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International Journal of Nanomedicine 2024Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has...
BACKGROUND
Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy.
METHODS
In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer.
RESULTS
The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe in cells through the release of Fe, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis.
CONCLUSION
In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.
Topics: Ferroptosis; Female; Humans; Breast Neoplasms; Hydroxides; Simvastatin; Apoptosis; Animals; Cell Line, Tumor; Nanoparticles; Drug Synergism; Mice; Antineoplastic Agents; Mice, Nude; Mice, Inbred BALB C; MCF-7 Cells; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 38766657
DOI: 10.2147/IJN.S455427 -
Bioactive Materials Jul 2024Zinc (Zn) alloys have demonstrated significant potential in healing critical-sized bone defects. However, the clinical application of Zn alloys implants is still...
Imidazole functionalized photo-crosslinked aliphatic polycarbonate drug-eluting coatings on zinc alloys for osteogenesis, angiogenesis, and bacteriostasis in bone regeneration.
Zinc (Zn) alloys have demonstrated significant potential in healing critical-sized bone defects. However, the clinical application of Zn alloys implants is still hindered by challenges including excessive release of zinc ions (Zn), particularly in the early stage of implantation, and absence of bio-functions related to complex bone repair processes. Herein, a biodegradable aliphatic polycarbonate drug-eluting coating was fabricated on zinc-lithium (Zn-Li) alloys to inhibit Zn release and enhance the osteogenesis, angiogenesis, and bacteriostasis of Zn alloys. Specifically, the photo-curable aliphatic polycarbonates were co-assembled with simvastatin and deposited onto Zn alloys to produce a drug-loaded coating, which was crosslinked by subsequent UV light irradiation. During the 60 days long-term immersion test, the coating showed distinguished stable drug release and Zn release inhibition properties. Benefiting from the regulated release of Zn and simvastatin, the coating facilitated the adhesion, proliferation, and differentiation of MC3T3-E1 cells, as well as the migration and tube formation of EA.hy926 cells. Astonishingly, the coating also showed remarkable antibacterial properties against both and . The rabbit critical-size femur bone defects model demonstrated that the drug-eluting coating could efficiently promote new bone formation and the expression of platelet endothelial cell adhesion molecule-1 (CD31) and osteocalcin (OCN). The enhancement of osteogenesis, angiogenesis, and bacteriostasis is achieved by precisely controlling of the released Zn at an appropriate level, as well as the stable release profile of simvastatin. This tailored aliphatic polycarbonate drug-eluting coating provides significant potential for clinical applications of Zn alloys implants.
PubMed: 38756420
DOI: 10.1016/j.bioactmat.2024.03.037 -
Cureus Apr 2024Introduction The vast pleiotropic effect of statins has intrigued many researchers to select them as potential candidates against bacterial infections. The role of...
Introduction The vast pleiotropic effect of statins has intrigued many researchers to select them as potential candidates against bacterial infections. The role of statins against bacterial pathogens remains debatable. This study was undertaken to evaluate and compare the antibacterial effect of commonly available statins against the most frequently isolated bacterial pathogens causing respiratory tract infections in our tertiary care hospital using sputum as a sample. Materials and methods The study was conducted in the Microbiology Laboratory of our hospital. Drugs including atorvastatin, rosuvastatin, and simvastatin were purchased in pure form from Sigma Aldrich. Dimethylsulfoxide (DMSO) was used as a solvent for all three drugs. The positive controls used were gentamycin and amoxicillin for Gram-negative and Gram-positive bacteria, respectively. Data regarding all the culture and sensitivity results of sputum samples of patients admitted to the Respiratory Intensive Care Unit over the past 12 months were analyzed. The most common bacterial pathogens and isolated from sputum specimens were taken for our study. The antibacterial effect of statins was studied using two methods: the agar cup diffusion method and the broth dilution method. The zone of inhibition and minimum inhibitory concentration of the drugs were calculated and analyzed. Statistical analysis was performed using GraphPad Prism software version 10.2.0. A one-way ANOVA test was used to determine if there was any statistical difference between the different statins and antibiotic groups. An unpaired t-test was used to determine the statistical difference between the statins. Results and discussion For the agar cup diffusion method, our results displayed a lack of antibacterial activity of all three statins atorvastatin, rosuvastatin, and simvastatin against all three bacterial strains and after overnight incubation by agar cup method at concentrations of 3.125 μg/ml, 6.25 μg/ml, 12.5 μg/ml, 25 μg/ml and 50 μg/ml, respectively. The zone of inhibition observed was less than 4 mm (resistant) for all the serial dilutions of atorvastatin, rosuvastatin, and simvastatin. For the broth dilution method, the ANOVA test showed amoxicillin and gentamicin to have high statistically significant microbial growth inhibitory activity (p-value < 0.005) compared to atorvastatin and rosuvastatin. Statistically, though atorvastatin showed significant antimicrobial activity compared to normal saline and rosuvastatin, this was not considered clinically significant as the antimicrobial activity shown by atorvastatin was very negligible compared to the controls used and did not correspond to the serial dilutions of the drug. Conclusion Atorvastatin, rosuvastatin, and simvastatin lacked antibacterial activity against all three bacterial strains isolated from sputum specimens: and . Hence, the use of statins as an antimicrobial drug for respiratory tract infections has limited applications.
PubMed: 38741867
DOI: 10.7759/cureus.58108 -
JACC. Advances Apr 2024Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to...
BACKGROUND
Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E (baseline LDL-C), (2) ED (potency: median dose achieving 50% reduction in LDL-C); and (3) E (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown.
OBJECTIVE
We analyze the relationship between ED and E with real-world cardiovascular disease outcomes.
METHOD
We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED and E to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality.
RESULTS
We estimated ED and E for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED and E are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for E in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively.
CONCLUSION
The class-wide association of ED and E with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.
PubMed: 38737008
DOI: 10.1016/j.jacadv.2024.100894 -
Molecules (Basel, Switzerland) May 2024Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various... (Review)
Review
Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.
Topics: Humans; Female; Nanomedicine; Nanoparticles; Animals; Genital Diseases, Female; Drug Delivery Systems; Leiomyoma; Endometriosis; Polycystic Ovary Syndrome
PubMed: 38731586
DOI: 10.3390/molecules29092095 -
Food Science & Nutrition May 2024The increasing incidence of hyperlipidemia is a serious threat to public health. The development of effective and safe lipid-lowering drugs with few side effects is...
The increasing incidence of hyperlipidemia is a serious threat to public health. The development of effective and safe lipid-lowering drugs with few side effects is necessary. The purpose of this study was to assess the lipid-lowering activity of extract (SVE) in rat experiments and reveal the molecular mechanism by transcriptome analysis. Hyperlipidemia was induced in the animals using a high-fat diet for 4 weeks. At the end of the 4th week, hyperlipidemic rats were assigned into two control groups (model and positive simvastatin control) and three treatment groups that received SVE at 200, 400, or 800 mg kg day for another 4 weeks. A last control group comprised normal chow-fed rats. At the end of the 8th week, rats were sacrificed and lipid serum levels, histopathology, and liver transcriptome profiles were determined. SVE was demonstrated to relieve the lipid disorder and improve histopathological liver changes in a dose-dependent manner. The transcriptomic analysis identified changes in hepatocyte gene activity for major pathways including steroid biosynthesis, bile secretion, cholesterol metabolism, AMPK signaling, thyroid hormone signaling, and glucagon signaling. The changed expression of crucial genes in the different groups was confirmed by qPCR. Collectively, this study revealed that SVE could relieve hyperlipidemia in rats, the molecular mechanism might be to promote the metabolism of lipids and the excretion of cholesterol, inhibit the biosynthesis of cholesterol by activating the AMPK signaling pathway, the thyroid hormone signaling pathway, and the glucagon signaling pathway.
PubMed: 38726415
DOI: 10.1002/fsn3.4002 -
Frontiers in Endocrinology 2024A serious consequence of diabetes is diabetic nephropathy (DN), which is commonly treated by statins. Studies evaluating the effects of statin medication have yielded...
BACKGROUND
A serious consequence of diabetes is diabetic nephropathy (DN), which is commonly treated by statins. Studies evaluating the effects of statin medication have yielded inconsistent results regarding the potential association with diabetic nephropathy. To manage diabetic nephropathy's onset and improve the quality of life of patients, it is imperative to gain a comprehensive understanding of its contributing factors.
DATA AND METHODS
Our study was conducted using the National Health and Nutrition Examination Survey (NHANES) as well as weighted multivariate logistic regression models to determine the odds ratio (OR) and 95% confidence intervals (95%CI) for diabetic nephropathy. We conducted stratified analyses to examine the impact of statins and the duration of their usage on diabetic nephropathy in different subgroups. A nomogram model and the receiver operating characteristic (ROC) curve were also developed to predict DN risk.
RESULTS
Statin use significantly increased the incidence of DN (OR=1.405, 95%CI (1.199,1.647), p<0.001). Individuals who used statins for 5 to 7 years were more likely to develop diabetic nephropathy (OR=1.472, 95%CI (1.057,2.048), p=0.022) compared to those who used statins for 1-3 years (OR=1.334, 95%CI (1.058,1.682), p=0.015) or <1 year (OR=1.266, 95%CI (1.054,1.522), p = 0.012). Simvastatin has a greater incidence of diabetic nephropathy (OR=1.448, 95%CI(1.177, 1.78), P < 0.001).
CONCLUSION
Taking statins long-term increases the risk of DN. Statin use is associated with an increased risk of DN. Caution should be exercised when prescribing atorvastatin and simvastatin for long-term statin therapy.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diabetic Nephropathies; Male; Female; Nutrition Surveys; Middle Aged; United States; Adult; Aged; Incidence; Risk Factors
PubMed: 38726340
DOI: 10.3389/fendo.2024.1381746 -
BMC Pulmonary Medicine May 2024Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases....
BACKGROUND
Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms.
METHODS
The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway.
RESULTS
Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions.
CONCLUSIONS
Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.
Topics: Animals; Male; Rats; Acetophenones; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Disease Models, Animal; Epithelial-Mesenchymal Transition; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Pneumonia; Pulmonary Fibrosis; Ribonucleotides; Signal Transduction; Silicon Dioxide; Silicosis; Simvastatin; Transforming Growth Factor beta1
PubMed: 38720270
DOI: 10.1186/s12890-024-03014-9 -
Cureus Apr 2024Cardiovascular diseases (CVDs) continue to be a worldwide health concern, requiring effective strategies for risk reduction. This article explores the extensive... (Review)
Review
Cardiovascular diseases (CVDs) continue to be a worldwide health concern, requiring effective strategies for risk reduction. This article explores the extensive collaboration between medical therapy and lifestyle modifications in the management of CVDs, aiming to interpret whether a single approach holds the key to reducing major cardiovascular events. In the realm of pharmaceutical therapy, statins, beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, and antiplatelet agents have shown significant effectiveness, as evidenced by landmark trials such as Scandinavian Simvastatin Survival Study (4S) and Heart Outcomes Prevention Evaluation (HOPE). Concurrently, lifestyle adjustments, encompassing physical activity, dietary changes, and management of stress, emerge as indispensable elements in cardiovascular care. The article discusses the pivotal role of patient adherence, tailored approaches, and the synergistic impact of combining medical therapy and lifestyle modifications. Challenges, such as socioeconomic disparities and uncertainties in lipid management, underscore the need for ongoing research and precision medicine. Digital health interventions offer novel avenues for personalized care. Despite advancements, uncertainties persist regarding the optimal balance between medical and lifestyle interventions in lowering major cardiovascular event risks. This article emphasizes the ongoing evolution of cardiovascular care, highlighting the imperative need for evidence-based guidelines tailored to individual patient needs.
PubMed: 38716006
DOI: 10.7759/cureus.57742 -
American Heart Journal May 2024The response of low-density lipoprotein cholesterol (LDL-C) to statin therapy is variable, and may be affected by the presence of co-morbid conditions or the use of...
BACKGROUND
The response of low-density lipoprotein cholesterol (LDL-C) to statin therapy is variable, and may be affected by the presence of co-morbid conditions or the use of concomitant medications. Systematic variation in the response to statins based on these factors could affect the selection of the statin treatment regimen in population subgroups. We investigated whether common comorbidities and co-medications had clinically important effects on statin responses in individual patients.
METHODS
This register-based cohort study included 89,006 simvastatin or atorvastatin initiators with measurements of pre-statin and on-statin LDL-C levels, in Denmark, 2008-2018. We defined statin response as the percentage reduction in LDL-C, and used linear regression to estimate percentage reduction differences (PRD) according to 175 chronic comorbidities and 99 co-medications. We evaluated both the statistical significance (p-values corrected for multiple testing) and the clinical importance (PRD of 5 percentage points or more) of the observed associations.
RESULTS
Concomitant use of oral blood-glucose lowering drugs, which included metformin in 96% of treated individuals, was associated with a greater response to statin therapy that was both statistically significant and clinically important, with a PRD of 5.18 (95% confidence interval: 4.79 to 5.57). No other comorbidity or co-medication reached the prespecified thresholds for a significant, clinically important effect on statin response. Overall, comorbidities and co-medications had little effect on statin response, and altogether explained only 1.7% of the total observed population variance.
CONCLUSION
Most of the studied comorbidities and co-medications did not have a clinically important effect on statin response, suggesting no need to modify treatment regimens. However, use of metformin was associated with a significantly enhanced LDL-C response to statins, suggesting that lower statin doses may be effective in patients taking metformin.
PubMed: 38710378
DOI: 10.1016/j.ahj.2024.04.018