Uterine leiomyomas, commonly known as fibroids, are benign tumors of the female reproductive tract. They are the most common tumor of the female reproductive system and the leading cause of hysterectomy in the United States. Progesterone, estrogen, and their receptors are important drivers for the development and growth of leiomyomas. How estrogen drives leiomyoma growth remains unclear. We have previously shown that simvastatin can inhibit leiomyoma growth by modulating intracellular calcium. This suggests that calcium signaling is important for leiomyoma growth. We therefore hypothesized that estrogen may drive leiomyoma growth by stimulating calcium release through the membrane estrogen receptor GPR30 (also known as GPER). We found that estrogen dose-dependently induced calcium release in leiomyoma cells. The GPR30-specific agonist G-1 also induced calcium release, indicating that GPR30 mediates estrogen-mediated calcium release. The GPR30 antagonist G-15 blocked estrogen-induced calcium release and significantly reduced leiomyoma proliferation. Our results demonstrate that GPR30 is a major driver of estrogen-dependent growth in leiomyoma cells by modulating intracellular calcium. These findings may have high therapeutic relevance to leiomyomas and other estrogen-dependent tumors.

Despite considerable advances in cancer immunotherapy, the persistent immunosuppressive tumor microenvironment (TME) seriously limits its performance in solid tumors. Here, we reveal that trogocytosis-an intercellular membrane transfer process-between tumor-associated macrophages (TAMs) and cancer cells serves as a critical mechanism driving this immunosuppression. We demonstrate that trogocytosis efficiency, inversely correlated with tumor cell cortical stiffness, varies substantially across cancer types and dictates immunosuppressive intensity through upregulation of CXCL5 and Arg-1, leading to CD8[+] T cell exhaustion. Importantly, this mechano-immunological axis is conserved in humans, as evidenced by study with human cell lines and a strong correlation between trogocytosis markers and T cell exhaustion in clinical patient samples. Increasing tumor cell stiffness with simvastatin effectively suppressed trogocytosis, reversed T cell dysfunction, and synergistically enhanced the efficacy of adoptive T cell therapy. These findings establish macrophage trogocytosis as a fundamental driver of immunosuppressive heterogeneity and highlight its targeting as a promising strategy to potentiate cancer immunotherapy.

Statins are widely regarded as the gold standard first-line treatment for hyperlipidemia, as they inhibit HMG-CoA reductase in the liver. This effectively reduces LDL cholesterol levels and reduces cardiovascular risks, such as heart attack and stroke. Simvastatin is a well-established, effective, and cost-efficient statin for lowering LDL cholesterol and reducing cardiovascular risk. However, it causes myopathy, rhabdomyolysis, myalgia, constipation, kidney failure, headache, abdominal pain, diarrhoea, nausea, and increased blood sugar levels with its use and higher doses of 80 mg/day. To address this, a liposomal simvastatin formulation with particle sizes of 150-250 nm was developed for intravenous administration. This formulation can potentially accumulate in the liver via passive targeting via the RES, thereby enhancing hepatic uptake and improving safety. The liposome was formulated using the thin-film hydration method and optimised using a central composite design. The optimized formulation's vesicle size was 204.66 ± 2.84 nm, with a PDI of 0.27 and a zeta potential of -58.11 mV, indicating uniform distribution and high stability. In-vitro drug release demonstrated controlled release of up to 92.46% over 60 h. The cellular toxicity assay showed that the optimized liposome was 10 times safer than pure simvastatin. In-vivo, the liposomal formulation significantly reduced lipid levels after administration of a 5 mg/kg dose in Triton X-100-induced hyperlipidemic rats, outperforming marketed formulations and standard drugs. Simvastatin-liposomes are safe, stable, and a more potent alternative to traditional oral simvastatin, offering improved liver targeting and a reduced toxicity profile.

The mevalonate pathway generates sterols and isoprenoids essential for membrane biosynthesis and signaling. Increased activity of the mevalonate pathway is a common feature of cancer and has emerged as a potential therapeutic vulnerability. Here, we showed that the mevalonate pathway sustains de novo serine biosynthesis and aspartate production by maintaining NAD[+] regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impaired oxidative phosphorylation, lowered the NAD[+]/NADH ratio, suppressed serine and aspartate biosynthesis, and activated the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limited purine and pyrimidine biosynthesis. Genetic and pharmacological disruption of ubiquinone synthesis recapitulated the metabolic defects, whereas expression of the bacterial NADH oxidase LbNOX restored the NAD[+]/NADH ratio and reversed the metabolic and growth defects induced by statin treatment. Importantly, impairment of NAD[+] regeneration reduced PHGDH-dependent de novo serine synthesis, thereby sensitizing neuroblastoma cells to PHGDH inhibition. Accordingly, simvastatin enhanced the anti-proliferative effects of the PHGDH inhibitor NCT-503 in vitro and exhibited elevated anti-tumor activity in combination with NCT-503 in neuroblastoma xenograft models. Together, these findings establish ubiquinone-dependent NAD[+] regeneration as a key mechanism linking the mevalonate pathway to amino acid and nucleotide biosynthesis and provide a mechanistic rationale for combined targeting of the mevalonate pathway and serine biosynthesis in cancer.

Background/Objectives: People Living with HIV (PLWH) often have comorbidities require polypharmacy, increasing the risk of adverse events (AEs) associated with drug-drug/drug-supplement interactions (DDIs/DSIs). However, DDIs and DSIs, including those involving antiretrovirals (ARVs), and their related effects have not been exhaustively assessed. This study aimed to determine, in HIV patients on HAART who are taking multiple medications, the prevalence of DDIs and DSIs involving both ARVs and non-ARV co-medications, and their clinical relevance and consequences. Methods: In this longitudinal observational study, PLWH receiving HAART were consecutively enrolled at the University Hospital of Salerno and followed up during scheduled visits. Demographic, clinical, and pharmacological data were collected. DDIs/DSIs were identified using Drugs.com, Lexicomp, and the Liverpool HIV Interaction Checker. Interactions classified as major (Drugs.com), consider therapy modification or avoid combination (Lexicomp), and do not coadminister (Liverpool) were deemed highly clinically relevant. This assessment was supplemented with review of SmPCs and the available literature. Results: Among 84 PLWH, 229 interactions were identified, and 37/229 (16.2%) were highly clinically relevant. Eight patients (9.5%) experienced AEs predicted by the tools. Four were DDIs: cobicistat/alprazolam associated with sedation and dyspnoea, rilpivirine/hydroxychloroquine with QT prolongation, bictegravir/ursodeoxycholic acid with rising viremia, and atorvastatin/fenofibrate with myalgia. Four DSIs between bictegravir and supplements containing divalent ions have been associated with increasing viremia. After medication review, alprazolam was replaced with zolpidem, rilpivirine-based HAART with bictegravir/emtricitabine/tenofovir alafenamide, and atorvastatin/fenofibrate with simvastatin/ezetimibe, and ursodeoxycholic acid and supplements were discontinued. These interventions were temporally associated with clinical improvement of interaction-related AEs and good virological control. Conclusions: This study highlights the importance of predicting DDIs/DSIs in PLWH undergoing polypharmacy. Medication review supports clinical decision-making, preventing avoidable adverse outcomes.

Chronic oral and maxillofacial diseases are frequently associated with progressive alveolar bone loss, leading to impaired structural integrity of the jaw and increased risk of implant failure, microbial colonization, and microfracture formation. Ceramic scaffolds such as those made of hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP) have attracted considerable attention because of their controlled resorption properties and the promotion of rapid new vital bone formation. The aim of this research is to enhance the performance of scaffolds composed of HA and β-TCP used for guided bone tissue regeneration in oral surgery. HA/β-TCP scaffolds were loaded with simvastatin (SIMV) and coated with multiple layers of alginate (ALG). The proposed strategy was designed to achieve a local and prolonged drug release while simultaneously improving mechanical properties. The scaffolds were characterized in terms of porosity, water absorption, in vitro degradation, in vitro bioactivity, and SIMV release. In addition, microscale mechanical properties were evaluated using Brillouin microscopy before and after the coating process. Cytocompatibility was further evaluated by using murine macrophages as an in vitro cellular model. The results demonstrated that ALG coatings significantly modulated SIMV release, promoting a delayed drug release. Moreover, ALG deposition improved the micromechanical properties of the scaffolds, conferring a dual structure analogous to those of bone tissue. These findings indicate that ALG-coated SIMV-loaded HA/β-TCP scaffolds represent a promising multifunctional platform for the medical field.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally; its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), has limited pharmacological options beyond the recently approved resmetirom. The statin-ezetimibe combination, widely co-prescribed for dyslipidemia in patients with MASH, significantly reduces hepatic fat versus statin monotherapy in the ESSENTIAL randomized trial, yet macrophage-driven mechanisms linking this lipid-lowering combination to hepatic inflammation and fibrosis remain poorly characterized. We investigated these mechanisms using in vivo and in vitro approaches. Methods: Male C57BL/6 mice (n = 6/group; 6 groups) received a high-fat diet (HFD; 45% kcal) plus thioacetamide (TAA; 300 mg/kg twice-weekly, 8 weeks) to establish MASH with advanced fibrosis. Simvastatin (5 mg/kg) and/or Ezetimibe (10 mg/kg) were added to the diet for 4 weeks. Blinded hepatic histology (H&E, Picrosirius red, Oil Red-O), qPCR, immunohistochemistry, and Western blot were performed. Macrophage polarization and NF-κB nuclear translocation were assessed in RAW 264.7 cells and thioglycolate-elicited peritoneal macrophages by flow cytometry and immunofluorescence. Results: Combination therapy significantly reduced steatosis, inflammation, and fibrosis versus HFD-TAA controls. Pro-inflammatory (IL-1β, IL-6, TNF-α, iNOS) and fibrosis-related (collagen-I, α-SMA, TGF-β1) markers were markedly suppressed (p < 0.01). In vitro, the combination reduced the proportion of iNOS[+] macrophages to approximately 50% of the LPS control (normalized to each experiment), although statistical significance was not reached; monotherapies showed weaker and variable trends and inhibited NF-κB p65 nuclear translocation in cultured macrophages (Holm-adjusted p < 0.01); MAPK signaling was not significantly altered under the present conditions. Anti-fibrotic effects were consistent with a macrophage-mediated mechanism, with no direct stellate cell suppression observed by LX-2 assays. Conclusions: Statin-Ezetimibe combination exerts anti-inflammatory and anti-fibrotic effects in a multi-hit murine model of MASH with advanced fibrosis associated with macrophage NF-κB inhibition in vitro and with reduced hepatic inflammatory signaling in vivo. These findings provide mechanistic rationale for the hepatic benefits of this widely used regimen in MASH patients with dyslipidemia, supporting its evaluation as a drug-repurposing strategy.

To evaluate and compare the clinical and microbiological efficacy of locally administered 1.2% Rosuvastatin (RSV) gel and 1.2% Simvastatin (SMV) gel as an adjunct to scaling and root planing (SRP) in the treatment of patients with chronic periodontitis. In this exploratory comparative study, 60 qualifying periodontal pockets (probing pocket depth [PPD] of 5-7 mm) from patients aged 25-55 years were randomized into three groups ($n = 20$ pockets per group): Group I received SRP + local delivery of 1.2% RSV gel; Group II received SRP + local delivery of 1.2% SMV gel; and Group III (control) received SRP + placebo gel. Clinical parameters-Plaque Index (PI), Modified Gingival Index (MGI), Sulcus Bleeding Index (SBI), PPD, and Clinical Attachment Loss (CAL)-were evaluated at baseline, 6 weeks, and 3 months. Microbiological assessment of Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa) was performed using Polymerase Chain Reaction (PCR) at baseline and 6 weeks. All 60 sites completed the study with no dropouts or adverse reactions. At 6 weeks and 3 months, both statin groups (Groups I and II) demonstrated statistically significant reductions in MGI, SBI, PPD, and CAL compared to the placebo group ($P < 0.05$). The statin groups also showed significantly lower levels of Aa and Pg at 6 weeks. Comparison between the two statins revealed that the SMV group achieved greater reductions in clinical indices (MGI, SBI, PPD, CAL) and bacterial counts (Aa and Pg) than the RSV group; however, this difference was not statistically significant (P < 0.05). No significant differences in PI scores were found between any of the groups at any interval (P < 0.05). The local delivery of both 1.2% simvastatin gel and 1.2% rosuvastatin gel as adjuncts to non-surgical periodontal therapy significantly improved clinical and microbiological outcomes in chronic periodontitis. While simvastatin demonstrated slightly greater absolute improvements than rosuvastatin, the overall therapeutic difference between the two statins was not statistically significant.

Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease. Although it is known that metabolic disturbances alter macrophage metabolism, inflammatory responses and the ability to maintain immune homeostasis, these changes have not been well studied out of the context of atherosclerosis. Our aim was to investigate the effect of dyslipidemia caused by ApoE deficiency on macrophages and on antigen-induced arthritis in mice. Toward this aim, mice deficient in the ApoE gene were used which exhibit high total cholesterol (TC) levels distributed primarily in VLDL/IDL fractions, normal triglycerides and low HDL-C levels associated with distribution at lower densities and lower PON-1 activity. ApoE KO peritoneal macrophages had an M1-like polarization and an increased respiration rate. Importantly, ApoE KO mice developed more severe knee joint swelling compared to control mice. At the end of the arthritis protocol, spleen macrophages had increased expression of M1 cell surface markers. Simvastatin treatment reduced serum TC, increased HDL-C and PON-1 activity and improved HDL density. Additionally, treatment of ApoE KO mice with simvastatin limited the M1-associated cell surface markers on spleen macrophages and reduced arthritic joint swelling. Collectively, our findings support further investigation of lipid-modifying strategies in the context of inflammatory arthritis associated with dyslipidemia.

Dendritic cell (DC)-based immunotherapy shows limited efficacy against hepatic fibrosis, and the underlying mechanometabolic crosstalk remains unclear. Here, from a mechanobiological perspective, we demonstrate that increased extracellular matrix (ECM) stiffness in the fibrotic liver triggeres antigen-independent abnormal DC maturation, characterized by elevated co-stimulatory molecules, impaired phagocytic capacity, reduced IL-10 secretion, and suppressed regulatory T cell (Treg) differentiation. Mechanistically, the stiff ECM inhibites the AMPK-LXRα-ABCG1 signaling axis in DCs, reducing cholesterol efflux and promoting intracellular cholesterol accumulation. Cholesterol depletion or AMPK activation reverses stiffness-induced abnormal DC maturation. In mouse models, combined treatment with pirfenidone and simvastatin reduced liver stiffness and collagen deposition, and restored immune tolerance by correcting DC cholesterol metabolism. Our study identifies a mechanometabolic pathway linking matrix stiffness to DC dysfunction, providing a promising immunometabolic strategy for antifibrotic therapy.

Statins, anti-hyperlipidemic drugs, are associated with skeletal muscle myopathy. New strategies to preserve muscle strength in statin-induced myopathy (SIM) are needed. This study assessed the effect of quercetin on simvastatin-induced myopathy in adult male rats, focusing on the modulation of autophagy-apoptosis crosstalk. Forty adult albino male rats were randomly divided into four groups. The control group (C) received distilled water, the quercetin group (Q) received quercetin (50 mg/kg/day, orally), the simvastatin (S) group received simvastatin (80 mg/kg/day, orally), and the quercetin + simvastatin (Q + S) group received both quercetin (50 mg/kg/day) and simvastatin (80 mg/kg/day, orally), all for 30 days. Gastrocnemius muscle contractility, muscle weight/tibial length ratio, histopathological examination, serum creatine kinase (CK) levels, oxidative stress markers, lipid profile, autophagy-related gene expression (LC3 and LAMP2), and apoptosis markers (BAX and caspase-3) were evaluated. Simvastatin induced muscle atrophy and significantly elevated serum CK levels. These changes were associated with increased oxidative stress, altered expression of autophagy-related genes (increased LC3 and decreased LAMP2), and increased expression of the apoptotic markers BAX and Caspase-3. Quercetin ameliorated these alterations by improving muscle contractility, reducing CK levels and oxidative stress, attenuating apoptosis, and modulating autophagy-related gene expression. Quercetin alleviated simvastatin-induced myopathy through its antioxidant and antiapoptotic effects and was associated with modulation of autophagy-related gene expression. These findings suggest that quercetin may represent a promising adjuvant strategy for mitigating statin-associated myopathy. Further studies evaluating autophagic flux at the protein level are warranted to clarify the underlying mechanisms.

Background: Hyperlipidemia is a major risk factor for cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), and is closely associated with oxidative stress. Opuntia ficus-indica (OFI) cladodes are recognized as a rich source of bioactive phytochemicals; however, the molecular mechanisms underlying their metabolic benefits remain incompletely understood. Objectives: This study aimed to comprehensively evaluate the hypolipidemic and hepatoprotective potential of a polyphenol-rich O. ficus-indica cladode extract (OCE) using an integrated approach combining in vivo evaluation, untargeted metabolomics (UHPLC-Orbitrap-MS/MS), molecular docking, and ADMET prediction. Methods: Hyperlipidemic mice fed a high-fat diet (HFD) were treated with OCE, while molecular docking was performed on ten major annotated phytochemicals against twelve key proteins involved in lipid metabolism and cholesterol homeostasis, including HMGCR, FAS, PPARα, PCSK9, and NPC1L1, using simvastatin as the reference compound. Results: OCE treatment significantly improved plasma and hepatic lipid profiles, improved glucose homeostasis, and markedly reduced hepatic malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. Histopathological analysis further supported a pronounced hepatoprotective effect, with a substantial reduction in hepatic steatosis. Untargeted metabolomics enabled the annotation of 102 metabolites, putatively identifying piscidic acid as the predominant phenolic constituent together with a diverse profile of flavonoids and phenolic acids. Molecular docking supported the potential contribution of these phytochemicals to the regulation of lipid metabolism through favorable interactions with multiple therapeutic targets, while ADMET prediction suggested an overall favorable pharmacokinetic and toxicity profile despite the lower intestinal permeability predicted for glycosylated derivatives. Conclusions: Overall, these findings support O. ficus-indica cladodes as a promising source of dietary bioactive compounds with potential applications in the nutritional management and prevention of hyperlipidemia and related cardiometabolic disorders.