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Abstract Background Osteoporosis is a major health concern for postmenopausal women, and the effect of simvastatin (Sim) on bone metabolism is controversial. This study aimed to investigate the effect of simvastatin on the bone microstructure and bone mechanical properties in ovariectomized (OVX) mice. Methods 24 female C57BL/6J mice (8-week-old) were randomly allocated into three groups including the OVX + Sim group, the OVX group and the control group. At 8 weeks after operation, the L4 vertebral bones were dissected completely for micro-Computed Tomography (micro-CT) scanning and micro-finite element analysis (µFEA). The differences between three groups were compared using ANOVA with a LSD correction, and the relationship between bone microstructure and mechanical properties was analyzed using linear regression. Results Bone volume fraction, trabecular number, connectivity density and trabecular tissue mineral density in the OVX + Sim group were significantly higher than those in the OVX group (P

Abstract Background Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. Methods/Design VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. Conclusions VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. Trial registration EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.

Junyu Chen,1,* Yupei Yuan,2,* Ying Hu,1 Liang Liang1,3 1Department of Psychology, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 3Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liang Liang, Department of Psychology, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China, Tel +8609915848029, Email 79023556@qq.comBackground: The adjunctive therapeutic potential of simvastatin in schizophrenia treatment has generated interest due to its anti-inflammatory and neuroprotective properties. This meta-analysis aims to assess the efficacy of simvastatin as an adjunct treatment for schizophrenia, synthesizing results from various controlled trials.Methods: We performed a comprehensive search of databases including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) evaluating the efficacy of simvastatin as an adjunct therapy in patients with schizophrenia. The primary outcome measures were improvements in the Positive and Negative Syndrome Scale (PANSS) scores. Secondary outcomes included changes in overall clinical condition and level of functioning. Data were pooled using random-effects models, and heterogeneity was assessed through I² statistics.Results: The four RCTs included in the analysis represented 425 participants. The combined results demonstrated no significant advantage of simvastatin over placebo in reducing PANSS total scores with a pooled effect size (Standard Mean Difference, SMD) of − 0.36 (95% Confidence Interval, CI: − 0.82 to 0.11) at 1 month, and − 1.80 (95% Confidence Interval, CI: − 4.82 to 1.21) at 3 months, indicating minimal to no effect. Similarly, analyses of secondary outcomes showed no significant improvements in overall clinical condition and level of functioning. The studies exhibited low heterogeneity (I² = 0%).Conclusion: This meta-analysis provides evidence that simvastatin, used as adjunctive therapy, does not significantly improve the symptomatic outcomes of schizophrenia compared to placebo. Although simvastatin is well-tolerated, its role in enhancing antipsychotic treatment efficacy in patients with schizophrenia appears limited. These findings suggest that simvastatin should not be recommended as an adjunctive treatment in the clinical management of schizophrenia. Further research may explore the potential subgroups that could benefit from such treatment or identify the biological reasons for the lack of efficacy.Keywords: schizophrenia, simvastatin, adjunctive therapy, meta-analysis, randomized controlled trials, efficacy

Introduction: Ezetimibe inhibits cholesterol uptake by modulation of intestinal sterol absorption. Currently, although some studies have shown alterations in ezetimibe levels caused by alterations in the ABCG5, ABCG8, NPC1L1 or UGT1A1 genes, there are no pharmacogenetic guidelines to confirm these biomarkers. The aim of this work was to evaluate the effect of 49 variants in 22 pharmacogenes related to metabolism and transport. Methods: A total of 96 healthy volunteers from four bioequivalence clinical trials of ezetimibe as monotherapy or in combination with simvastatin were studied. Blood samples were extracted for unconjugated ezetimibe plasma quantification and genotyping. Results and Discussion: No association of metabolizing enzyme variants with ezetimibe pharmacokinetic parameters was found. The results show some trends in the univariate analysis for ABCB1 rs2032582 or ABCC2 rs2273697 and Cmax (p univariate (puv) = 0.056 and 0.087, respectively), which finally reach significance in the multivariate analysis (p multivariate (pmv) = 0.049 and 0.048, respectively). Nevertheless, these results need to be validated in future studies. [ABSTRACT FROM AUTHOR]

The need to develop synthetic bone substitutes with structures, properties, and functions similar to bone and capable of preventing microbial infections is still an ongoing challenge. This research is focused on the preparation and characterization of three-dimensional porous scaffolds based on hydroxyapatite (HA)-functionalized calcium carbonate loaded with silver nanoparticles and simvastatin (SIMV). The scaffolds were prepared using the foam replica method, with a polyurethane (PU) sponge as a template, followed by successive polymer removal and sintering. The scaffolds were then coated with poly(lactic-co-glycolic) acid (PLGA) to improve mechanical properties and structural integrity, and loaded with silver nanoparticles and SIMV. The scaffolds were characterized by X-ray powder diffraction (XRD), field emission scanning electron microscopy (FE-SEM), ATR FT-IR, and silver and SIMV loading. Moreover, the samples were analyzed by Brillouin and Raman microscopy. Finally, in vitro bioactivity, SIMV and silver release, and antimicrobial activity against Staphylococcus aureus and Staphylococcus epidermidis were evaluated. From the Brillouin spectra, samples showed characteristics analogous to those of bone tissue. They exhibited new hydroxyapatite growth, as evidenced by SEM, and good antimicrobial activity against the tested bacteria. In conclusion, the obtained results demonstrate the potential of the scaffolds for application in bone repair. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the autoinflammatory effect and biological behaviour of simvastatin (SIM) on adamantinomatous craniopharyngioma (ACP) cells. Methods: Craniopharyngiomas imaging, intraoperative observations, and tumour histopathology were employed to investigate the correlation between esters and craniopharyngiomas. Filipin III fluorescent probe verified the validity of SIM on the alternations of synthesized cholesterol in craniopharyngioma cells. The cell counting kit-8 (CCK8) assay detected the impacts of SIM on cell proliferation and determined the IC50 value of tumour cells. Reverse transcription polymerase chain reaction (RT-PCR) measured the expression of inflammatory factors. Flow cytometry technique detected the cell cycle and apoptosis, and cell scratch assay judged the cell migration. Meanwhile, Western blot was adopted to determine the expression of proteins related to inflammation, proliferation, and apoptosis signalling pathways. Results: In the ACP tumour parenchyma, many cholesterol crystalline clefts were observed, and the deposition of esters was closely associated with craniopharyngioma inflammation. After SIM intervention, a reduction in cholesterol synthesis within ACP was noted. RT-PCR analysis revealed SIM inhibited the transcription of inflammatory factors in ACP cells. Western blot analysis demonstrated SIM inhibited nuclear factor-kappa B p65 activation expression while promoted the expressions of Cl-caspase-3 and P38 MAPK. CCK8 assay indicated a decrease in ACP cell activity upon SIM treatment. Scratch assay signified that SIM hindered ACP cell migration. Flow cytometry results suggested that the drug promoted ACP cell apoptosis. Conclusion: SIM suppressed the inflammatory response to craniopharyngiomas by inhibiting craniopharyngioma cholesterol synthesis, inhibited proliferation of ACP cells, and promoted their apoptosis. [ABSTRACT FROM AUTHOR]

Purpose: Anti-hyperlipidemic drug treatments are effective in reducing the risk of cardiovascular disease. In a long-term retrospective inception cohort study, we aimed to assess the real-world comparative effectiveness of anti-hyperlipidemic monotherapies for primary prevention of cardiovascular events. Patients and Methods: Patients aged 18 years and older, who initiated primary prevention with anti-hyperlipidemic monotherapy, were selected from the University of Groningen IADB.nl dispensing database. In intention-to-treat (ITT) analysis we included all patients, whereas in per-protocol (PP) analysis we included both all patients independent of adherence (PPIA) and adherent patients (PPA). Study outcome was the time to first prescription of acute cardiac drug therapy measured by valid drug proxies to identify a first major cardiovascular event. We applied inverse probability of treatment-weighted (IPTW) analysis using Cox regression and time-varying Cox regression with simvastatin as the reference category to estimate the average treatment effect hazard ratios (HR) and their corresponding 95% confidence intervals (CI). Results: Atorvastatin users had significantly higher hazards compared to simvastatin users (HR range: 1.27 to 1.47, 95% CI: 1.15 to 1.69). Similarly, Pravastatin users also exhibited increased hazards compared to simvastatin users (HR range: 1.41 to 1.56, 95% CI: 1.14 to 2.04). Similar patterns were observed in patients with diabetes, rheumatoid arthritis, and asthma/COPD. No differences were found in the hazards of rosuvastatin, fluvastatin, fibrates, and simvastatin. Conclusion: Atorvastatin and pravastatin users had higher long-term rates of cardiovascular events compared to simvastatin monotherapy in primary prevention, the difference may be attributed to the confounding by severity, but also possibly due to differences in drug mechanisms or patient response. These findings could influence current guideline recommendations, suggesting a potential preference for simvastatin in primary prevention, underscoring the need for further research to explore long-term impacts and underlying mechanisms, especially in diverse populations. [ABSTRACT FROM AUTHOR]

We developed a sustained-release transdermal drug delivery system (TDDS) containing simvastatin (SIM) and captopril (CAP) to treat hypertension and hyperlipidemia and overcome treatment drawbacks, including significant liver first-pass effects, low bioavailability, and the short half-life of SIM and CAP oral tablets. We used a transdermal diffusion meter to preselect the formula of the SIM-CAP TDDS. Based on in vitro permeation experiments, we optimized the formula of the SIM-CAP TDDS to include 24% SIM, 24% CAP, 34% polyvinyl alcohol (PVA), 16% oleic acid (OA)–azone, and 2% polyacrylic acid resin II. We evaluated the optimized SIM-CAP TDDS formula by its appearance, stability, stickiness, drug content, in vivo pharmacokinetics, and skin irritation tests. The results indicated that the patch had good stability and stickiness. The SIM and CAP contents were 5.02 ± 0.41 mg/cm2 in the 1 cm2 SIM-CAP TDDS. The pharmacokinetic results indicated that the system continuously released SIM and CAP for 24 h and significantly enhanced their bioavailability, with a higher area under the curve. The SIM-CAP TDDS exhibits a sustained-release effect with good characteristics and pharmacokinetics. And it is safe and has no irritating effects on the skin; therefore, it is an ideal formulation. [ABSTRACT FROM AUTHOR]

Management of cancer is challenging due to non-targeting and high side effect issues. Drug repurposing is an innovative method for employing medications for other disease therapy in addition to their original use. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor, is a lipid-lowering drug that is being studied for the treatment of cancer in various in vitro and in vivo models. Nanotechnology offers a potential platform for incorporation of drugs with enhanced pharmaceutical (solubility, release characteristics, stability, etc.) and biological characteristics (targeting, pharmacokinetic, pharmacodynamic). Utilizing a variety of resources such as Scopus, Springer, Web of Science, Elsevier, Bentham Science, Taylor & Francis, and PubMed, a thorough literature search was carried out by looking through electronic records published between 2003 and 2024. The keywords used were simvastatin, drug repurposing, anti-cancer simvastatin, pharmaceutical properties of simvastatin, simvastatin nanoformulations, simvastatin patents, clinical trials, etc. Numerous articles were looked for, filtered, checked out, and incorporated. Pure simvastatin has been researched as a repurposed medication for the treatment of cancer in several in vitro and in vivo models, such as carcinoma of the lung, colon, liver, prostate, breast, and skin. Simvastatin also incorporated into different nanocarriers (nanosuspensions, microparticles/nanoparticles, liposomes, and nanostructured lipid carriers) and showed improvement in solubility, bioavailability, drug loading, release kinetics, and targeting. Clinical trial and patent reports suggest potential of simvastatin in cancer therapy. The preclinical studies of pure simvastatin in in vitro and in vivo models showed the potential for its ability to inhibit cancer cell growth and further incorporation into nanoformulations strengthened its preclinical and pharmaceutical characteristics. [ABSTRACT FROM AUTHOR]

In this study, poly(2‐hydroxyethyl methacrylate‐N‐methacryloyl‐L‐tryptophan methyl ester) cryogel membranes were synthesized in different concentrations by using molecular imprinting technique, for controlled release of simvastatin. The cryogel membranes were prepared in various compositions and thus the releases of cryogels containing 0.5, 0.75 and 1 mg hydrophilic simvstatin were compared. The chemical and morphological properties of the poly(HEMA‐MATrp) cryogel membranes were evaluated through a series of characterization techniques. The membranes were subjected to swelling tests to assess their ability to absorb water and their degree of crosslinking. Fourier‐transform infrared spectroscopy was applied to determine the functional groups present in the cryogel matrix and to evaluate the degree of chemical modification that occurred during synthesis. Additionally, scanning electron microscopy was employed to visualize the cryogel at high resolution, providing insights into the pore structure and overall architecture of the matrix. Then, cryogel membranes were evaluated for cell proliferation abilities by 3‐(4,5‐dimethyl/thiazol‐2‐yl) 2,5‐diphenyltetra zolium bromide thiazolyl blue (MTT) assay for cell viability. The prepared cryogel membranes have a diameter and thickness of about 10 mm and 1.0 mm, respectively. The increasing attention towards the use of cryogel membranes in tissue‐engineering has resulted in demonstrating the dependency of release profiles of simvastatin cryogel membranes on their composition. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusion The lipid‐lowering simvastatin (SIM) has been shown to be an effective inhibitor of keloid proliferation. However, due to its low water solubility and short half‐life, simvastatin aggregates to the liver and does not reach the skin lesions after oral administration, which restricts its widespread clinical use. The development of nanomedicine provides the possibility for us to break through this bottleneck problem clinically. The objective of this study was to investigate the feasibility of using complex nanocontrolled delivery system (CNDS), simvastatin‐loaded polyethylene glycol‐poly lactic‐co‐glycolic acid (PEG‐PLGA), in the treatment of keloids.In the in vitro study, the release of simvastatin in fibroblasts by CNDS@Simvastatin and its effect on inhibition of the proliferation of fibroblasts, Col Ι, and CTGF by the slow release of simvastatin were assessed. The efficacy of CNDS@Simvastatin in improving keloids and the biocompatibility and safety of CNDS@Simvastatin were examined in vivo by establishing a murine ear keloid model.CNDS@Simvastatin showed sustained and uniform inhibition of the proliferation of fibroblasts, Col Ι, and CTGF via the gradual release of simvastatin over 72 h. It was efficient in the treatment of the murine ear keloid with no observable toxic side effects on various organs.Simvastatin‐loaded copolymer acid‐sensitive nanocarriers, CNDS@Simvastatin nanospheres, were successfully developed in this study, and these were characterized by favorable physicochemical properties and biocompatibility. [ABSTRACT FROM AUTHOR]

Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. Methods/Design: VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. Conclusions: VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. Trial registration: EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is a major health concern for postmenopausal women, and the effect of simvastatin (Sim) on bone metabolism is controversial. This study aimed to investigate the effect of simvastatin on the bone microstructure and bone mechanical properties in ovariectomized (OVX) mice. Methods: 24 female C57BL/6J mice (8-week-old) were randomly allocated into three groups including the OVX + Sim group, the OVX group and the control group. At 8 weeks after operation, the L4 vertebral bones were dissected completely for micro-Computed Tomography (micro-CT) scanning and micro-finite element analysis (µFEA). The differences between three groups were compared using ANOVA with a LSD correction, and the relationship between bone microstructure and mechanical properties was analyzed using linear regression. Results: Bone volume fraction, trabecular number, connectivity density and trabecular tissue mineral density in the OVX + Sim group were significantly higher than those in the OVX group (P < 0.05). For the mechanical properties detected via µFEA, the OVX + Sim group had lower total deformation, equivalent elastic strain and equivalent stress compared to the OVX group (P < 0.05). In the three groups, the mechanical parameters were significantly correlated with bone volume fraction and trabecular bone mineral density. Conclusions: The findings suggested that simvastatin had a potential role in the treatment of osteoporosis. The results of this study could guide future research on simvastatin and support the development of simvastatin-based treatments to improve bone health. [ABSTRACT FROM AUTHOR]

Introduction: Despite years of efforts to develop new antibiotics for eradicating multidrug-resistant (MDR) and multi-virulent Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Staphylococcus aureus (VRSA) infections, treatment failures and poor prognoses in most cases have been common. Therefore, there is an urgent need for new therapeutic approaches targeting virulence arrays. Our aim is to discover new anti-virulence therapies targeting MRSA and VRSA virulence arrays. Methodology: We employed phenotypic, molecular docking, and genetic studies to screen for anti-virulence activities among selected promising compounds: Coumarin, Simvastatin, and Ibuprofen. Results: We found that nearly all detected MRSA and VRSA strains exhibited MDR and multi-virulent profiles. The molecular docking results aligned with the phenotypic and genetic assessments of virulence production. Biofilm and hemolysin productions were inhibited, and all virulence genes were downregulated upon treatment with sub-minimum inhibitory concentration (sub-MIC) of these promising compounds. Ibuprofen was the most active compound, exhibiting the highest inhibition and downregulation of virulence gene products. Moreover, in vivo and histopathological studies confirmed these results. Interestingly, we observed a significant decrease in wound area and improvements in re-epithelialization and tissue organization in the Ibuprofen and antimicrobial treated group compared with the group treated with antimicrobial alone. These findings support the idea that a combination of Ibuprofen and antimicrobial drugs may offer a promising new therapy for MRSA and VRSA infections. Conclusion: We hope that our findings can be implemented in clinical practice to assist physicians in making the most suitable treatment decisions. [ABSTRACT FROM AUTHOR]

Recombinant AAV (rAAV) vectors are increasingly favored for gene therapy due to their useful features of vectorology, such as transfection of dividing and nondividing cells, the presence of tissue-specific serotypes, and biosafety considerations. This study investigates the impact of commonly used therapeutic drugs—acetaminophen, budesonide, and simvastatin—on rAAV transduction efficiency in HEK-293 cells. Cells were transduced with an AAV mosaic vector under the control of a cytomegalovirus (CMV) promoter encoding green fluorescent protein (GFP). Transduction efficiency was assessed by qPCR and fluorescent microscopy. Analysis of functional interactions between genes potentially involved in rAAV transduction in drug-exposed cells was also performed. This study showed a clear effect of drugs on rAAV transmission. Notably, acetaminophen enhanced transduction efficiency by 9-fold, while budesonide and simvastatin showed 2-fold and 3-fold increases, respectively. The gene analysis illustrates the possible involvement of genes related to cell membranes in the potentiation of rAAV transduction induced by the drugs under investigation. Attention should be paid to S100A8, which is a common drug-modified gene for drugs showing anti-inflammatory effects (budesonide and simvastatin), demonstrating an interaction with the gene encoding the receptor for AAV (HGFR). This study underscores the significance of assessing rAAV pharmacokinetics/pharmacodynamics (PKs/PDs) and drug–gene therapy interactions in optimizing gene therapy protocols. [ABSTRACT FROM AUTHOR]

Background: Variable benefits have been reported from the adjunctive use of simvastatin and the 5HT3 receptor antagonist, ondansetron, in patients with schizophrenia. We investigated their independent efficacy and possible synergy to improve negative symptoms of schizophrenia within a single trial. Methods: A 6-month, randomised, double-blind, placebo-controlled trial with a 4-arm, 2 × 2 factorial design, in three centres in Pakistan. In total, 303 people with stable treated schizophrenia aged 18–65 were randomly allocated to add-on ondansetron, simvastatin, both or neither. The primary outcome was a Positive and Negative Syndrome Scale (PANSS) negative score at 3 and 6 months. Results: Mixed model analysis and analysis of covariance revealed no main effects of simvastatin or ondansetron but a significant negative interaction between them (p = 0.03); when given alone, both drugs significantly reduced negative symptoms compared to placebo but they were ineffective in combination. Individual treatment effects versus placebo were −1.9 points (95%CIs −3.23, −0.49; p = 0.01) for simvastatin and −1.6 points for ondansetron (95%CIs −3.00, −0.14; p = 0.03). Combined treatment significantly increased depression and side effects. In those with less than the median 5 years of treatment, ondansetron improved all PANSS subscales, global functioning measures and verbal learning and fluency, whereas simvastatin did not. Conclusion: Small improvement in negative symptoms on simvastatin and ondansetron individually are not synergistic in combination in treating negative symptoms of schizophrenia. Ondansetron showed broad efficacy in patients on stable antipsychotic treatment within 5 years of illness. The findings suggest that ondansetron should be evaluated in patients at risk of psychosis or early in treatment. [ABSTRACT FROM AUTHOR]

The clinical application of the therapeutic approach in myelodysplastic syndromes (MDS) remains an insurmountable challenge for the high propensity for progressing to acute myeloid leukemia and predominantly affecting elderly individuals. Thus, the discovery of molecular mechanisms underlying the regulatory network of different programmed cell death holds great promise for the identification of therapeutic targets and provides insights into new therapeutic avenues. Herein, we found that disulfiram/copper (DSF/Cu) significantly repressed the cell viability, increased reactive oxygen species (ROS) accumulation, destroyed mitochondrial morphology, and altered oxygen consumption rate. Further studies verified that DSF/Cu induces cuproptosis, as evidenced by the depletion of glutathione (GSH), aggregation of lipoylated DLAT, and induced loss of Fe–S cluster–containing proteins, which could be rescued by tetrathiomolybdate and knockdown of ferredoxin 1 (FDX1). Additionally, GSH contributed to the tolerance of DSF/Cu-mediated cuproptosis, while pharmacological chelation of GSH triggered ROS accumulation and sensitized cell death. The xCT-GSH-GPX4 axis is the ideal downstream component of ferroptosis that exerts a powerful protective mechanism. Notably, classical xCT inhibitors were capable of leading to the catastrophic accumulation of ROS and exerting synergistic cell death, while xCT overexpression restored these phenomena. Simvastatin, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, has beneficial effects in repurposing for inhibiting GPX4. Similarly, the combination treatment of DSF/Cu and simvastatin dramatically decreased the expression of GPX4 and Fe–S proteins, ultimately accelerating cell death. Moreover, we identified that the combination treatment of DSF/Cu and simvastatin also had a synergistic antitumor effect in the MDS mouse model, with the reduced GPX4, increased COX-2 and accumulated lipid peroxides. Overall, our study provided insight into developing a novel synergistic strategy to sensitize MDS therapy by targeting ferroptosis and cuproptosis. [Display omitted] • DSF/Cu causes the accumulation of ROS accompanied by the exhausting of GSH in the MDS cell lines. • GSH contributed to the tolerance of DSF/Cu-induced cuproptosis. • Targeting the xCT-GSH-GPX4 pathway can enhance the effectiveness of DSF/Cu-induced cell death in MDS cells. [ABSTRACT FROM AUTHOR]

The development of an inhalation powder (IP) for cancer therapy is desired to improve the therapeutic response and patient compliance. The latest studies highlighted that statins, a class of drugs used in hypercholesterolemia, can have anticancer and antiinflammatory properties. Therefore, the aim of the study was to develop an IP containing liposomes loaded with simvastatin using spray drying technology, as well as to investigate the influence of formulation factors on the quality attributes of the IP by means of experimental design. Results highlighted that the composition of liposomes, namely type of phospholipid and cholesterol concentration, highly influences the quality attributes of IP, and the use of optimal concentrations of excipients, i.e. D-mannitol and L-leucine, is essential to preserve the characteristics of liposomes throughout the spray drying process. The in vitro characterization of the optimal IP formulation revealed that the total percentage of released drug is higher from the IP formulation compared to the powder of active substance (53.38 vs. 42.76%) over a period of six hours, and 39.67% of dry particles have a size less than 5 µm, making them suitable for inhalation. As a conclusion, spray drying technology can be effectively used in the development and preparation of IP containing liposomes. [ABSTRACT FROM AUTHOR]

Phytomedicine is gaining acceptance as well preference in health care management for various diseases. Drug combinations are mostly used clinically for hyperlipidemia, as single-agent therapy is insufficient. Statins remain the cornerstone of hyperlipidemia. The objective of the present research is to manage hyperlipidemia with the least amount of medicine effective clinically, thereby limiting its side effects. Study was carried out with 140 registered hyperlipidemia patients, divided into two groups. Group-A received simvastatin 20mg oral daily & Group B received a combination of simvastatin and beta-valgaris capsules twice a day for 90 days. Pre and post treatment values were compared within the groups and between the groups. Group B shows statistically significant decrease (p<0.05) in serum total cholesterol, low density lipoprotein (LDL), triglycerides (TG) and CRP levels. Also significant improvement (p<0.05) was noted for high density lipoprotein (HDL) levels (20.1% to 57.4%) in group B after completion of study. On the basis of our study results, we can conclude that statins remained to be the mainstay treatment for patients with elevated cholesterol levels. However, the combination has a synergistic effect and reduces oxidative stress (OS) as well. [ABSTRACT FROM AUTHOR]

Simvastatin is a widely used statin medication that is commonly prescribed to lower cholesterol levels and reduce the risk of cardiovascular events. It is marketed under the brand name Zocor and is known for its effectiveness in treating high cholesterol and managing cardiovascular disease. Monacolin J is an important precursor used to synthesize simvastatin and is mainly produced by chemical methods in industry. Here, monacolin J was synthesized through an enzymatic method under optimized reaction conditions. One recombinant Escherichia coli BL21 (DE3) strain containing lovastatin hydrolase (encoded by CDV55_102090) from Aspergillus turcosus was constructed, which effectively transformed 100 g/L of lovastatin to monacolin J within 3.5 h at pH 8.0 and 30 °C, with a conversion rate of >99.8%. Furthermore, the T5010, the temperature at which the residual activity was half of the initial enzymatic activity after 10 min of heat treatment, was >50 °C, indicating the tremendous potential of this bioprocess for synthesizing monacolin J at an industrial scale. [ABSTRACT FROM AUTHOR]

Background: Our knowledge of the pathophysiology of vitiligo has advanced significantly. However, there are still some unclear aspects. Chemokine C-X-C motif ligand 10 (CXCL10) is a biomarker of vitiligo activity and chemokine C–C motif ligand 8 (CCL8) is a chemokine that has been studied recently in vitiligo pathogenesis. Objective: The primary objective was to compare the efficacy and safety of adding low-dose simvastatin to narrowband ultraviolet B (NB-UVB) versus NB-UVB monotherapy for vitiligo treatment including the effect on CXCL10 and CCL8. The secondary objective was to look for any potential links between CCL8 and vitiligo. Patients and methods: In this interventional comparative study 50 vitiligo patients were enlisted and randomly split into two groups: the treatment group received NB-UVB plus simvastatin, while the control group received NB-UVB alone for 3 months. Enzyme-linked immunosorbent assay kits were used to test the serum levels of CXCL10 and CCL8, and the vitiligo area scoring index (VASI) score was computed both before and after therapy. Results: Following treatment, the median values of the VASI score reduction were considerably higher (P =0.037) in the treatment group (1.50) in comparison with controls (0.52). In addition, the median serum levels of CXCL10 and CCL8 were significantly lower (P =0.003 and 0.030, respectively) in the treatment group (132.6 and 110.8 ng/l, respectively) than in the control group (155 and 122.8 ng/l, respectively). There were no side effects noted. CCL8 and CXCL10 serum levels had a positive correlation. Conclusion: The outcomes of the therapy point to the potential for simvastatin to work in conjunction with NB-UVB to treat vitiligo. Current findings also suggest that CCL8 may play a role in the pathogenesis of vitiligo. In this study, CXCL10 is not correlated with disease severity. [ABSTRACT FROM AUTHOR]

Background: There are knowledge gaps regarding the relative efficacy of statins for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to examine the comparative effectiveness and determine the ranking of different statins with network meta‑analysis in patients with aSAH. Methods: MEDLINE, Embase, Pubmed, and Cochrane Central Register of Controlled Trials were searched from database inception until December 15, 2022. Outcomes included delayed cerebral ischemia (DCI), functional recovery, and mortality. Relative risk (RRs) ratios and associated 95% confidence intervals (CIs) were estimated. The values derived from surface under the cumulative ranking curve were obtained to rank the treatment hierarchy in the analysis. Results: We identified 13 trials involving 1,885 patients. Atorvastatin 20 mg (RR 0.68, 95% CI 0.53–0.86), pravastatin 40 mg (RR 0.51, 95% CI 0.31–0.77), and simvastatin 80 mg (RR 0.54, 95% CI 0.40–0.70) were superior to the placebo in preventing DCI. Additionally, simvastatin 80 mg (RR 0.60, 95% CI 0.42–0.84) and pravastatin 40 mg (RR 0.56, 95% CI 0.32–0.93) were associated with a decreased risk of DCI than simvastatin 40 mg. Comparisons across treatment durations suggested that short-term (RR 0.62, 95% CI 0.50–0.76) statin therapy reduced risk of DCI. Conclusions: Simvastatin 80 mg might be the most effective intervention in reducing DCI. Additionally, short-term therapy might provide more benefits. Further research with longer follow-up is warranted to validate the current findings in patients with aSAH who are at high risk of DCI. [ABSTRACT FROM AUTHOR]

The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open‐label, randomized, 3‐period, 3‐sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20 mg of simvastatin and 10 mg of ezetimibe as a single‐dose tablet, separated by a minimum of 2‐week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography‐tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin β‐hydroxy acid determination was done via a validated ultra‐performance liquid chromatography‐tandem mass spectrometry. Each assay was preceded by a liquid‐liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration‐time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log‐transformed under the concentration‐time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%‐125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is an acute inflammatory process in the lungs associated with high morbidity and mortality. Previous research has studied both nonpharmacologic and pharmacologic interventions aimed at targeting this inflammatory process and improving ventilation. Hypothesis: To date, only nonpharmacologic interventions including lung protective ventilation, prone positioning, and high positive end-expiratory pressure ventilation strategies have resulted in significant improvements in patient outcomes. Given the high mortality associated with ARDS despite these advancements, interest in subphenotyping has grown, aiming to improve diagnosis and develop personalized treatment approaches. Data Collection: Previous trials evaluating pharmacologic therapies in heterogeneous populations have primarily demonstrated no positive effect, but hope to show benefit when targeting specific subphenotypes, thus increasing their efficacy, while simultaneously decreasing adverse effects. Results: Although most studies evaluating pharmacologic therapies for ARDS have not demonstrated a mortality benefit, there is limited data evaluating pharmacologic therapies in ARDS subphenotypes, which have found promising results. Neuromuscular blocking agents, corticosteroids, and simvastatin have resulted in a mortality benefit when used in patients with the hyper-inflammatory ARDS subphenotype. Therapeutic Opinion: The use of subphenotyping could revolutionize the way ARDS therapies are applied and therefore improve outcomes while also limiting the adverse effects associated with their ineffective use. Future studies should evaluate ARDS subphenotypes and their response to pharmacologic intervention to advance this area of precision medicine. [ABSTRACT FROM AUTHOR]

Little is known about the effects of statins, which are cholesterol-lowering drugs, on the bioenergetic functions of mitochondria in the brain. This study aimed to elucidate the direct effects of atorvastatin and simvastatin on the bioenergetics of isolated rat brain mitochondria by measuring the statin-induced changes in respiratory chain activity, ATP synthesis efficiency, and the production of reactive oxygen species (ROS). Our results in isolated brain mitochondria are the first to demonstrate that atorvastatin and simvastatin dose-dependently significantly inhibit the activity of the mitochondrial respiratory chain, resulting in a decreased respiratory rate, a decreased membrane potential, and increased ROS formation. Moreover, the tested statins reduced mitochondrial coupling parameters, the ADP/O ratio, the respiratory control ratio, and thus, the oxidative phosphorylation efficiency in brain mitochondria. Among the oxidative phosphorylation complexes, statin-induced mitochondrial impairment concerned complex I, complex III, and ATP synthase activity. The calcium-containing atorvastatin had a significantly more substantial effect on isolated brain mitochondria than simvastatin. The higher inhibitory effect of atorvastatin was dependent on calcium ions, which may lead to the disruption of calcium homeostasis in mitochondria. These findings suggest that while statins are effective in their primary role as cholesterol-lowering agents, their use may impair mitochondrial function, which may have consequences for brain health, particularly when mitochondrial energy efficiency is critical. [ABSTRACT FROM AUTHOR]

The aim of the current work was to improve the solubility and dissolution rate of poorly water-soluble drug, simvastatin (SM) by using the liquisolid compact technique (LS; SM-LS). Liquid load factors, and excipient ratios were used to calculate the required amounts of excipients necessary to prepare the SM-LS and compressed to tablets according to mathematical models. Avicel PH102, Aerosil 200 and Crosspovidone (CP) was used as carrier, coating material and disintegrant, respectively. Drug-excipient mixtures were evaluated compatibility by Attenuated total reflectance (ATR) and differential scanning calorimetry (DSC). Prepared SM-LS formulations were evaluated for various pre-compression and post-compressional parameters, in-vitro dissolution, and stability studies (40 ± 2°C / 75 ± 5% RH) for 3 months. Among the different formulations, LS10 formulation which contains 30% drug, 5% CP, Avicel pH 102: Aerosil 200 (1:10) showed 14-folds increase in dissolution rate when compared with pure SM powder. FTIR-ATR and DSC studies confirmed that there was no interaction between the drug and excipients. Further, the LS10 formulation had shown comparable dissolution profile with commercially available tablet formulation. The LS10 formulation showed no significant changes in the physicochemical properties over 3 months during stability studies. Therefore, the SM loaded LS formulation could be considered as an alternative approach to enhance the solubility and dissolution for commercial formulations. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins as single agents at relatively high doses restrained PDAC development. Here, four-week-old mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, high calorie diet that promotes early PDAC development were randomized onto low dosage metformin, simvastatin, or both drugs in combination administered orally. Dual treatment attenuated weight gain, fibro-inflammation, and development of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in male KC mice, without significant effect in females or when administered individually. Dual-treated KC mice had reduced proliferation of PanIN cells and decreased transcriptional activity of the Hippo effectors, YAP and TAZ, which are important regulators of PDAC development. Metformin and simvastatin also synergistically inhibited colony formation of pancreatic cancer cells in vitro. Together, our data demonstrated that a combination of low doses of metformin and simvastatin inhibits PDAC development and imply that both drugs are promising agents for being tested in clinical trials for preventing pancreatic cancer progression.

Background: Colorectal cancer (CRC) and osteosarcoma (OS) and all other cancers represents one of the most challenger issues to the humanity for long time, due to their associated sever health lesions, emotional and psychological hardships, and significant economic encumbrances. Adding to that, the poor curing fate achieved with current therapeutic strategies of cancer. The invention of new drugs for cancer treatment required long time reaching to years as well as consuming the huge money budget, so that the focusing on the aspect of the repositioning of conventional drugs (like simvastatin) has gradually take a large consideration as they can participate in the alleviation of cancer treatment burden in view of this work promising results and preceding hopeful findings and conclusions have been obtained from the studies conducted in this field. The Aim: assessment of the cytotoxic effects of a lipid lowering drug, simvastatin, in human CRC and OS cells. Methods: SW480 (CRC) and MG-63 (OS) cell lines were utilized in this work and have been treated with various doses of simvastatin, then its cytotoxic effects have been evaluated by MTT assay. Thereafter, the VEGF and GDF-15 suppression effects of simvastatin have been measured in SW480 and MG-63 cells. Results: exposure of CRC and OS cells to simvastatin resulted in significant cellular growth inhibition, and VEGF and GDF-15 suppression effects. Conclusions: Simvastatin has a promising antineoplastic potential and its role in cancer therapy cannot be underestimated, and encourage the utilization and surveying of other preexisting drugs in cancer treatment path.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type (WT) mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using H&E staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.

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.

Mengjuan Sun,1,&ast; Jun Wei,1,&ast; Yanhui Su,1,&ast; Yangjingwan He,1 Liang Ge,1 Yan Shen,1 Bohui Xu,2 Yanlong Bi,3 Chunli Zheng1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2School of Pharmacy, Nantong University, Nantong, People’s Republic of China; 3Pediatric Intensive Care Unit, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunli Zheng; Yanlong Bi, Email zhengchunli@cpu.edu.cn; pulong123@163.comPurpose: The purpose of this study is to address the high mortality and poor prognosis associated with Acute Respiratory Distress Syndrome (ARDS), conditions characterized by acute and progressive respiratory failure. The primary goal was to prolong drug circulation time, increase drug accumulation in the lungs, and minimize drug-related side effects.Methods: Simvastatin (SIM) was used as the model drug in this study. Employing a red blood cell surface-loaded nanoparticle drug delivery technique, pH-responsive cationic nanoparticles loaded with SIM were non-covalently adsorbed onto the surface of red blood cells (RBC), creating a novel drug delivery system (RBC@SIM-PEI-PPNPs).Results: The RBC@SIM-PEI-PPNPs delivery system effectively extended the drug’s circulation time, providing an extended therapeutic window. Additionally, this method substantially improved the targeted accumulation of SIM in lung tissues, thereby enhancing the drug’s efficacy in treating ARDS and impeding its progression to ARDS. Crucially, the system showed a reduced risk of adverse drug reactions.Conclusion: RBC@SIM-PEI-PPNPs demonstrates promise in ARDS and ARDS treatment. This innovative approach successfully overcomes the limitations associated with SIM’s poor solubility and low bioavailability, resulting in improved therapeutic outcomes and fewer drug-related side effects. This research holds significant clinical implications and highlights its potential for broader application in drug delivery and lung disease treatment.Keywords: acute lung injury, simvastatin, respiratory distress syndrome, pH response

Siyan Pang,1,2 Chenchen Geng,1,2 Zihan Fan,2 Min Hou,1,3 Huilan Mao,1,2 Shuang Tao,1,4 Jing Wang,1,4 Yulun Wu,1,2 Ke Wei,1,4 Yunhao Li,1,2 Liuyang Yan,1,2 Qingling Yang,1,4,5 Changjie Chen,1,4,5 Wenrui Wang1,2,6 1Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical University, Anhui, People’s Republic of China; 2Department of Life Sciences, Bengbu Medical University, Anhui, People’s Republic of China; 3School of Basic Courses, Bengbu Medical University, Anhui, People’s Republic of China; 4Clinical Testing and Diagnose Experimental Center, Bengbu Medical University, Anhui, People’s Republic of China; 5Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui, People’s Republic of China; 6Department of Biotechnology, Bengbu Medical University, Anhui, People’s Republic of ChinaCorrespondence: Wenrui Wang; Changjie Chen, Anhui Province Key Laboratory of Cancer Translational Medicine, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, Anhui, 233030, People’s Republic of China, Email wenrui-wang1983@163.com; tochenchangjie@163.comBackground: 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 Fe2+ in cells through the release of Fe3+, 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.Keywords: layered double hydroxides, apoptosis, ferroptosis, simvastatin, breast cancer

Abstract 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.