Pleiotropic Effects Of Statins Research Articles

Pleiotropic effect of statin on vascular smooth muscle cell mechanics and migration

Statins are well known drugs to inhibit cellular cholesterol biosynthesis and widely prescribed to patients with hypercholesterolemia or related cardiovascular conditions. However, the pleiotropic effects of statins on vascular cells functions other than cholesterol management are not fully understood. Phenotypic shifting and migration of vascular smooth muscle cells (VSMCs) play key roles in the progression of atherosclerosis. Phenotypic switching in VSMCs induces the alterations in cell-extracellular matrix (ECM) adhesion and cell migration.

Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of ‘beyond lipid-lowering’.

Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases.

An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications of diabetes and obesity. The aim of this study is to summarize the current knowledge about the pathogenic mechanisms of urolithiasis in relation to the development of endothelial dysfunction and cardiovascular morbidities. Methods: A non-systematic review has been performed mixing the terms “urolithiasis”, “kidney stone” or “nephrolithiasis” with “cardiovascular disease”, “myocardial infarction”, “stroke”, or “endothelial dysfunction”. Results: Patients with nephrolithiasis develop a higher incidence of cardiovascular disease with a relative risk estimated between 1.20 and 1.24 and also develop a higher vascular disease risk scores. Analyses of subgroups have rendered inconclusive results regarding gender or age. Endothelial dysfunction has also been strongly associated with urolithiasis in clinical studies, although no systemic serum markers of endothelial dysfunction, inflammation or oxidative stress could be clearly related. Analysis of urine composition of lithiasic patients also detected a higher expression of proteins related to cardiovascular disease. Experimental models of hyperoxaluria have also found elevation of serum endothelial dysfunction markers. Conclusions: Endothelial dysfunction has been strongly associated with urolithiasis and based on the experimental evidence, should be considered as an intermediate and changeable feature between urolithiasis and cardiovascular diseases. Oxidative stress, a key pathogenic factor in the development of endothelial dysfunction has been also pointed out as an important factor of lithogenesis. Special attention must be paid to cardiovascular morbidities associated with urolithiasis in order to take advantage of pleiotropic effects of statins, angiotensin receptor blockers and allopurinol.

Pleiotropic Effects of Statins: New Therapeutic Approaches to Chronic, Recurrent Infection by Staphylococcus aureus.

An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects of statin drugs have been examined for therapeutic usefulness beyond the treatment of hypercholesterolemia. Interest originated after retrospective studies reported decreases in the risk of death due to bacteremia or sepsis for those on a statin regimen. Although subsequent clinical trials have yielded mixed results and earlier findings have been questioned for biased study design, in vitro and in vivo studies have provided clear evidence of protective mechanisms that include immunomodulatory effects and the inhibition of host cell invasion. Ultimately, the benefits of statins in an infection setting appear to require attention to the underlying host response and to the timing of the dosage. From this examination of statin efficacy, additional novel host-directed strategies may produce adjunctive therapeutic approaches for the treatment of infection where traditional antimicrobial therapy continues to yield poor outcomes. This review focuses on the opportunistic pathogen, Staphylococcus aureus, as a proof of principle in examining the promise and limitations of statins in recalcitrant infection.

Systematic Review and Meta-Analysis of the Effect of Statins on Circulating E-Selectin, L-Selectin, and P-Selectin

The pleiotropic effects of statins might involve preventing inflammatory cell adhesion to the endothelium, which is a critical step in the pathogenesis of atherosclerosis. We conducted a systematic review and meta-analysis of the effects of statins on the circulating cell adhesion molecules E-Selectin, L-Selectin, and P-Selectin. A literature search was conducted in PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 61 studies, statins significantly reduced P-selectin (standard mean difference, SMD = −0.39, 95% CI −0.55 to −0.22, p < 0.001; moderate certainty of evidence), L-selectin (SMD = −0.49, 95% CI −0.89 to −0.10, p = 0.014; very low certainty of evidence), and E-Selectin (SMD = −0.73, 95% CI −1.02 to −0.43, p < 0.001; moderate certainty of evidence), independently of baseline lipid profile and other study and patient characteristics. The corresponding pooled SMD values in sensitivity analysis were not substantially altered when individual studies were sequentially removed. Simvastatin had a significant lowering effect on both P-selectin and E-selectin. Therefore, statins significantly reduce circulating selectins. Further studies are required to investigate whether selectin lowering mediates cardiovascular risk reduction with these agents. (PROSPERO registration number: CRD42021282778).

Гиполипидемическая терапия у пациентов с хроническими заболеваниями печени: что нужно знать гастроэнтерологу

Dyslipidemia is one of the main risk factors for the development of cardiovascular diseases (CVD), which remain the leading cause of death worldwide. Lipid level control is the most effective strategy for the prevention of CVD and its complications (CVC). Statins are the first-line drugs of hypolipidemic therapy. Dyslipidemia is often found in patients with chronic liver diseases (CLD). From a clinical point of view, a number of CLD have an increased risk of CVD. Due to insufficient awareness of doctors about the possibilities of using statin and non-statin lipid-lowering therapy in patients with CLD, the possibility of treating CVD and reducing the risk of CVC in this category of patients is often missed. The purpose of the review is to study modern approaches to lipid-lowering therapy (statin and non-statin) in patients with CVD of various etiologies, including at the stage of liver cirrhosis (LC). Conclusion. CLD should not be considered as a contraindication to the use of statins and other lipid-lowering drugs. Pleiotropic effects of statins, in addition to hypolipidemic action, create new prospects for their use in patients with CLD. Hypolipidemic therapy is recommended for patients with CLD (including at the stage of compensated LC), if they have dyslipidemia and an increased risk of CVD. It is important to compare the benefits and risks of prescribing statins in patients with CLD

HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden: A registry-based cohort study.

The relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality. This cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins. In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%). A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens. Statin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.

Dose-dependent effects of rosuvastatin on circulating microRNAs-27a and 221 levels in patients with coronary artery disease with type 2 diabetes mellitus

Abstract Background Circulating microRNAs are capable of mediating cell-cell communication. MicroRNAs-27a and 221 serve an important regulatory role in both atherosclerosis and type 2 diabetes mellitus (T2DM). The lipid-lowering and pleiotropic effects of statins might be mediated by microRNAs. The purpose of the study was to investigate the dose-dependent effects of rosuvastatin on the circulating miRNAs-27a and 221 levels in patients with coronary artery disease (CAD) with T2DM. Methods The study included 22 patients with stable CAD with T2DM with rosuvastatin treatment at least 3 months (rosuvastatin 10 mg/day – 10 patients, rosuvastatin 20–40 mg/day – 12 patients), 16 patients with stable CAD with T2DM treated without statins. All patients received aspirin, beta-blockers, ACE inhibitors or sartans, metformin or its combination with sulfonylurea. The control group consisted of 16 healthy persons. MicroRNAs-27a-3p and 221-3p were determined in blood plasma by real time polymerase chain reaction. Small nuclear RNA U6 was used as endogenous control. Results expressed in relative units. Results In non-statin-treated patients with CAD with T2DM both microRNAs-27a (0,33 [0,15; 0,87]) and 221 (0,59 [0,27; 1,15]) levels were lower than in the control group ((0,90 [0,54; 2,62]), p=0,006 and (1,05 [0,57; 1,75]), p=0,043, respectively). In patients with CAD with T2DM treated with rosuvastatin 10 mg/day microRNA-27a level (0,44 [0,34; 0,69]) was decreased significantly in comparison with the control group (p=0,012) and was increased non-significantly in comparison non-statin-treated patients (p=0,439). In patients treated with rosuvastatin 20–40 mg/day microRNA-27a level (1,26 [0,31; 1,50]) was non-significantly higher than in the control group (p=0,559) and was significantly increased compared with non-statin-treated patients (p=0,038). MicroRNA-221 levels in patients treated both with rosuvastatin 10 mg/day (0,50 [0,28; 0,89]) and with rosuvastatin 20–40 mg/day (0,63 [0,40; 0,84]) were decreased in comparison with the control group (p=0,031 and p=0,042, respectively) and did not change significantly compared to patients treated without statins (p=0,928 and p=0,837, respectively). Conclusions In patients with CAD with T2DM circulating microRNAs-27a and -221 levels significantly decreased in comparison with control. Treatment with rosuvastatin in high doses (20–40 mg/day) but not in moderate dose (10 mg/day) was associated with the elevation of microRNA-27a level. Rosuvastatin at any doses did not influence on circulating microRNA-221 levels. These results revealed that rosuvastatin may serve protective roles in patients with CAD with T2DM by influencing on some microRNAs expression. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): This research was funded by the Government as part of the research project to study the effects of circulating micro-ribonucleic acids in coronary artery disease with concomitant type 2 diabetes mellitus. This research did not receive any specific grant from funding.

The Role of Lipid and the Benefit of Statin in Augmenting Rifampicin Effectivity for a Better Leprosy Treatment

Although leprosy remains as a serious disease of the skin and nervous system, the current treatment is still lacking in its effectiveness. This literature review will explore the association of lipid and leprosy, as well as the potential of statin and other lipid-lowering agents as adjunctive drugs to combat leprosy. Articles were searched through the PubMed, EBSCOhost, and Google Scholar with the keywords: immunomodulation, lipid-body, lipids, leprosy, Mycobacterium leprae, pathogenesis, rifampin or rifampicin, and statins. A manual searching is also carried out to find an additional relevant information to make this literature review more comprehensive. The literatures showed that lipids are highly correlated with leprosy through alterations in serum lipid profile, metabolism, pathogenesis, and producing oxidative stress. Statins can diminish lipid utilization in the pathogenesis of leprosy and show a mycobactericidal effect by increasing the effectiveness of rifampicin and recover the function of macrophages. In addition, Statins have anti-inflammatory properties which may aid in preventing type I and II reactions in leprosy. Standard multidrug therapy might reduce the efficacy of statins, but the effect is not clinically significant. The statin dose-response curve also allows therapeutic response to be achieved with minimal dose. The various pleiotropic effects of statins make it a potential adjunct to standard treatment for leprosy in the future.

Effects of Statins After Transcatheter Aortic Valve Implantation in Key Patient Populations.

Statin therapy after transcatheter aortic valve replacement (TAVI) is associated with better short-term and long-term outcomes. It is of interest to identify specific patient populations that may profit from statin therapy. In this retrospective, observational analysis of 2862 patients with symptomatic aortic stenosis after successful transfemoral TAVI, survival during a three-year observation period was characterized by Kaplan-Meier analyses according to statin therapy. Hazard ratios and potential interactions for specific subgroups of patients were determined by Cox regression analyses. At hospital discharge 1761 patients were on low-intensity or moderate-intensity statins, 246 patients were on high-intensity statins, and 855 patients did not take statins. Statin therapy adherence during the first 3 months post-TAVI was 91%. Mortality rates were 18.5%, 12.9%, and 6.9% for patients with no statin, low-intensity or moderate-intensity statins, and high-intensity statins (P < 0.001). Any statin therapy proved to be effective in patients in different classes of age, risk, and manifest cardiovascular disease and was independent of background medication. Statins were of particular benefit in high-risk patients with coronary artery disease [hazard ratio (HR) = 0.57], ejection fraction <40% (HR = 0.64), or low-flow low-gradient aortic stenosis (HR = 0.58) and showed additional benefit even in patients taking renin-angiotensin system blockers (HR = 0.74). Statins also reduced mortality in patients with malignant disease (HR = 0.47). Our analysis confirmed the beneficial effect of statins on survival after TAVI and documented this phenomenon in key patient subsets. The protective effect of statins in our study is consistent with the cardioprotective mechanisms but must be explained by other, yet undetermined pleiotropic effects of statins.

Plausible Positive Effects of Statins in COVID-19 Patient

Since the onset of the global COVID-19 pandemic, there has been much discussion about the advantages and disadvantages of ongoing chronic drug therapies in SARS-CoV-2-positive patients. These discussions include also statins treatment. The statins are among the most widely used drugs in the global population. Statins aim to lower cholesterol, which is essential for many biological processes but can lead to heart disease if levels are too high; however, also the pleiotropic effects of statins are well known. So could the anti-inflammatory or the potential antiviral effects of statins be helpful in avoiding extreme inflammation and severity in COVID-19? To date, there are conflicting opinions on the effects of statins in the course of COVID-19 infection. The aim of this article is to describe the molecular and pharmacological basis of the pleiotropic effects of statins that could be more involved in the fight against COVID-19 infection and to investigate the current epidemiological evidence in the literature on the current and important topic.

Anti-Inflammatory Effect of Very High Dose Local Vessel Wall Statin Administration: Poly(L,L-Lactide) Biodegradable Microspheres with Simvastatin for Drug Delivery System (DDS).

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 μm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.

Statins and clinical outcomes in hospitalized COVID-19 patients with and without Diabetes Mellitus: a retrospective cohort study with propensity score matching

BackgroundThe pleiotropic effects of statins may reduce the severity of COVID-19 disease. This study aims to determine the association between inpatient statin use and severe disease outcomes among hospitalized COVID-19 patients, especially those with Diabetes Mellitus (DM).Research design and methodsA retrospective cohort study on hospitalized patients with confirmed COVID-19 diagnosis. The primary outcome was mortality during hospitalization. Patients were classified into statin and non-statin groups based on the administration of statins during hospitalization. Analysis included multivariable regression analysis adjusting for confounders and propensity score matching to achieve a 1:1 balanced cohort. Subgroup analyses based on presence of DM were conducted.ResultsIn the cohort of 922 patients, 413 had a history of DM. About 27.1% patients (n = 250) in the total cohort (TC) and 32.9% patients (n = 136) in DM cohort received inpatient statins. Atorvastatin (n = 205, 82%) was the most commonly prescribed statin medication in TC. On multivariable analysis in TC, inpatient statin group had reduced mortality compared to the non-statin group (OR, 0.61; 95% CI, 0.42–0.90; p = 0.01). DM modified this association between inpatient statins and mortality. Patients with DM who received inpatient statins had reduced mortality (OR, 0.35; 95% CI, 0.21–0.61; p < 0.001). However, no such association was noted among patients without DM (OR, 1.21; 95% CI, 0.67–2.17; p = 0.52). These results were further validated using propensity score matching.ConclusionsInpatient statin use was associated with significant reduction in mortality among COVID-19 patients especially those with DM. These findings support the pursuit of randomized clinical trials and inpatient statin use appears safe among COVID-19 patients.

The impact of atherosclerotic cardiovascular disease, dyslipidaemia and lipid lowering therapy on Coronavirus disease 2019 outcomes: an examination of the available evidence.

Coronavirus Disease 2019 (COVID19) has caused significant global morbidity and mortality, especially in persons with underlying cardiovascular disease. There have been concerns that lipid-lowering therapy (LLT) increases angiotensin-converting enzyme 2 levels. Conversely, pleiotropic effects of statins can theoretically protect against severe COVID19 infection, supporting evidence from other respiratory illnesses in which statin use probably confers benefit. There is an abundance of studies that show that statins are safe and potentially protect against severe COVID19 infection (critical illness and death), even when adjustment for potential confounders is undertaken. However, the evidence is limited to retrospective cohorts. The benefit for patients with diabetes is less clear. There is a paucity of evidence for other LLT agents. Available clinical guidelines recommend the ongoing use of LLT in patients with COVID19 (unless specifically contra-indicated) and the data from available studies support these. In patients with COVID19 infection, LLT should be continued. However, the current findings need substantiating in larger prospective clinical studies with specific examination of the possible mechanisms by which LLT confers benefit from COVID19.

Abstract MP69: A Proteomic Approach For Investigating The Pleiotropic Effects Of Statins In The Atherosclerosis Risk In Communities (ARIC) Study

Background: Statins are prescribed to reduce LDL-cholesterol (LDL-c) and the risk of cardiovascular disease. Statins may influence other outcomes such as dementia through pleiotropic effects unrelated to lipid metabolism. We compared the proteome of statin users and nonusers. We hypothesized that statin use would be associated with proteins in biological pathways unrelated to lipid metabolism. Methods: Among 11,471 participants enrolled in the ARIC study at visit 3 (1993-95), plasma concentrations of 4,638 proteins were determined using the SOMAlogic DNA aptamer-based capture array. We identified 402 participants who initiated statin use within the 2 years prior. Propensity scores (PS) were calculated based on visit 2 (1990-92) LDL-c levels and visit 3 demographic characteristics, CVD risk factors and medications, kidney function, and prevalent CVD. Statin users were matched to nonusers (controls) based on PS similarity, yielding 382 matched pairs. Log2-transformed and standardized protein levels were compared between statin users and controls using t-tests. The false discovery rate (FDR) adjusted for multiple comparisons. Ingenuity Pathway Analysis (IPA) was used to identify potentially altered biological pathways. Results: After PS matching, LDL-c levels at visit 3 were lower in statin users vs controls (125.4 vs 147.1 mg/dL; p &lt;.0001), but all other covariates were balanced. We identified 344 enriched and 298 depleted proteins in statin users (p &lt;.05). After FDR adjustment, 12 proteins were enriched and 17 were depleted. Proteins involved in lipid metabolism were altered in statin users, including proteins in the mevalonate pathway. Proteins unrelated to lipid metabolism also differed between groups (Figure). IPA analysis suggested 20 pathways were altered among statin users. Conclusion: Several proteins unrelated to lipid metabolism differed by statin use. Pending external validation, exploring the biological functions of these proteins could elucidate pleiotropic effects of statins.

The anti-cancer effect of statins in obese esophageal cancer patients undergoing esophagectomy.

e16012 Background: In addition to lowering lipid levels and treating atherosclerotic disease, statins have demonstrated anti-inflammatory and anti-tumor activity in various cancer types. We evaluate this effect in esophageal cancer patients undergoing esophagectomy. Methods: All patients undergoing esophagectomy for esophageal cancer at Roswell Park Comprehensive Cancer Center between March 2007 and December 2015 were included. The association between pre-surgery statin use with overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) was analyzed using Cox proportional hazards regression, with age, sex, American Society of Anesthesia (ASA) score, neoadjuvant therapy, surgical technique, tumor stage, histology, and grade considered in multivariable analyses. Survival analyses were independently performed for body mass index (BMI)-based patient subgroups. Results: 212 patients met inclusion criteria for this study. Median follow up period was 36 months. Estimated five-year RFS for the patient cohort overall was 55.7% and estimated five-year DSS was 53.9%. Estimated five-year OS was 45.4%. There was no significant association between statin use and outcomes of esophagectomy patients overall. However, in subgroup analysis analyzing patients by BMI category, there was a significant association between statin use and outcomes in patients with BMI ≥ 30 (n = 95 patients). Multivariate analysis in obese patients demonstrated an association of statins with improved OS (HR 0.52, p = 0.049), DSS (HR 0.46, p = 0.034) and RFS (HR 0.43, p = 0.036). The other variables significantly associated with outcome measures were stage ≥ 2 (OS HR 2.36, p = 0.010; RFS HR 2.50, p = 0.018; DSS HR 2.51, p = 0.011) and ASA score ≥ 3 (RFS HR 2.26, p = 0.037; DSS HR 2.33, p = 0.019). Conclusions: Statin use is associated with improved RFS, DSS and OS of obese patients undergoing esophagectomy for esophageal cancer. This novel finding suggests an interaction between the pathophysiologic state of obesity and the pleiotropic effects of statins. BMI could be explored as a potential biomarker for adjunctive statin use in future trials.[Table: see text]

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders.

Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.

The role of anti-proliferative effects of atorvastatin on uterine fibroids: findings from a clinical study

Aim Uterine myomas/fibroids are one of the most common benign tumors of the reproductive system in women. Given pleiotropic effects of statins, the aim of this study is to evaluate the therapeutic effects of atorvastatin on uterine fibroids in women of reproductive age. Materials and Methods This randomized clinical study included 90 women aged 35–45 years with uterine fibroids. The patients were randomly allocated into the intervention group (received one tablet, 20 mg of atorvastatin every day for three months) and placebo. Ultrasound was performed every month, and the change in the size of fibroids was recorded for each patient. At the end of the study, the data obtained were analyzed using SPSSv22 and a p value < .05 was considered statistically significant. Results The mean age in the placebo and intervention group was 39.63 ± 36.3 and 40.35 ± 3.32 years, respectively. The number and location of the tumor was comparable for the two groups. We observed a statically significant reduction in fibroid size from the treatment initiation until completion of three months, (41.06 ± 6.68 mm3 vs 35.16 ± 6.67 mm3) p = .0001. However, the decrease in fibroid size from 1st month to the 3rd month was not statistically significant, p = .189 (36.71 ± 5.54 mm3 vs 35.16 ± 6.67 mm3). Conclusion This study shows that treatment with atorvastatin might positively reduce the size of fibroids. The decrease was only statistically significant during the first month. Further studies with a detailed analysis of the intervention's clinical impact are required to consider statins as a therapeutic tool.

The advantages of drug treatment with statins in patients with SARS-CoV-2 infection.

On 11 March 2020 the World Health Organization (WHO) declared a status of global pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019, COVID-19). The pandemic is currently underway, and to date has caused approximately 2.42 million deaths worldwide. The first vaccines have recently been licensed; however, research continues to identify therapeutic agents to prevent serious complications, such as anti-inflammatory, immunomodulatory, anticoagulant or antiviral agents authorized for other therapeutic indications. Epidemiological evidence shows that advanced age and comorbidities, such as diabetes, heart disease, and dyslipidemia may represent COVID-19 risk factors. In particular, in patients with hypercholesterolemia treated with statins, it is recommended that treatment should not be discontinued if COVID-19 infection occurs. The pleiotropic effects of statins are well known. In this brief review, we propose that the use of statins can potentially protect against SARS-CoV-2-induced tissue damage and improve lung function in COVID-19 patients through several pleiotropic effects. Pleiotropic effects of statins that may be a significant benefit in patients with hypercholesterolemia treated with statins and COVID-19 positive. Recent evidence shows promising results.

Fluvastatin protects neuronal cells from hydrogen peroxide-induced toxicity with decreasing oxidative damage and increasing PI3K/Akt/mTOR signalling.

Statins, the most effective lipoprotein-cholesterol lowering drugs, are widely used for patients with cardiovascular disease. The pleiotropic effects of statins have been recently gained attention for their both beneficial and deleterious effects on neurons. We investigated the effects and molecular mechanisms of fluvastatin at clinically relevant concentrations on neuronal cells after induction of oxidative stress. Both SH-SY5Y, a representative cell line for in vitro neurone model, and human primary neuronal cells were applied. Cellular and biochemical assays were used to investigate the effects of fluvastatin in neurone cells. Fluvastatin significantly restored H2O2-induced neuronal death in a dose-dependent manner (P < 0.05) and reversed H2O2-induced oxidative stress and damage via restoring mitochondrial function in neuronal cells (P < 0.05). Although fluvastatin inhibited prenylation in neuronal cells, the protective effects of fluvastatin against H2O2-induced neuronal cytotoxicity are not associated with prenylation inhibition or AMPK activation. In contrast, PI3K/Akt/mTOR activation mediated fluvastatin's neuroprotective activity (P < 0.05). Our work demonstrates the beneficial effects of fluvastatin in neuronal cells under pathological conditions, and, furthermore, this is via prenylation-independent activation of PI3K/Akt/mTOR pathway. Our data highlights the functional significance of the PI3K/Akt/mTOR pathway in neuronal cells in response to oxidative stress.