR-alpha(-/-) OLs. Similarly treated B12 oligodenroglial cells co-transfected with PPAR-alpha siRNAs/pTK-PPREx3-Luc, and LPS exposed PPAR-alpha(-/-) pregnant mice treated with NAC or WY14643 further suggested that PPAR-alpha activity mediates NAC-induced protective effects. Collectively, these data provide unprecedented evidence that LPS-induced peroxisomal dysfunction exacerbates cerebral white matter injury and its attenuation by NAC via a PPAR-alpha dependent mechanism expands therapeutic avenues for CP and related demyelinating diseases.

Oxidative imbalance in nonstimulated X-adrenoleukodystrophy-derived lymphoblasts.

X-Adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by accumulation of very-long-chain (VLC) fatty acids, which induces inflammatory disease and alterations in cellular redox, both of which are reported to play a role in the pathogenesis of the severe form of the disease (childhood cerebral ALD). Here, we report on the status of oxidative stress (NADPH oxidase activity) and inflammatory mediators in an X-ALD lymphoblast cell line under nonstimulated conditions. X-ALD lymphoblasts contain nearly 7 times higher levels of the C(26:0) fatty acid compared to controls; these levels were downregulated by treatment with sodium phenylacetate (NaPA), lovastatin or the combination of both drugs. In addition, free-radicals synthesis was elevated in X-ALD lymphoblasts, and protein levels of the NADPH oxidase gp91(PHOX) membrane subunit were significantly upregulated, but no changes were observed in the p47(PHOX) and p67(PHOX) cytoplasmic subunits. Unexpectedly, there was no increase in gp91(PHOX) mRNA levels in X-ALD lymphoblasts. Furthermore, X-ALD lymphoblasts produced higher levels of nitric oxide (NO) and cytokines (tumor necrosis factor-alpha and interleukin 1 beta), and treatment with NaPA or lovastatin decreased the synthesis of NO. Our data indicate that X-ALD lymphoblasts are significantly affected by the accumulation of VLC fatty acids, which induces changes in the cell membrane properties/functions that may, in turn, play a role in the development/progression of the pathogenesis of X-ALD disease.

Molecular organization of peroxisomal enzymes: protein-protein interactions in the membrane and in the matrix.

The beta-oxidation of fatty acids in peroxisomes produces hydrogen peroxide (H2O2), a toxic metabolite, as a bi-product. Fatty acids beta-oxidation activity is deficient in X-linked adrenoleukodystrophy (X-ALD) because of mutation in ALD-gene resulting in loss of very long chain acyl-CoA synthetase (VLCS) activity. It is also affected in disease with catalase negative peroxisomes as a result of inactivation by H2O2. Therefore, the following studies were undertaken to delineate the molecular interactions between both the ALD-gene product (adrenoleukodystrophy protein, ALDP) and VLCS as well as H2O2 degrading enzyme catalase and proteins of peroxisomal beta-oxidation. Studies using a yeast two hybrid system and surface plasmon resonance techniques indicate that ALDP, a peroxisomal membrane protein, physically interacts with VLCS. Loss of these interactions in X-ALD cells may result in a deficiency in VLCS activity. The yeast two-hybrid system studies also indicated that catalase physically interacts with L-bifunctional enzyme (L-BFE). Interactions between catalase and L-BFE were further supported by affinity purification, using a catalase-linked resin. The affinity bound 74-kDa protein, was identified as L-BFE by Western blot with specific antibodies and by proteomic analysis. Additional support for their interaction comes from immunoprecipitation of L-BFE with antibodies against catalase as a catalase- L-BFE complex. siRNA for L-BFE decreased the specific activity and protein levels of catalase without changing its subcellular distribution. These observations indicate that L-BFE might help in oligomerization and possibly in the localization of catalase at the site of H2O2 production in the peroxisomal beta-oxidation pathway.

Dysfunction of peroxisomes in twitcher mice brain: a possible mechanism of psychosine-induced disease.

Psychosine (galactosylsphingosine) accumulates in the brain of Krabbe disease (KD) patients as well as twitcher mice, a murine model of KD, resulting in loss of oligodendrocytes and myelin. This study documents progressive loss of peroxisomal proteins/functions and induction of expression of inflammatory cytokine TNF-alpha in twitcher brain. The observed decrease in peroxisomal proteins was accompanied by decreased level of peroxisome proliferator-activated receptor-alpha (PPAR-alpha), one of the transcription factors required for expression of peroxisomal protein genes. The role of psychosine in down-regulation of PPAR-alpha activity was further supported by decreased PPAR-alpha mediated PPRE transcriptional activity in cells transfected with PPAR-alpha and PPRE reporters. The psychosine-induced down-regulation of PPAR activity and cell death was attenuated by sPLA2 inhibitor. Therefore, this study provides the first evidence of peroxisomal abnormality in a lysosomal disorder, suggesting that such dysfunction of peroxisomes may play a role in the pathogenesis of Krabbe disease.

Oral administration of prednisone to control refractory vertigo in Ménière's disease: a pilot study.

OBJECTIVE: To establish whether the oral administration of moderate doses of prednisone reduces refractory vertigo in Ménière's disease. STUDY DESIGN: Blinded, randomized, controlled trial. SETTING: Tertiary referral center. PATIENTS: Patients with Ménière's disease with limited vertigo control (Class C) and severe disability (Scale 3). INTERVENTIONS: Two groups (n = 8 per group) were treated orally with either diphenidol (25 mg/d) plus acetazolamide (250 mg/48 h) (control group), or the same treatment plus prednisone (0.35 mg/kg) daily for 18 weeks (prednisone group). MAIN OUTCOME MEASURES: The variables evaluated were the frequency and duration of vertigo, tinnitus, aural fullness, and audiographic parameters. The clinical surveillance was performed for 12 months after prednisone withdrawal. RESULTS: The frequency and duration of vertigo episodes were reduced by 50% and 30%, respectively, by prednisone treatment. Prednisone-treated patients manifested a significant reduction in tinnitus. No changes were observed in aural fullness or hearing. No metabolic or infectious disorders were observed. CONCLUSION: Oral prednisone helps to control refractory vertigo in Ménière's disease. These preliminary data suggest that prednisone can be a good noninvasive antivertigo management regimen for these patients.

Inhibition of peroxisomal functions due to oxidative imbalance induced by mistargeting of catalase to cytoplasm is restored by vitamin E treatment in skin fibroblasts from Zellweger syndrome-like patients.

Many of the peroxisomal diseases exhibit excessive oxidative stress leading to neurological alterations and dysfunction. The role of peroxisomal oxidative stress in cellular function was highlighted by the loss of metabolic functions in peroxisomes of mutant cell lines, where catalase is mistargeted to the cytoplasm, but restored to peroxisomes by genetic manipulation (Sheikh et al. [Proc. Natl. Acad. Sci. USA 95 (1998) 2961)]. We report here that two human skin fibroblast cell lines from Zellweger syndrome-like patients are defective in the import of catalase into peroxisomes, causing impairment of metabolic function of this organelle. However, by lowering the cell culturing temperature (30 degrees C) the targeting of catalase to peroxisomes was restored, and with it the metabolic functions. Furthermore, mislocalization of catalase induces an oxidative imbalance in the cells which on treatment with a natural antioxidant, alpha-tocopherol (vitamin E), resulted in reduction of the oxidative levels and restoration of metabolic function (peroxisomal beta-oxidation and levels of very long chain fatty acids and plasmalogen as well as alpha-oxidation of branched-chain fatty acids). However, restoration of peroxisomal functions was not associated with the targeting of catalase to peroxisomes. Therefore, our finding suggests that correction of mistargeted catalase to peroxisomes is a temperature sensitive event and supports the hypotheses that its location outside peroxisomes induces an oxidative imbalance that results in metabolic dysfunction. The imbalance can be reversed by treatment with vitamin E, leading to normalization of peroxisomal functions. These findings open a novel approach for therapeutic treatment of certain peroxisomal disorders where gene or hypothermic therapies are not an option.

Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment.

Peroxisomes are ubiquitous subcellular organelles and abnormality in their biogenesis and specific gene defects leads to fatal demyelinating disorders. We report that neuroinflammatory disease in brain of experimental autoimmune encephalomyelitis (EAE) rats decreased the peroxisomal functions. Degradation of very long chain fatty acids decreased by 47% and resulted in its accumulation (C26:0, 40%). Decreased activity (66% of control) of dihydroxyacetonephosphate acyltransferase (DHAP-AT), first enzyme in plasmalogens biosynthesis, resulted in decreased levels of plasmalogens (16-30%). Catalase activity, a peroxisomal enzyme, was also reduced (37%). Gene microarray analysis of EAE spinal cord showed significant decrease in transcripts encoding peroxisomal proteins including catalase (folds 3.2; p<0.001) and DHAP-AT (folds 2.6; p<0.001). These changes were confirmed by quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, suggesting that decrease of peroxisomal functions in the central nervous system will have negative consequences for myelin integrity and repair because these lipids are major constituents of myelin. However, lovastatin (a cholesterol lowering and anti-inflammatory drug) administered during EAE induction provided protection against loss/down-regulation of peroxisomal functions. Attenuation of induction of neuroinflammatory mediators by statins in cultured brain cells [J. Clin. Invest. 100 (1997) 2671-2679], and in central nervous system of EAE animals and thus the EAE disease [J. Neurosci. Res. 66 (2001) 155-162] and the studies described here indicate that inflammatory mediators have a marked negative effect on peroxisomal functions and thus on myelin assembly and that these effects can be prevented by treatment with statins. These observations are of importance because statins are presently being tested as therapeutic agents against a number of neuroinflammatory demyelinating diseases.

Brain lipid metabolism in the cPLA2 knockout mouse.

We examined brain phospholipid metabolism in mice in which the cytosolic phospholipase A(2) (cPLA(2,) Type IV, 85 kDa) was knocked out (cPLA(2)(-/-) mice). Compared with controls, these mice demonstrated altered brain concentrations of several phospholipids, reduced esterified linoleate, arachidonate, and docosahexaenoate in choline glycerophospholipid, and reduced esterified arachidonate in phosphatidylinositol. Unanesthetized cPLA(2)(-/-) mice had reduced rates of incorporation of unlabeled arachidonate from plasma and from the brain arachidonoyl-CoA pool into ethanolamine glycerophospholipid and choline glycerophospholipid, but elevated rates into phosphatidylinositol. These differences corresponded to altered turnover and metabolic loss of esterified brain arachidonate. These results suggests that cPLA(2) is necessary to maintain normal brain concentrations of phospholipids and of their esterified polyunsaturated fatty acids. Reduced esterified arachidonate and docosahexaenoate may account for the resistance of the cPLA(2)(-/-) mouse to middle cerebral artery occlusion, and should influence membrane fluidity, neuroinflammation, signal transduction, and other brain processes.

Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues.

Recent literature provides a basis for understanding the behavioral, functional, and structural consequences of nutritional deprivation or disease-related abnormalities of n-3 polyunsaturated fatty acids. The literature suggests that these effects are mediated through competition between n-3 and n-6 polyunsaturated fatty acids at certain enzymatic steps, particularly those involving polyunsaturated fatty acid elongation and desaturation. One critical enzymatic site is a delta6-desaturase. On the other hand, an in-vivo method in rats, applied following chronic n-3 nutritional deprivation or chronic administration of lithium, indicates that the cycles of de-esterification/re-esterification of docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) within brain phospholipids operate independently of each other, and thus that the enzymes regulating each of these cycles are not likely sites of n-3/n-6 competition.