Pre-treatment and continuous administration of simvastatin during sepsis improve metabolic parameters and prevent CNS injuries in survivor rats.

Sepsis causes overproduction of inflammatory cytokines, organ dysfunction, and cognitive impairment in survivors. In addition to inflammation, metabolic changes occur according to the stage and severity of the disease. Understanding the role and place of metabolic disturbances in the pathophysiology of sepsis is essential to evaluate the framework of septic patients, predict the syndrome progress, and define the treatment strategies. We investigated the effect of simvastatin on the disease time course and on metabolic alterations, especially with respect to their possible consequences in the CNS of surviving rats. The animals of this study were weighed daily and followed for 10 days to determine the survival rate. In the first experiment, control or cecal ligation and puncture (CLP)-animals were randomized in 24 h, 48 h, and 10 days after septic induction, for bacterial load determination and quantification of cytokines. In the second experiment, control or CLP-animals were treated or not with simvastatin and randomized in the same three time points for cytokines quantification and assessment of their body metabolism and locomotor activity (at 48 h and 10 days), as well as the evaluation of cytoarchitecture and astrogliosis (at 10 days). The CLP-rats treated with simvastatin showed a reduction in plasma cytokines and improvement in metabolic parameters and locomotor activity, followed by minor alterations compatible with apoptosis and astrogliosis in the hippocampus and prefrontal cortex. These results suggest that the anti-inflammatory effect of simvastatin plays a crucial role in restoring energy production, maintaining a hypermetabolic state necessary for the recovery and survival of these CLP-rats.

¿Reducen las estatinas el riesgo de glaucoma? revisión de las evidencias / Do statins reduce the risk of glaucoma? review of the evidences

Introducción: Los objetivos de este trabajo son revisar y resumir los datos publicados hasta el momento que relacionen el uso de estatinas con el riesgo de aparición o de agravamiento de glaucoma y plantear una hipótesis que explique los efectos protectores de las estatinas y su asociación con un menor riesgo de glaucoma. Método: se realizó una revisión en PubMed usando los términos “statins, hmg coa” o “hmg coa inhibitors” y “glaucoma” o “open angle glaucoma” o “intraocular pressure”. Se seleccionaron todos los artículos que incluían estudios clínicos o meta-análisis y se excluyeron comentarios, cartas a editor, artículos retractados e investigación en modelos animales. Todos los artículos fueron posteriores a 2004. Se emplearon en la revisión 17 artículos. Resultados: la mayor parte de los estudios muestran un efecto protector de las estatinas frente a la aparición y agravamiento del glaucoma de ángulo abierto. Sin embargo, otros estudios no llegan a encontrar una relación significativa e incluso alguno muestra una relación entre el glaucoma y el empleo de estatinas a altas dosis. Los efectos neuroprotectores y la inhibición de la Rho-quinasa podrían explicar los efectos encontrados. Conclusiones: la evidencia publicada no es suficiente como para recomendar el tratamiento con estatinas con el objetivo de prevenir el avance o la aparición del glaucoma. (AU)

Introduction: The objectives of this article are to review and summarize the updated published data that show the relation between treatment with statins and the incidence and progression of glaucoma. We also aimed to pose a hypothesis to explain the protective effects of statins and its association with glaucoma risk. Method: a review of the literature was carried out in the PubMed database considering the MeSH terms “statins, hmg coa” or “hmg coa inhibitors” and “glaucoma” or “open angle glaucoma” or “intraocular pressure”. All articles including clinical studies and meta-analysis were selected. Comments, letters to editors, retracted articles and research on animal models were excluded. All the articles were published from 2004. 17 articles were finally selected for review. Results: most of the studies showed a protective effect of statins on incidence or progression of open angle glaucoma. Nevertheless, other studies did not find a significant association and even one study found association between statin treatment at high doses and more incidence of glaucoma. Neuroprotective effects of statin and inhibition of Rho-kinase may help explain the described effects. Conclusions: The published results are not enough evidence to support statin recommendation as preventive treatment for the incidence or progression of glaucoma. (AU)

Effects of statins on myocarditis: A review of underlying molecular mechanisms.

Myocarditis refers to the clinical and histological characteristics of a diverse range of inflammatory cellular pathophysiological conditions which result in cardiac dysfunction. Myocarditis is a major cause of mortality in individuals less than 40 years of age and accounts for approximately 20% of cardiovascular disease (CVD) events. Myocarditis contributes to dilated cardiomyopathy in 30% of patients and can progress to cardiac arrest, which has a poor prognosis of <40% survival over 10 years. Myocarditis has also been documented after infection with SARS-CoV-2. The most commonly used lipid-lowering therapies, HMG-CoA reductase inhibitors (statins), decrease CVD-related morbidity and mortality. In addition to their lipid-lowering effects, increasing evidence supports the existence of several additional beneficial, 'pleiotropic' effects of statins. Recently, several studies have indicated that statins may attenuate myocarditis. Statins modify the lipid oxidation, inflammation, immunomodulation, and endothelial activity of the pathophysiology and have been recommended as adjuvant treatment. In this review, we focus on the mechanisms of action of statins and their effects on myocarditis, SARS-CoV-2 and CVD.

Statin Effects on Incidence, Treatment Success, and Mortality of Clostridium difficile Infections.

PURPOSE: To review the effects of statin use in patients at risk for or diagnosed with Clostridium difficile infection (CDI) on CDI incidence, treatment success, and mortality. METHODS: A literature search was performed through January 2019 using the following terms: statins, HMG-CoA inhibitors, Clostridium difficile, Clostridium difficile associated diarrhea, and Clostridium difficile infection. Additional references were identified from a review of literature citations. Studies evaluating statin effects on C difficile-related outcomes were included. RESULTS: A total of 8 studies were identified for inclusion in this review. All studies were retrospective. Five studies reported the association between statin use and the development of CDI, suggesting that statins may decrease risk of CDI development in patients already on statin. In one study, there was an improved treatment response against CDI with the use of statin. Three retrospective studies evaluated statin use and mortality from CDI and only one study found significant mortality benefit in statin users. CONCLUSIONS: Statin use may have a protective effect against the development of CDI and improve CDI treatment success; however, it is unclear if use confers a mortality benefit. Current data remain sparse and larger, prospective studies are needed to confirm current results and identify the specific population that may benefit the most from this intervention.

Statins in aortic disease.

BACKGROUND: Numerous studies indicate that statins have also multiple beneficial actions (known as 'pleiotropic actions') on cardiovascular system through the improvement of endothelial dysfunction, inflammation, oxidative stress, increased arterial thrombosis, and the stabilization of the atherosclerotic plaque. Aortic disease primarily consists of aortic valve stenosis, aortic valve regurgitation, aneurysm disease, and genetic disorders such as Marfan syndrome, bicuspid aortic valve and aortic coarctation. Many studies have revealed the cardio-protective actions of statins in aortic disease. OBJECTIVE: Our aim was to present current data concerning present status of treatment with statins in aortic diseases. METHODS: A thorough search of PubMed and the Cochrane Database was conducted in order to identify the majority of studies and novel articles related to their use in aortic disease. RESULTS: Numerous studies in animals and humans indicate a beneficial effect of treatment with statins in the previous conditions apart from a few conflicting data. CONCLUSION: There is a need of further investigation in this field, especially for the estimation of the optimal type and dose of statins required in each clinical condition of aortic disease.

Brain Oxidative Stress During Experimental Sepsis Is Attenuated by Simvastatin Administration.

During sepsis, brain damage is associated with oxidative stress due to overproduction of reactive oxygen species (ROS). Although there are recent reports about the benefits of statins in experimental sepsis and endotoxemia in peripheral organs, little is known about their effects in the CNS. Here, we investigated the antioxidant properties of simvastatin and its possible neuroprotective role during experimental sepsis. Male Wistar rats (250-300 g) were submitted to cecal ligation and puncture (CLP, n = 34) or remained as non-manipulated (naive, n = 34). Both groups were treated by gavage with simvastatin (20 mg/kg) or an equivalent volume of saline. The animals submitted to CLP were treated 4 days before and 48 h after surgery. One animal group was decapitated and the blood and brain were collected to quantify plasma levels of cytokines and assess astrogliosis and apoptosis in the prefrontal cortex and hippocampus. Another group was perfused with PBS (0.01 M), and the same brain structures were dissected to analyze oxidative damage. The CLP rats treated with simvastatin showed a reduction in nitric oxide (P < 0.05), IL1-ß (P < 0.001), IL-6 (P < 0.01), and TBARS levels (P < 0.001) and an increase in catalase activity (P < 0.01), citrate synthase enzyme (P < 0.05), and normalized GSH/GSSG ratio. In addition, the histopathological analysis showed a reduction (P < 0.001) in reactive astrocytes and caspase 3-positive apoptotic cells. The results suggest a possible neuroprotective effect of simvastatin in structures responsible for spatial learning and memory and indicate the need for behavioral studies evaluating the impact on cognitive damage, as frequently seen in patients surviving sepsis.

Atorvastatin attenuation of ABCB1 expression is mediated by microRNA miR-491-3p in Caco-2 cells.

AIM: Atorvastatin, a HMG-CoA reductase inhibitor, used in the treatment of hypercholesterolemia, has been previously shown to regulate ABCB1 expression in vivo and in vitro. We hypothesized that the statin could regulate gene expression of ABCB1 transporter via microRNAs. METHODS: Expression of microRNAs and ABCB1 mRNA was examined in atorvastatin-treated and control cells using real-time PCR. miR-491-3P mimic and inhibitor were transfected in Caco-2 and ABCB1 expression was monitored by western blot and real-time PCR. RESULTS: In HepG2 cells, none of the microRNAs predicted to target ABCB1 3'UTR was regulated by atorvastatin treatment. In agreement with this, ABCB1 3'UTR activity was not modulated in HepG-2 cells after 48h-treatment as measured by luciferase assay. In Caco-2 cells, atorvastatin treatment provoked a decrease in luciferase activity and, accordingly, miR-491-3p was upregulated about 2.7 times after 48h-statin treatment. Luciferase analysis of miR-491-3p with a mimetic or inhibitor of miR-491-3p revealed that this microRNA could target ABCB1 3'UTR, as after miR-491-3p inhibition, ABCB1 levels were increased by two-fold, and miR-491-3p superexpression decreased ABCB1 3'UTR activity. Finally, functional analysis revealed that treatment with miR-491-3p inhibitor could reverses atorvastatin attenuation of ABCB1 (Pg-p) protein levels. CONCLUSION: Our results suggest atorvastatin control ABCB1 expression via miR-491-3p in Caco-2 cells. This finding may be an important mechanism of statin drug-drug interaction, since common concomitant drugs used in the prevention of cardiovascular diseases are ABCB1 substrates.

Lovastatin production: From molecular basis to industrial process optimization.

Lovastatin, composed of secondary metabolites produced by filamentous fungi, is the most frequently used drug for hypercholesterolemia treatment due to the fact that lovastatin is a competitive inhibitor of HMG-CoA reductase. Moreover, recent studies have shown several important applications for lovastatin including antimicrobial agents and treatments for cancers and bone diseases. Studies regarding the lovastatin biosynthetic pathway have also demonstrated that lovastatin is synthesized from two-chain reactions using acetate and malonyl-CoA as a substrate. It is also known that there are two key enzymes involved in the biosynthetic pathway called polyketide synthases (PKS). Those are characterized as multifunctional enzymes and are encoded by specific genes organized in clusters on the fungal genome. Since it is a secondary metabolite, cultivation process optimization for lovastatin biosynthesis has included nitrogen limitation and non-fermentable carbon sources such as lactose and glycerol. Additionally, the influences of temperature, pH, agitation/aeration, and particle and inoculum size on lovastatin production have been also described. Although many reviews have been published covering different aspects of lovastatin production, this review brings, for the first time, complete information about the genetic basis for lovastatin production, detection and quantification, strain screening and cultivation process optimization. Moreover, this review covers all the information available from patent databases covering each protected aspect during lovastatin bio-production.

Statin treatment and new-onset diabetes: a review of proposed mechanisms.

New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic ß-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of ß-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.

Statins and vascular dementia: a review.

The impact of statin therapy on dementia has been a hot topic of debate over the last decade and still remains highly controversial. Among all causes of dementia, vascular dementia (VaD) is the one type that is more likely to benefit from statins. To date no randomized clinical trials have been published and no systematic review has investigated a possible preventive effect of statins on the VaD subtype. In the present literature review, we tried to identify all available data on the effect of statins specifically in patients with VaD, and to further discuss this possible association. Our literature search highlighted two cross-sectional studies, two prospective cohort studies, and one retrospective cohort study. Two of the studies found a significant positive effect of statin treatment on VaD, depicted by the lower incidence of VaD in statin users, while the others reported non-significant associations. The relatively small numbers of VaD patients and statin users, as well as the presence of confounders and biases, make the interpretation of results extremely difficult. Statins may exert a benefit in the prevention of all-type dementia and VaD, through several mechanisms except for hyperlipidemia reduction. A well-designed randomized clinical trial is the ideal study design to address the effect of statin therapy in VaD and to draw final conclusions.

Pleiotropic effects of the HMG-CoA reductase inhibitors.

The HMG-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia. They have also demonstrated a benefit in a variety of other disease processes. These secondary actions are known as pleiotropic effects. Our paper serves as a focused and updated discussion on the pleiotropy of statins and emphasizes the importance of randomized placebo-controlled trials to further elucidate this interesting phenomenon.