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Asian Pacific Journal of Cancer... Dec 2022We hypothesized that superlative dual cytotoxicity-antiinflammtion bioefficacies of 9 selected lipophilic statins correlate to their chelation effect of...
BACKGROUND
We hypothesized that superlative dual cytotoxicity-antiinflammtion bioefficacies of 9 selected lipophilic statins correlate to their chelation effect of 3,5-dihydroxyheptanoic acid.
METHODOLOGY
Lipophilic-acid chelating statins have been screened for in vitro duality of proliferation inhibition and NO-radical scavenging capacities.
RESULTS
Their spectrum of selectivity indices for safety in PDL fibroblasts -based 72h incubations was reported. Surprisingly despite its lack on macrophages LPS-triggered inflammation over 5-200 µM and unlike the 8 statins; cerivastatin had growth inhibition IC50 values of 40nM (SW620), 110nM (HT29), 2.9 µM (HCT116), 6µM (SW480), and most notably 38µM (<50 µM, in Caco2). Exclusively cerivastatin exerted antitumorigenesis IC50 values <50 µM in all T47D, MCF7 and PANC1 72h cultures. In statins with greater antiinflammation affinity than indomethacin's; lovastatin had cytotoxicity IC50 values <20 µM in SW620
50µM in T47D, MCF7 and PANC1; pravastatin had viability reduction IC50 values <50µM in HT2950 µM were for statins in remaining colorectal cancer cell lines, breast cancer and pancreatic cancer cell lines. CONCLUSION
Among the rest, cerivastatin warrants further novel scaffold development to maximize efficacy and optimal molecular action mechanisms of chemotherapy/prevention.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Caco-2 Cells; Atorvastatin; Anti-Inflammatory Agents; Pancreatic Neoplasms; Indomethacin
PubMed: 36579985
DOI: 10.31557/APJCP.2022.23.12.4047 -
Cureus Jan 2022Antiphospholipid syndrome (APS) is an autoimmune disease that can lead to thrombotic or obstetric complications. Recent histopathological studies have shown the absence... (Review)
Review
Antiphospholipid syndrome (APS) is an autoimmune disease that can lead to thrombotic or obstetric complications. Recent histopathological studies have shown the absence of placental thrombosis, leading to the consideration of other pathophysiological pathways such as inflammation and complement activation. Due to this, various clinical studies are being carried out with different drug agents in order to avoid their complications. The combination of prophylactic heparin treatment and low doses of aspirin today result in successful pregnancies in most cases. Despite this, a minority of patients require alternative therapies to avoid recurrent miscarriage and decrease obstetric morbidity. Thanks to the better understanding of its pathophysiology, other treatments such as low doses of glucocorticoids, hydroxychloroquine (HCQ), immunoglobulin, pravastatin, and plasmapheresis have been considered in refractory cases, achieving favorable results. Despite the great advances regarding its treatment, unfortunately, there are no treatments with a good level of evidence to reduce late obstetric complications. The evaluation of preconception risk factors, as well as the antiphospholipid antibody profile, is necessary to establish individual risk and thus anticipate possible complications.
PubMed: 35165550
DOI: 10.7759/cureus.21090 -
Expert Review of Clinical Pharmacology Mar 2024Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the...
BACKGROUND
Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the association between statins and neurocognitive disorders using the FDA Adverse Event Reporting System (FAERS).
RESEARCH DESIGN AND METHODS
Data from 2004 to 2022 were obtained from the FAERS database. After deduplication and standardization of drug names, we extracted neurocognitive disorder event (NCDE) cases reported with statins as the suspected drugs. The significant association between statins and NCDE was evaluated using the reporting odds ratio (ROR) and information component.
RESULTS
In total, 6,959 NCDE cases with statins as the primary suspected drugs were identified. Signals were detected in pravastatin (ROR, 1.49; 95% CI: 1.32-1.67), atorvastatin (ROR, 1.39; 95% CI: 1.34-1.44), and simvastatin (ROR, 1.31; 95% CI: 1.25-1.38). Age-stratified analysis showed that (1) in the population aged 65 years and older, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin; and (2) in populations under 65 years of age, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, and lovastatin.
CONCLUSIONS
This study suggests a significant association between the NCDE and statins, including atorvastatin, simvastatin, and pravastatin. The intensity of the association increased with age.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Atorvastatin; Pravastatin; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Simvastatin; Lovastatin; Neurocognitive Disorders
PubMed: 38275183
DOI: 10.1080/17512433.2024.2311875 -
Cell Death & Disease Jul 2023Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of...
Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of α-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both α-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and α-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased α-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-β-cyclodextrin or statins reversed α-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated α-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.
Topics: Animals; Mice; alpha-Synuclein; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Protein Aggregates; Simvastatin
PubMed: 37500624
DOI: 10.1038/s41419-023-05977-9 -
Hypertension (Dallas, Tex. : 1979) Apr 2024Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower...
BACKGROUND
Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin.
METHODS
Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries.
RESULTS
Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release.
CONCLUSIONS
Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.
Topics: Humans; Pregnancy; Female; Animals; Mice; Placenta; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Placenta Growth Factor; Pravastatin; Up-Regulation; Prospective Studies; Pre-Eclampsia; Fluvastatin; Vascular Endothelial Growth Factor Receptor-1; Lipoproteins, LDL; Biomarkers; Chemokines; Intercellular Signaling Peptides and Proteins
PubMed: 38361240
DOI: 10.1161/HYPERTENSIONAHA.123.22457 -
Translational Stroke Research Aug 2020Statins, drugs known for lipid lowering capabilities and reduction of cardiovascular disease, have demonstrated neuroprotective effects following ischemic stroke in... (Meta-Analysis)
Meta-Analysis Review
Statins, drugs known for lipid lowering capabilities and reduction of cardiovascular disease, have demonstrated neuroprotective effects following ischemic stroke in retrospective clinical and animal studies. However, dosing (methods, time, type of statin, and quantity) varies across studies, limiting the clinical applicability of these findings. Furthermore, a comprehensive review of statins in edema and blood-brain barrier (BBB) breakdown is needed to provide insight on diverse, less explored neuroprotective effects. In the present study, we conduct a meta-analysis of publications evaluating statin administration in animal models of ischemic stroke. We review statins' most effective dosing regimen in four outcomes-infarct, edema, BBB breakdown, and functional outcome-to characterize several parameters of benefit associated with statin administration. A search term was constructed to identify experimental murine studies exploring statin use after transient middle cerebral artery occlusion (tMCAO) in PubMed, Web of Science, and Embase. Extracted data included statin type, dose, time and method of administration, and the four predetermined outcomes (functional outcome, edema, BBB breakdown, and infarction). A meta-analysis and stratified meta-regression were conducted using the standardized mean difference (SMD) method for continuous measurements. Included publications were assessed for bias using SYRCLE's RoB tool for animal studies. A total of 24 studies were included. Statin administration significantly reduced infarct volume (p < 0.0001), edema volume (p < 0.002), and neurological deficit (p < 0.0001). Simvastatin and pravastatin were most effective in reducing infarct volume when compared with atorvastatin (p = 0.0475, p = 0.0004) and rosuvastatin (p = 0.0036, p < 0.0001). Pravastatin outperformed all others in functional outcome. Subcutaneous (SC) injection was most effective in all outcomes. Statin therapy reduced BBB breakdown according to our systematic review. Mean study quality was 4.6/10. While statin therapy evidently improves neurological outcome following ischemic stroke, this analysis adds to our understanding of dosing and statins' effects on edema and BBB breakdown. These findings will aid the design of future studies investigating statin use and have larger implications for the clinical care of ischemic stroke patients.
Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Stroke; Lovastatin; Mice; Neuroprotective Agents; Rats
PubMed: 31788761
DOI: 10.1007/s12975-019-00750-7 -
Toxics Oct 2022The well-known 3-hydroxyl 3-methyl glutaryl-Coenzyme A reductase inhibitors, called statins, have been the main medication used in the treatment of hypercholesterolemia... (Review)
Review
The well-known 3-hydroxyl 3-methyl glutaryl-Coenzyme A reductase inhibitors, called statins, have been the main medication used in the treatment of hypercholesterolemia and some cases of cardiovascular diseases. The effectiveness of this drug in controlling cholesterol production is impeccable, however, patients often complain of a variety of side effects, such as myalgia, muscle atrophy, and in some cases, rhabdomyolysis. Not only has the use of statins caused the aforementioned side effects, but they are also shown to cause testicular discomfort, erectile dysfunction, altered semen parameters, and modified steroid hormone production. These reported adverse effects on male fertility are not generally agreed upon, as some have shown the use to be beneficial. Hence, this makes the aftermath effect of statin use on male fertility debatable and controversial. The negative effects have been associated with imbalanced or reduced steroid hormones, which are necessary for proper spermatogenesis and other sexual functions. Meanwhile, the beneficial effects are related to statin's anti-inflammatory and cardioprotective properties. These contradictory findings are in part due to the different age of users, concentrations of statins, the type and duration of treatment, and the underlying disease and/or comorbidities. Therefore, the current study aims to analyze the literature and gather evidence as to the effects of statin on male sexual health and reproductive parameters, and subsequently give recommendations for the direction of future studies.
PubMed: 36287907
DOI: 10.3390/toxics10100627 -
Current Medicinal Chemistry 2024Previous studies have found a potential role for statins in liver cancer prevention. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies have found a potential role for statins in liver cancer prevention.
OBJECTIVE
This study aimed to explore the effect of different types of statins on the incidence of liver cancer.
METHODS
Relevant articles were systematically retrieved from PubMed, EBSCO, Web of Science, and Cochrane Library databases from inception until July 2022 to explore the relationship between lipophilic statins or hydrophilic statins exposure and the incidence of liver cancer. The main outcome was the incidence of liver cancer.
RESULTS
Eleven articles were included in this meta-analysis. The pooled results showed a reduced incidence of liver cancer in patients exposed to lipophilic statins (OR=0.54, p < 0.001) and hydrophilic statins (OR=0.56, p < 0.001) compared with the non-exposed cohort. Subgroup analysis showed that both exposures to lipophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.59, p < 0.001) and hydrophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.66, p=0.019) statins reduced the incidence of liver cancer in Eastern and Western countries, and the reduction was most significant in Eastern countries. Moreover, atorvastatin (OR=0.55, p < 0.001), simvastatin (OR=0.59, p < 0.001), lovastatin (OR=0.51, p < 0.001), pitavastatin (OR=0.36, p=0.008) and rosuvastatin (OR=0.60, p=0.027) could effectively reduce the incidence of liver cancer, unlike fluvastatin, cerivastatin and pravastatin.
CONCLUSION
Both lipophilic and hydrophilic statins contribute to the prevention of liver cancer. Moreover, the efficacy was influenced by the region and the specific type of statins used.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Simvastatin; Lovastatin; Liver Neoplasms
PubMed: 37393552
DOI: 10.2174/0929867330666230701000400 -
American Journal of Reproductive... Feb 2023Hypertensive disorders of pregnancy (HDP) are one of the commonest maladies, affecting 5%-10% of pregnancies worldwide. The American College of Obstetricians and... (Review)
Review
Hypertensive disorders of pregnancy (HDP) are one of the commonest maladies, affecting 5%-10% of pregnancies worldwide. The American College of Obstetricians and Gynecologists (ACOG) identifies four categories of HDP, namely gestational hypertension (GH), Preeclampsia (PE), chronic hypertension (CH), and CH with superimposed PE. PE is a multisystem, heterogeneous disorder that encompasses 2%-8% of all pregnancy-related complications, contributing to about 9% to 26% of maternal deaths in low-income countries and 16% in high-income countries. These translate to 50 000 maternal deaths and over 500 000 fetal deaths worldwide, therefore demanding high priority in understanding clinical presentation, screening, diagnostic criteria, and effective management. PE is accompanied by uteroplacental insufficiency leading to vascular and metabolic changes, vasoconstriction, and end-organ ischemia. PE is diagnosed after 20 weeks of pregnancy in women who were previously normotensive or hypertensive. Besides shallow trophoblast invasion and inadequate remodeling of uterine arteries, dysregulation of the nonimmune system has been the focal point in PE. This results from aberrant immune system activation and imbalanced differentiation of T cells. Further, a failure of tolerance toward the semi-allogenic fetus results due to altered distribution of Tregs such as CD4+FoxP3+ or CD4+CD25+CD127(low) FoxP3+ cells, thereby creating a cytotoxic environment by suboptimal production of immunosuppressive cytokines like IL-10, IL-4, and IL-13. Also, intracellular production of complement protein C5a may result in decreased FoxP3+ regulatory T cells. With immune system dysfunction as a major driver in PE pathogenesis, it is logical that therapeutic targeting of components of the immune system with pharmacologic agents like anti-inflammatory and immune-modulating molecules are either being used or under clinical trial. Cholesterol synthesis inhibitors like Pravastatin may improve placental perfusion in PE, while Eculizumab (monoclonal antibody inhibiting C5) and small molecular inhibitor of C5a, Zilucoplan are under investigation. Monoclonal antibody against IL-17(Secukinumab) has been proposed to alter the Th imbalance in PE. Autologous Treg therapy and immune checkpoint inhibitors like anti-CTLA-4 are emerging as new candidates in immune horizons for PE management in the future.
Topics: Pregnancy; Female; Humans; Pre-Eclampsia; Placenta; Maternal Death; Hypertension, Pregnancy-Induced; Forkhead Transcription Factors
PubMed: 36565013
DOI: 10.1111/aji.13670 -
BioMed Research International 2021Type 2 diabetes mellitus is a chronic metabolic disease caused by insulin resistance or insulin deficiency resulting in elevated blood glucose levels. Poorly controlled... (Review)
Review
OBJECTIVE
Type 2 diabetes mellitus is a chronic metabolic disease caused by insulin resistance or insulin deficiency resulting in elevated blood glucose levels. Poorly controlled diabetes is associated with the development of cardiovascular disease and dyslipidemia. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statin) are an important class of therapeutic agents used to control hyperlipidemia and prevent cardiovascular disease in diabetic and nondiabetic patients. Since the effect of diabetes on the pharmacokinetics and pharmacodynamics of drugs and toxins has been shown, the aim was to review previous studies on the efficacy of statins such as atorvastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, and rosuvastatin in clinical and preclinical studies in both diabetic and nondiabetic groups.
METHOD
For this purpose, Web of Science, PubMed, Scopus, and Google Scholar databases were reviewed, and related English articles published until October 2020 were included in this review article.
RESULTS
The findings revealed that diabetes affected statin effectiveness through changes in pharmacokinetic parameters such as clearance and biotransformation biomarkers at mRNA and protein levels. Plasma and serum concentrations of statins were accompanied by alteration in cellular activities including oxidative stress, Akt inhibition, and endothelial nitric oxide synthase (eNOS) and phosphorylation that were reflected in changes in the adverse drug reaction profile of the differing statins.
CONCLUSION
Given that dyslipidemia frequently accompanies diabetes and statin therapy is common, more clinical studies are needed regarding the effects of diabetes on the effectiveness of these drugs.
Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus; Disease Models, Animal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 33834073
DOI: 10.1155/2021/6698743