Statins Research Articles

PIN1 prolyl isomerase promotes initiation and progression of bladder cancer through the SREBP2-mediated cholesterol biosynthesis pathway.

Identities of functional pSer/Thr.Pro protein substrates of the PIN1 prolyl isomerase and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we found that PIN1 positively regulated bladder cancer cell proliferation, cell motility and urothelium clearance capacity in vitro and controlled tumor growth and potential metastasis in vivo. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways and a decrease in free/total cholesterol levels in PIN1-knockout bladder cancer cells. Moreover, we showed that PIN1 interacted with SREBP2 following its phosphorylation by the JNK MAP kinase at Ser455, which lies near the Site-2 cleavage site that generates the active, nuclear-form of SREBP2. Therapeutically, a combination of the sulfopin PIN1 covalent inhibitor and the simvastatin HMGCoA reductase inhibitor suppressed cell proliferation in vitro and tumor growth in vivo synergistically. Together, these findings emphasize that PIN1 can act as a driver and potential therapeutic target in bladder cancer.

Multiomic Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.

The impact of drug eluting stents on the co-release of interleukin-6 in patients with stable angina

Background: Drug-eluting stents represent an important revolution in the treatment of coronary artery disease. However, the mechanical trauma of stent deployment can trigger vascular injury and inflammatory cytokine cascades, potentially precipitating in-stent restenosis. The release of cytokines is not firmly established in patients with stable angina. Aims: To evaluate the acute effect of drug-eluting stents on the acute inflammatory response in patients with stable angina by quantifying interleukin-6 levels. Methods and materials: A single-centre exploratory study was conducted on 13 patients with stable angina undergoing elective angioplasty. Arterial blood samples were collected before angioplasty and directly after angioplasty. Additionally, venous blood samples were collected 24 hours post-angioplasty. Concentrations of interleukin-6 were analysed to assess changes in the acute inflammatory response. Results: IL-6 concentration significantly increased immediately after stent placement (5.95 ± 0.49 pg/ml, p = <0.05) and 24 hours post-stent placement (8.96 ± 1.16 pg/ml, p= <0.01). Gender-based analysis indicated significant increases in IL-6 levels in males post-stent placement (5.94 ± 0.08 pg/ml, p= < 0.05) and 24 hours post-stent placement (7.27 ± 0.56 pg/ml, p= < 0.01). Statin medication significantly reduced IL-6 expression in patients at baseline (3.27 ± 0.71 pg/ml versus 5.44 ± 0.18 pg/ml, p= < 0.05), but this distinction diminished rapidly after stent insertion, resulting in comparable IL-6 levels at 24 hours post-stent insertion in both groups. Conclusion: Interleukin-6 levels markedly increased immediately after coronary stenting, suggesting its role as an early initiator of the inflammatory response to coronary stenting. While limited by sample size, it lays the groundwork for larger, more comprehensive research to optimize drug-eluting stents outcomes and inflammatory management.

Effectiveness and safety of daily versus alternate-day rosuvastatin dose in dyslipidemic patients: a prospective, randomized and open-label study

Background: Dyslipidemia is considered to be an important risk factor for development of atherosclerotic cardiovascular disease (ASCVD). Statins, also called HMG CoA reductase inhibitors are considered to the most effective lipid lowering agents. This study assessed the effectiveness and safety of daily versus alternate day dosing regimens of rosuvastatin in dyslipidemia patients. Methods: This study was conducted for a period of 12 weeks. Study subjects comprised patients of either sex in age group 18-65 years diagnosed with dyslipidemia and a total of 90 subjects completed study who were randomly distributed to three groups, A (rosuvastatin 10 mg daily), B (rosuvastatin 10 mg on alternate days) and C (rosuvastatin 20 mg on alternate days). Results: Rosuvastain significantly lowered total cholesterol, low density lipoprotein-cholesterol and triglycerides in all groups (p<0.001). High density lipoprotein-cholesterol increased, but non-significantly (p>0.05). Intergroup differences were not statistically significant. Group A reported slightly more adverse events than group B and group C. Conclusions: Alternate-day rosuvastatin therapy showed effectiveness statistically similar to the daily dose therapy in dyslipidemic individuals. It also exhibited fewer side effects, suggesting it could be a feasible approach for managing dyslipidemia, providing a more economical and potentially safer alternative to daily administration.

Group-Based Trajectory Models to Evaluate the Association of Lipid Testing and Statin Adherence.

Performing lipid testing after statin initiation is recommended to monitor response. Inadequate response may indicate non-adherence, which is associated with an increased risk of cardiovascular events and increased costs. Group-based trajectory modeling is an approach to establish probabilistic developmental trajectories of adherence, differentiating individuals by their distinct longitudinal medication-taking behaviors. We examined whether lipid testing is associated with distinct trajectories of statin adherence among individuals enrolled in a Medicare fee-for-service plan in the USA. A retrospective cohort study was conducted using the Centers for Medicare & Medicaid Chronic Condition Warehouse 5% sample of Medicare fee-for-service data between 2006 and 2015. Statin use and lipid testing were identified using claims data. The proportion of days covered was calculated for each 30 days after the index date, which was used to estimate the probability of belonging to each potential adherence trajectory. In a cohort of 138,101 statin initiators, four statin adherence trajectory groups were identified. The four groups were differentiated as "rapid decline" (21.53%), "gradual decline" (10.25%), "decline first then improve later" (26.47%), and "high adherence" (41.75%). Compared with "high adherence," initiators who had lipid tests within 360 days after statin initiation were less likely to fall into "rapid decline" (adjusted odds ratio: 0.661; 95% confidence interval 0.641-0.683), "gradual decline" (adjusted odds ratio: 0.834; 95% confidence interval 0.801-0.868), and "decline first then improve later" groups (adjusted odds ratio: 0.936; 95% confidence interval 0.910-0.962). Lipid testing is positively associated with greater use of statin medication across different adherence trajectories in the present study.

FDFT1 maintains glioblastoma stem cells through activation of the Akt pathway

BackgroundCancer stem cells (CSCs) have unique metabolic characteristics and are hypothesized to contribute significantly to the recurrence and drug resistance of glioblastoma multiforme (GBM). However, the reliance on mitochondrial metabolism and the underlying mechanism of glioblastoma stem cells (GSCs) remains to be elucidated.MethodsTo quantify differential mitochondrial protein expression between GSCs and differentiated cells, a mass spectrum screen was applied by the Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) technique. Functional experiments including CCK8, neurosphere formation, flow cytometry, transwell, and wound healing assays were conducted to evaluate GBM cell malignant phenotype. The potential molecular mechanism of FDFT1 was screened by RNA-seq analyses. The candidate target genes were validated through RT-qPCR and western blot analyses.ResultsAs a top candidate, FDFT1 protein expression in GSCs was elevated relative to their differentiated counterparts. Functionally, the knockdown of FDFT1 suppressed the GBM cell proliferation and migration, while simultaneously enhancing sensitivity to temozolomide. Treatment with both the FDFT1 inhibitor (YM-53601) and simvastatin (an HMG-CoA reductase inhibitor) induced apoptosis in GSCs. Mechanistically, FDFT1 was transcriptionally regulated by SREBP2 but not SREBP1. Furthermore, FDFT1 activates the AKT pathway to regulate tumor metabolism and maintain the stemness of tumor cells.ConclusionsGSCs exhibit a dependency on FDFT1-mediated mevalonate metabolism. Inhibition of FDFT1 could represent a potent strategy to eliminate GSCs.

Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3.

B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization in cis activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI). Notably, the HTS identified several compounds that converged on lipid metabolism (including HMG-CoA reductase inhibitors, also known as statins) as significant inhibitors of 4Ig-B7-H3 dimerization (p < 0.01). In vitro and in vivo murine studies provided evidence that statin-mediated disruption of 4Ig-B7-H3 dimerization was associated with anti-tumor effects. Statin-mediated anti-cancer efficacy was selective for B7-H3-expressing tumors and retrospective analysis of clinical tumor specimens supported the hypothesis that concurrent statin use enhanced clinical outcomes for patients in a B7-H3 restricted manner. Thus, disruption of 4Ig-B7-H3 dimerization provides an unanticipated molecular mechanism linking statin use in cancer therapy and prevention with immune checkpoint.

HMG-CoA reductase inhibitor simvastatin ameliorates trimethyltin neurotoxicity and cognitive impairment through reversal of Alzheimer's-associated markers.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder in elderly. The neurotoxicant trimethyltin (TMT) induces neurodegenerative changes, as observed in AD. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin (SV) has shown protective and promising therapeutic effects in neurological disorders such as AD and Parkinson's disease. The present study aimed to assess neuroprotective effect of simvastatin (SV) against trimethyltin (TMT) memory decline and hippocampal neurodegeneration. For inducing AD-like phenotype, rats were i.p. injected with TMT at 8mg/kg and were treated with simvastatin daily for 3 weeks at 10 or 30mg/kg. Our analysis of data indicated that simvastatin-treated TMT group has lower learning and memory deficits in behavioral tasks comprising Barnes maze, Y maze, and novel object discrimination (NOD). In addition, hippocampal inflammatory, oxidative, and apoptotic factors were attenuated besides reduction of acetylcholinesterase (AChE) activity and Alzheimer's pathology factors including presenilin-1 and hyperphorphorylated Tau (p-Tau) upon simvastatin. Moreover, simvastatin treatment of TMT group inverted hippocampal changes of Wnt, β-catenin, ERK, and Akt, ameliorated astrocytic and microglial reactivity, and also prevented injury of CA1 neurons. This study unraveled that simvastatin is capable to prevent TMT-induced Alzheimer's-like phenotype in association with Wnt/β-catenin/ERK/Akt as well as restraining hippocampal neurodegeneration.

Statin Use and Hyperglycemia: Do Statins Cause Diabetes?

Atherosclerotic cardiovascular disease (ASCVD) and diabetes are leading causes of morbidity and mortality in the United States and globally. Statin medications, a cornerstone of ASCVD prevention and treatment strategies, have been demonstrated to cause hyperglycemia and new onset diabetes mellitus (NODM). The purpose of this review is to summarize existing and emerging knowledge around the intersection of statins and these two important clinical problems. Since initial reporting of statin-induced hyperglycemia and NODM, the totality of available data corroborates an association between incident diabetes and statin use. A consensus that high-intensity statin and individuals with obesity or glycemic parameters approximating diabetes thresholds constitute the majority of risk exists. Alterations in insulin signaling, glucose transport and gastrointestinal microbiota are leading hypotheses underlying the mechanisms of statin-induced hyperglycemia. The probability of NODM based on an individual's risk factors and statin specific properties can be anticipated. This risk needs to be contextualized with the risk of ASCVD. In order to effectively adjudicate the risk of NODM, improvement in formulating and ultimately conveying a comprehensive ASCVD risk assessment to patients is necessary.

Regulatory effects of statins on CCL2/CCR2 axis in cardiovascular diseases: new insight into pleiotropic effects of statins

BackgroundHMG-CoA reductase inhibitors are well-known medications in the treatment of cardiovascular disorders due to their pleiotropic and lipid-lowering properties. Herein, we reviewed the effects of statins on the CCL2/CCR2 axis.MethodScopus and Pubmed databases were systematically searched using the following keywords:” Hydroxymethylglutaryl CoA Reductase Inhibitors”,” HMG-CoA Reductase Inhibitors”,” Statins”, “CCL2, Chemokine”, “Monocyte Chemoattractant Protein-1” and “Chemokine (C-C Motif) Ligand 2”. Evidence investigating the role of statin on MCP-1 in CVD was identified and bibliographies were completely evaluated to gather further related studies.ResultsThe anti-inflammatory effects of statins on the CCL2/CCR2 pathway have been widely investigated. Despite inconclusive results, a great body of research supports the regulatory roles of statins on this pathway due to their pleiotropic effects. By disrupting the CCL2/CCR2 axis, statins attenuate the infiltration of monocytes and macrophages into the zone of inflammation and hence down-regulate the inflammatory cascades in various CVDs including atherosclerosis, cardiac remodeling, and stroke, among others.ConclusionCCL2 plays a major role in the pathogenesis of cardiovascular disorders. Down-regulation of CCL2 is proposed as one of the pleiotropic properties of statins. However, more investigations are required to elucidate which statin in what dose exerts a more potent effect on CCL2/CCR2 pathway.

Study on the Effect of Percutaneous Coronary Intervention in the Treatment of Chronic Coronary Syndrome

Objective: To analyze the clinical effect of percutaneous coronary intervention in the treatment of chronic coronary syndrome. Methods: 120 cases of chronic coronary syndrome patients who received inpatient treatment in a hospital from July 2023 to June 2024 were selected as the object, and were divided into the control group and the observation group using the mean score method, each with 60 cases, the control group was treated with conventional medications (aspirin, carbamazepine, β-receptor blockers, angiotensin-converting enzyme inhibitors, statin and other medications), and the observation group was treated with percutaneous The observation group implemented percutaneous coronary intervention based on this treatment, comparing the therapeutic effects of the two groups. Results: The treatment efficiency of the observation group (98.33%) was significantly higher than that of the control group (86.67%), and the difference was statistically significant (P &lt; 0.05); before treatment, the IVPWTd and LVEDd indexes of the patients in the control group and the observation group were (10.39 ± 0.86) mm, (55.36 ± 5.67) mm and (10.41 ± 0.78) mm, (56.01 ± 6.80) mm, respectively. The difference was not statistically significant (P &gt; 0.05); after 3 weeks of treatment, all the indexes of the two groups decreased significantly, respectively (9.76 ± 0.62) mm, (53.28 ± 5.63) mm and (8.56 ± 0.49) mm, (49.65 ± 5.47) mm, and the observation group was significantly lower than the control group, and the difference was statistically significant (P &lt; 0.05). In the control group, 3 cases of arrhythmia and 2 cases of coronary artery spasm occurred during the treatment period, and 1 case each of residual cardiac insufficiency, acute thrombosis, chronic renal impairment, and cardiogenic death, with a total incidence rate of 15%, while in the observation group, only 1 case of arrhythmia and 1 case of coronary artery spasm occurred, with a total incidence rate of 3.33%, and the difference between the groups was statistically significant (P &lt; 0.05). Conclusion: Percutaneous coronary intervention for the treatment of chronic coronary syndrome combined with renal disease is effective, can significantly improve the level of patients’ left ventricular function and reduces the risk of related complications, and is recommended to be popularized and applied in the clinic.

Statin Use in Children and Adolescents - Dos, Don'ts and Practical Tips.

We review treatment criteria in the pediatric population, provide practical advice on how and when to prescribe statins, and share tips to improve compliance. Although long-term outcome studies of cardiovascular-related events, such as myocardial infarction (MI) and stroke, are lacking in this population, statin therapy initiated during adolescence has been shown to be safe and effective for up to 20years of continuous use. HMG-CoA reductase inhibitors (statins) are the most effective class of drugs for lowering low-density lipoprotein cholesterol (LDL-C) in children and adolescents.

Does EFSA statement on Monacolin content of nutraceutical combinations impair their lipid lowering effect? The LopiGLIK experience

BackgroundMonacolin-K, the active component of red yeast rice (RYR), reduces cholesterol by inhibiting HMG-CoA reductase. Following safety concerns, the European Food Safety Authority (EFSA) recommended limiting Monacolin-K intake to less than 3 mg/day due to adverse effects at higher doses.Case presentation: A study comparing Armolipid Plus® and LopiGLIK® found LopiGLIK® more effective in lowering LDL cholesterol, possibly due to slightly higher dosages of Berberine and Monacolin-K. Despite reducing Monacolin-K content to 2.99 mg following EFSA guidelines, LopiGLIK® maintained its cholesterol-lowering efficacy.ConclusionsTaken together, our results indicate that other ingredients, such as Morus alba, may contribute to LopiGLIK®’s enhanced effectiveness, challenging the notion that minor differences in Monacolin-K dosage account for the observed efficacy.

Causal associations of ischemic stroke, metabolic factors, and related medications with epilepsy: a Mendelian randomization study.

Earlier researches have demonstrated that ischemic stroke, metabolic factors, and associated medications may influence the risk of epilepsy. Nevertheless, the causality between these elements and epilepsy remains inconclusive. This study aims to examine whether ischemic stroke, metabolic factors, and related medications affect the overall risk of epilepsy. We used single nucleotide polymorphisms associated with ischemic stroke, hypothyroidism, hypertension, blood glucose levels, high cholesterol, serum 25-Hydroxyvitamin D levels, testosterone, HMG CoA reductase inhibitors, and beta-blocking agents as instrumental variables in a Mendelian randomization technique to investigate causality with epilepsy. Multiple sensitivity methods were performed to evaluate pleiotropy and heterogeneity. The IVW analysis revealed positive associations between ischemic stroke (OR = 1.29; p = 0.020), hypothyroidism (OR = 1.05; p = 0.048), high blood pressure (OR = 1.10; p = 0.028), high cholesterol (OR = 1.10; p = 0.024), HMG CoA reductase inhibitors (OR = 1.19; p = 0.003), beta-blocking agents (OR = 1.20; p = 0.006), and the risk of epilepsy. Conversely, blood glucose levels (OR = 0.79; p = 0.009), serum 25-Hydroxyvitamin D levels (OR = 0.75; p = 0.020), and testosterone (OR = 0.62; p = 0.019) exhibited negative associations with the risk of epilepsy. Sensitivity analyses confirmed the robustness of these findings (p > 0.05). Our research suggests that ischemic stroke, hypothyroidism, high blood pressure, high cholesterol, HMG CoA reductase inhibitors, and beta-blockers may increase the risk of epilepsy, whereas serum 25-Hydroxyvitamin D levels and blood glucose levels may reduce the risk.

Abstract 4132341: Systematic Examination of the AHA PREVENT Equations

Background: The novel AHA Predicting Risk of CVD Events (PREVENT) equations newly incorporate predictors (estimated glomerular filtration rate [eGFR]) and outcomes (heart failure [HF]) relevant to the novel construct of cardiovascular-kidney-metabolic (CKM) syndrome. Aims: We sought to characterize the intrinsic properties of the PREVENT equations by simulating different risk profiles across the age and CKM risk spectrum. Methods: We applied the PREVENT base equations to estimate 10-year predicted risk for total CVD, which includes atherosclerotic CVD and HF. First, we calculated risk estimates for a hypothetical individual varying age from 30-79 years with an average risk factor profile (mean population risk factor levels based on National Health and Nutrition Examination Survey 2011-2020 data without diabetes, not on anti-hypertensive or statin medication, and who does not smoke). Second, we examined at which age a hypothetical individual would exceed the previously defined intermediate risk threshold ≥7.5% established by national guidelines. Lastly, we examined the differences in predicted risk with or without diabetes and/or Stage 3 CKD (defined as eGFR 44.5 mL/min/1.73m 2 ). Results: For hypothetical individuals aged 30-79 years with average risk factor levels, predicted 10-year CVD risk is shown in the figure for females (Panel A) and males (Panel B). The predicted risk would exceed the intermediate risk threshold at age 68 years if female and 63 years if male. If the individual had Stage 3 CKD, the predicted risk would exceed the intermediate risk threshold at 60 if female and 55 years if male. If the individual had diabetes, the predicted risk would exceed the intermediate risk threshold at 59 if female and 52 years if male. If both diabetes and Stage 3 CKD were present, the predicted risk would exceed the intermediate risk threshold at age 42 years if female and 35 years if male. Conclusions: The PREVENT equations enable more granular differentiation of risk among individuals with varying CKM profiles. Understanding risk estimates across the spectrum of age and CKM can support interpretability among clinicians and patients.

Abstract 4112853: Trends in Statin Use for the Secondary Prevention of Atherosclerotic Cardiovascular Disease among U.S. Adults by Age, 1999-2020

Background: Current research focusing on trends in statin medication usage, particularly for different age groups, is limited. This study explored the change trends in statin usage from 1999 to 2020, with a specific focus on different age groups. Methods: Utilizing data from the National Health and Nutrition Examination Survey spanning the period from 1999 to 2020, our study included individuals aged 18 years and older diagnosed with atherosclerotic cardiovascular disease (ASCVD). Results: In the 18-44 years age group, usage changed from 18.34% (95% CI, 0.18 to 36.50) in 1999 to 16.63% (95% CI, 0.36 to 32.91) in 2020 (linear P value = 0.540, quadratic P value = 0.610) (Figure 1). For individuals aged 45-64 years, usage increased from 39.33% (95% CI, 29.62 to 49.05) in 1999 to 54.97% (95% CI, 47.10 to 662.83) in 2020 (linear P value &lt; 0.001, quadratic P value = 0.777) (Figure 1). In the group aged 65 years and older, usage increased from 35.17% (95% CI, 29.57 to 40.77) in 1999 to 60.62% (95% CI, 55.73 to 65.51) in 2010, and further to 68.62% (95% CI, 63.65 to 73.60) in 2020 (quadratic P value &lt; 0.001) (Figure 1). There was an interaction effect between statin usage trends and age (P for interaction &lt;0.001) (Figure 1). Conclusion: Overall, current health policies are effective for the use of statins for the secondary prevention of ASCVD. However, there was almost no improvement in statin usage within the 18-44 years age group. This highlights the need for greater focus on young ASCVD patients. Therefore, additional research is needed on statin use among young people.

Mitigating neuroinflammation in cognitive areas: exploring the impact of HMG-CoA reductase inhibitor.

Existing literature suggests that infection-specific mechanisms may play a significant role in the onset and progression of dementia, as opposed to the broader phenomenon of systemic inflammation. In addition, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors have been proposed as a potential therapeutic approach for sepsis, given their anti-inflammatory and antioxidant properties. We investigated the neuroprotective effect of an HMG-CoA reductase inhibitor (simvastatin) by analyzing neurodegenerative markers, mitochondrial respiration, and neuronal tracing in the prefrontal cortex (PFC) and thalamic nucleus reuniens (RE) of sepsis survivor animals. Adult Wistar rats were subjected to sepsis by cecal ligation and puncture or left non-manipulated. The animals were treated with simvastatin or vehicle for 4 days before and 10 days after surgery. The treatment preserved the non-associative memory (P < 0.05), recovered expression of Smad-3 in the hippocampus (P < 0.05), and prevented increased expression of calpain-1 (hippocampus: P < 0.0001; PFC: P < 0.05) and GSKβ (hippocampus: P < 0.0001; PFC: P < 0.0001) in the brain structures of the sepsis survivor animals. These animals also showed mitochondrial dysfunction and decreased axon terminals in the RE. Simvastatin seems to restore energy metabolism by improving the electron transfer system (ETS) values in the hippocampus (P < 0.01) and the oxidative phosphorylation/ETS (P/E) ratio in the PFC (P < 0.05), in addition to preventing the reduction of axon terminals in survivor animals. These results suggest a potential neuroprotective effect and the importance of considering HMG-CoA reductase inhibitors as a possible adjuvant therapy in sepsis.

QSAR Regression Models for Predicting HMG-CoA Reductase Inhibition.

HMG-CoA reductase is an enzyme that regulates the initial stage of cholesterol synthesis, and its inhibitors are widely used in the treatment of cardiovascular diseases. We have created a set of quantitative structure-activity relationship (QSAR) models for human HMG-CoA reductase inhibitors using nested cross-validation as the primary validation method. To develop the QSAR models, we employed various machine learning regression algorithms, feature selection methods, and fingerprints or descriptor datasets. We built and evaluated a total of 300 models, selecting 21 that demonstrated good performance (coefficient of determination, R2 ≥ 0.70 or concordance correlation coefficient, CCC ≥ 0.85). Six of these top-performing models met both performance criteria and were used to construct five ensemble models. We identified the descriptors most important in explaining HMG-CoA inhibition for each of the six best-performing models. We used the top models to search through over 220,000 chemical compounds from a large database (ZINC 15) for potential new inhibitors. Only a small fraction (237 out of approximately 220,000 compounds) had reliable predictions with mean pIC50 values ≥ 8 (IC50 values ≤ 10 nM). Our svm-based ensemble model predicted IC50 values < 10 nM for roughly 0.08% of the screened compounds. We have also illustrated the potential applications of these QSAR models in understanding the cholesterol-lowering activities of herbal extracts, such as those reported for an extract prepared from the Iris × germanica rhizome. Our QSAR models can accurately predict human HMG-CoA reductase inhibitors, having the potential to accelerate the discovery of novel cholesterol-lowering agents and may also be applied to understand the mechanisms underlying the reported cholesterol-lowering activities of herbal extracts.

Effect of diabetes mellitus on 3-year outcomes in patients with acute myocardial infarction with nonobstructive coronary arteries.

Diabetes mellitus (DM) is a significant factor in increased mortality rates among patients with acute myocardial infarction (AMI), but research on its impact on the long-term outcomes in patients with MI with nonobstructive coronary arteries (MINOCA) is limited. Thus, a comparison of the 3-year clinical outcomes between the DM and non-DM groups among patients with MINOCA was undertaken. From the Korea AMI Registry-National Institute of Health dataset, 10,774 AMI patients were enrolled. After applying the exclusion criteria, 379 patients with MINOCA were included. The primary clinical outcomes were major adverse cardiac and cerebrovascular events (MACCE), defined as all-cause death, recurrent myocardial infarction (MI), repeat coronary revascularization, and stroke. The secondary outcomes were the individual components of MACCE. The adjusted hazard ratios for 3-year MACCE (2.287, p = 0.010), all-cause death (2.845, p = 0.004), and non-cardiac death (non-CD, 3.914, p = 0.008) were higher in the DM group than in the non-DM group. It is speculated that the higher non-CD rate in the MINOCA group is attributable to a higher proportion of patients with non-ST-segment elevation MI in the total study population. The CD, recurrent MI, revascularization, and stroke rates were similar between the DM and non-DM groups. DM, advanced age, cardiopulmonary resuscitation on admission, and non-use of statin medications were significant predictors of MACCE. In this study involving patients with MINOCA, the DM group exhibited a higher 3-year mortality rate than the non-DM group. Thus, DM demonstrated a hazardous effect even in patients with MINOCA.

Immunomodulation by the combination of statin and matrix-bound nanovesicle enhances optic nerve regeneration

Modulating inflammation is critical to enhance nerve regeneration after injury. However, clinically applicable regenerative therapies that modulate inflammation have not yet been established. Here, we demonstrate synergistic effects of the combination of an HMG-CoA reductase inhibitor, statin/fluvastatin and critical components of the extracellular matrix, Matrix-Bound Nanovesicles (MBV) to enhance axon regeneration and neuroprotection after mouse optic nerve injury. Mechanistically, co-intravitreal injections of fluvastatin and MBV robustly promote infiltration of monocytes and neutrophils, which lead to RGC protection and axon regeneration. Furthermore, monocyte infiltration is triggered by elevated expression of CCL2, a chemokine, in the superficial layer of the retina after treatment with a combination of fluvastatin and MBV or IL-33, a cytokine contained within MBV. Finally, this therapy can be further combined with AAV-based gene therapy blocking anti-regenerative pathways in RGCs to extend regenerated axons. These data highlight novel molecular insights into the development of immunomodulatory regenerative therapy.