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Background: Despite advancements in therapeutic approaches, including taxane-based chemotherapy and androgen receptor-targeting agents, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable tumor, highlighting the need for novel strategies that can target the complexities of this disease and bypass the development of drug resistance mechanisms. We previously demonstrated the synergistic antitumor interaction of valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitory activity, with the lipid-lowering drug simvastatin (SIM). This combination sensitizes mCRPC cells to docetaxel treatment both in vitro and in vivo by targeting the cancer stem cell compartment via mevalonate pathway/YAP axis modulation. Methods: Here, using a combined proteomic and metabolomic/lipidomic approach, we characterized tumor samples derived from 22Rv1 mCRPC cell-xenografted mice treated with or without VPA/SIM and performed an in-depth bioinformatics analysis. Results: We confirmed the specific impact of VPA/SIM on the Hippo–YAP signaling pathway, which is functionally related to the modulation of cancer-related extracellular matrix biology and metabolic reprogramming, providing further insights into the molecular mechanism of the antitumor effects of VPA/SIM. Conclusions: In this study, we present an in-depth exploration of the potential to repurpose two generic, safe drugs for mCRPC treatment, valproic acid (VPA) and simvastatin (SIM), which already show antitumor efficacy in combination, primarily affecting the cancer stem cell compartment via MVP/YAP axis modulation. Bioinformatics analysis of the LC‒MS/MS and 1H‒NMR metabolomics/lipidomics results confirmed the specific impact of VPA/SIM on Hippo–YAP. [ABSTRACT FROM AUTHOR]

Introduction: Familial hypercholesterolemia, the highly prevalent form of dyslipidemia, is a well-known risk factor for premature heart disease and stroke worldwide. Statins, which inhibit 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, are the first-choice treatment for dyslipidemias, and have been effective in reducing the risk of stroke and myocardial infarction. However, emerging evidence indicates that statins may increase the incidence of new-onset type 2 diabetes by reducing β-cell mass and function. Notably, past in vitro reports studying the effects of statins on β-cells were performed without including free fatty acids in the model. This factor should have been addressed since these agents are used to treat individuals with hyperlipidemia. Methods: Here, we used a mouse insulinoma MIN6 β-cell culture model to assess the efficacy, cytotoxicity, and insulin-suppressive effects of simvastatin and pravastatin in the presence of palmitic, linoleic, and oleic acids cocktail to mimic mixed lipids challenge in a biologically relevant setting. Results and discussion: Our findings indicate that simvastatin was more effective in lowering intracellular cholesterol but was more cytotoxic as compared to pravastatin. Similarly, simvastatin exhibited a higher suppression of total insulin content and insulin secretion. Both drugs suppressed insulin secretion in phases 1 and 2, dose-dependently. No significant effect was observed on mitochondrial respiration. More importantly, elution experiments showed that insulin content diminution by simvastatin treatment was reversible, while exogenous mevalonate did not improve total insulin content. This suggests that simvastatin's influence on insulin content is independent of its specific inhibitory action on HMG-CoA reductase. In conclusion, our study identified that simvastatin was more effective in lowering intracellular cholesterol, albeit it was more toxic and suppressive of β-cells function. Notably, this suppression was found to be reversible. [ABSTRACT FROM AUTHOR]

The use of topical antimicrobials in wound healing presents challenges like risk of drug resistance and toxicity to local tissue. Simvastatin (SIM), a lipid-lowering agent which reduces the risk of cardiovascular events, is repurposed for its pleiotropic effect in wound healing. A bioactive bioadhesive polymer-based film forming spray (FFS) formulation of SIM was designed using chitosan, collagen, hyaluronic acid and optimised by employing the DoE approach. Optimised formulation demonstrated moderate viscosity (12.5 ± 0.3 cP), rapid film formation (231 ± 5.6 s), flexibility, tensile strength and sustained drug release (T80 – time for 80% drug release − 9.05 ± 0.7 h). Scanning electron microscopy (SEM) verified uniformly dispersed drug within the composite polymer matrix. SIM FFS demonstrated antimicrobial activity against gram positive and gram negative bacteria. In vivo excision wound model studies in mice affirmed the beneficent role of bioactive polymers and the efficacy of SIM FFS in wound contraction and closure, tissue remodelling and re-epithelization in comparison to standard antimicrobial preparation. Cytokines TNF- alpha, IL-6 were downregulated and IL-10 was upregulated. Biochemical markers; hydroxyproline, hexosamine and histopathology were consistent with wound contraction observed. This is an exploratory effort in repurposing SIM for wound healing in a novel dosage form, underscoring its potential as an alternative to conventional topical antimicrobials. [ABSTRACT FROM AUTHOR]

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]

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]

Background: 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. [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: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was

Abstract Objective Type 2 diabetes mellitus (T2DM) poses a substantial global health concern. Statins are widely used among T2DM patients for managing dyslipidemia, preventing cardiovascular disease (CVD), and offering renal protection. However, the extent to which their renal protective effects contribute to reducing the incidence of severe renal complications, including chronic kidney disease (CKD) and renal failure, is not well-defined. Methods This investigation scrutinizes the impact of simvastatin versus placebo on renal outcomes among T2DM patients utilizing data from the ACCORD trial. It encompasses incidence rate comparisons, Kaplan-Meier estimates, Cox proportional hazards models, and mediation analyses. Results The study consisted of 3,619 individuals diagnosed with T2DM, among which 2,753 were treated routinely with simvastatin, while 866 did not receive any statin therapy. After adjusting for baseline characteristics and time-dependent covariates, simvastatin treatment was associated with a 71% reduction in the risk of CKD (HR 0.29, 95% CI 0.27–0.31, p

Abstract Background Despite advancements in therapeutic approaches, including taxane-based chemotherapy and androgen receptor-targeting agents, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable tumor, highlighting the need for novel strategies that can target the complexities of this disease and bypass the development of drug resistance mechanisms. We previously demonstrated the synergistic antitumor interaction of valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitory activity, with the lipid-lowering drug simvastatin (SIM). This combination sensitizes mCRPC cells to docetaxel treatment both in vitro and in vivo by targeting the cancer stem cell compartment via mevalonate pathway/YAP axis modulation. Methods Here, using a combined proteomic and metabolomic/lipidomic approach, we characterized tumor samples derived from 22Rv1 mCRPC cell-xenografted mice treated with or without VPA/SIM and performed an in-depth bioinformatics analysis. Results We confirmed the specific impact of VPA/SIM on the Hippo–YAP signaling pathway, which is functionally related to the modulation of cancer-related extracellular matrix biology and metabolic reprogramming, providing further insights into the molecular mechanism of the antitumor effects of VPA/SIM. Conclusions In this study, we present an in-depth exploration of the potential to repurpose two generic, safe drugs for mCRPC treatment, valproic acid (VPA) and simvastatin (SIM), which already show antitumor efficacy in combination, primarily affecting the cancer stem cell compartment via MVP/YAP axis modulation. Bioinformatics analysis of the LC‒MS/MS and 1H‒NMR metabolomics/lipidomics results confirmed the specific impact of VPA/SIM on Hippo–YAP.