Search Results (365)

Endometriosis is a chronic inflammatory disease with frequent recurrence. Statins, due to their anti-inflammatory and antioxidant properties, may help control disease progression, but comparative data on local administration are limited. We evaluated simvastatin-, atorvastatin-, and rosuvastatin-loaded lipophilic gels on lesions, adhesions, and inflammatory markers in a rat model of peritoneal endometriosis. Forty rats were randomized to statin gels (n = 10 each), chitosan gel (vehicle; n = 5), or no treatment (control; n = 5). Two weeks later, lesion size, adhesions, histopathology, and serum Interleukin-6 (IL-6) and Interleukin-1β (IL-1β) were assessed. All statins significantly reduced endometriotic lesion size compared with controls. Lesion volume decreased by approximately 97% with simvastatin, 88% with atorvastatin, and 72% with rosuvastatin, whereas lesion volume increased in the control and vehicle-treated groups. Adhesion severity was markedly reduced, with Hoffman scores decreasing from 7.2 ± 2.25 in controls to 1.9 ± 1.1 with simvastatin, compared with more modest reductions observed with atorvastatin and rosuvastatin. Similarly, Lauder adhesion scores were reduced by approximately 71% with simvastatin, confirming its superior anti-adhesion effect. Serum IL-6 and IL-1β levels were significantly decreased in all statin-treated groups, with no significant differences among statins. Overall, topical statin gel therapy effectively reduced lesion size, adhesions, and inflammation, with simvastatin showing superior anti-adhesion effects. Full article

Background: Despite extensive preclinical evidence that statins enhance osteogenesis and the widespread clinical use of platelet-rich fibrin (PRF), the clinical effectiveness of statin-incorporated PRF (SIM-PRF) in limiting peri-implant crestal bone loss remains insufficiently validated. Objectives: To address the mentioned gap, we integrated in vitro assays on human periodontal ligament stem cells (hPDLSCs) with a controlled clinical trial to test whether SIM-PRF reduces early and 12-month marginal bone loss versus PRF alone and PRF with bone graft. Methods: In vitro, cytotoxicity, migration and osteogenic differentiation were assessed, in addition to the effect on basal inflammatory markers. Clinically, 24 immediate-implant cases were randomized to receive PRF, PRF+SIM, or PRF+bone graft, with CBCT-based crestal bone change measured at 0–3, 3–6, and 6–12 months. Results: Flow cytometry confirmed the mesenchymal identity of the isolated hPDLSCs, which exhibited dose-dependent responses to SIM treatment. Lower SIM concentrations (0.1 μM) enhanced osteogenic differentiation, as evidenced by increased mineralization, alkaline phosphatase activity, and expression of osteogenic markers (RUNX2 and osteocalcin), while maintaining cell viability and migration. Both SIM concentrations (0.1 μM and 1 μM) significantly reduced basal pro-inflammatory cytokine expression (TNF-α and IL-6). Radiographic analysis revealed significantly reduced crestal bone loss (p < 0.001) in the PRF-SIM and PRF-Bone groups compared to PRF alone, particularly during early postoperative intervals (0–3 and 3–6 months). Notably, no significant difference was observed between the PRF-SIM and PRF-Bone groups (p > 0.05) in preserving the peri-implant bone. Conclusions: These findings highlight the potential of SIM-loaded PRF as an effective, biocompatible, and patient-friendly approach to enhance bone regeneration and implant success. Full article

Voltage-gated potassium channel Kv1.3 plays an important role in the regulation of survival and apoptosis in many cell types, including both normal and cancer cells. Inhibitors of these channels may potentially find clinical applications in the treatment of various diseases, including certain cancers characterized by the over-expression of Kv1.3. In this study, the effects of isobavachalcone (IBC) and two non-prenylated chalcones—2′-hydroxy-4,3′-dimethoxychalcone (HDC) and 2′-hydroxy-2-methoxychalcone (HMC)—on Kv1.3 channel activity were investigated in the Jurkat T cancer cell line using the whole-cell patch-clamp technique. The electrophysiological measurements were preceded by experiments assessing cell viability, and the patch-clamp data were consistent with results obtained from MTT-based assays. We observed an almost complete and irreversible inhibition of Kv1.3 in the presence of IBC. The non-prenylated chalcones also inhibited the channels, but with lower potency and in a reversible and incomplete manner. The inhibitory effect of IBC was significantly enhanced upon co-application with simvastatin (SIM) and mevastatin (MEV). In contrast, inhibition by the non-prenylated chalcones was significantly increased only in the presence of mevastatin, but not simvastatin. The channel inhibition may be related to the anti-proliferative and pro-apoptotic activities of these compounds in Kv1.3-expressing cancer cells. Altogether, our results indicate that both prenylated and non-prenylated chalcones, particularly in combination with statins, may represent biologically active scaffolds, warranting further optimization and preclinical evaluation. Full article

Insufficient osteogenic activity and mechanical properties of poly-L-lactic acid (PLLA) are urgent problems to be solved in deepening their application in bone tissue engineering. In this work, PLLA/mesoporous bioactive glass (PLLA/MBG) scaffolds and PLLA/simvastatin-loaded mesoporous bioactive glass (PLLA/MBG@SIM) scaffolds with filler content of 5, 10, and 15 wt% MBG and MBG@SIM were fabricated via electrospinning technology. At 10 wt% MBG loading, the tensile strength and tensile modulus were 3.23 ± 0.26 MPa and 124.47 ± 8.68 MPa, respectively, over 50% higher than those of PLLA scaffolds, demonstrating a significant enhancement in mechanical properties. Moreover, the incorporation of MBG improved the bioactivity of the PLLA scaffold, promoting the formation of apatite on the surface of the scaffolds. All composite scaffolds were non-toxic with good biocompatibility. Furthermore, PLLA/MBG@SIM composite scaffolds displayed superior osteogenic effects, better than the pure PLLA scaffolds and PLLA/MBG scaffolds. This work presents a multifunctional scaffold system combining enhanced mechanical strength with potent osteogenic activity, showing great promise for bone tissue engineering applications. Full article

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC progression. Emerging evidence suggests that the widely prescribed lipid-lowering drugs, named statins, may reduce the risk of recurrence and blunt BC cell proliferation, mainly inhibiting the HMGCR-dependent activation of the mevalonate pathway. In this study, we investigated the effects of simvastatin, atorvastatin and rosuvastatin in BC cells stimulated by insulin. To this end, we used as a BC model system MCF7 cells and naturally immortalized BCAHC-1 cells, which are characterized by high IR-expression levels. Our investigation demonstrates that statins reduce the proliferation and clonogenic capacity of BC cells prompted by insulin treatment. Mechanistically, statins impair the IR-mediated signaling and downregulate the stress-inducible transcription factor NUPR1, a known regulator of cancer progression. Importantly, NUPR1 inhibition blunted the stimulatory action of insulin on BC cells. Consistent with these findings, survival analyses of large cohorts of patients revealed that high levels of NUPR1 are associated with poor BC prognosis. Overall, our results provide novel mechanistic evidence supporting the repositioning of statins in BC, particularly in tumors characterized by elevated IR expression and activity. Full article

In order to deeply understand the potential mechanisms underlying the metabolic disorders of Chinese giant salamander (Andrias davidianus), a total of two feeding trials were conducted in the present study. For experiment I, the diets containing five graded levels of lipids at 32.8, 58.7, 87.9, 122.4, and 149.2 g/kg were formulated, respectively, and fed to juvenile A. davidianus for 90 days. The quadratic regression analysis based on growth performance results indicated that the optimal dietary lipid level is 95.16–101.02 g/kg. Meanwhile, a dietary lipid level of 149.2 g/kg was found to reduce the growth performance of A. davidianus. Based on this, in experiment II, a normal-fat diet (86.8 g/kg crude lipid), a high-fat diet (HFD, 148.4 g/kg crude lipid), and an HFD supplemented with 0.1 g/kg simvastatin were prepared, respectively, and fed to the juveniles for 90 days. The results indicated that HFD feeding resulted in hyperlipidemia, hepatic damage, endoplasmic reticulum stress, and mitochondrial dysfunction, while simvastatin administration alleviated these symptoms. In conclusion, simvastatin could alleviate the HFD-induced metabolic disorders in A. davidianus, as may be achieved by inhibiting ER stress and enhancing mitochondrial function. Full article

Background and Clinical Significance: Statins are widely prescribed for cardiovascular risk reduction and generally demonstrate a favorable safety profile. While myalgia and elevations in liver enzymes are well-recognized adverse effects, headaches are less commonly reported and often underrecognized in clinical practice. This may result in unnecessary diagnostic evaluations, increased healthcare costs, and delayed identification of the underlying cause. Case Presentation: We describe an adult patient who developed intractable headaches that emerged after many years of statin therapy. The headaches persisted despite conventional analgesic treatment and resolved completely following discontinuation of the statin. Secondary causes were excluded, and comorbid conditions were systematically ruled out. Statin-associated headache is uncommon but clinically relevant. Proposed mechanisms include nitric-oxide-mediated vasodilation, central effects of lipophilic statins, and mitochondrial involvement. In this case, the patient was taking metoprolol succinate, lisinopril, simvastatin, clopidogrel, and tamsulosin. Except for lisinopril, none of the other comedications are strongly linked to new-onset headaches. Holding it did not resolve his headache, making simvastatin the most plausible contributor. This was confirmed by resolution of headache through its discontinuation. Because such headaches may be overlooked, clinicians should consider a statin-related cause when symptoms begin after initiation and may manage this by switching to a hydrophilic statin or using alternative lipid-lowering therapy. Conclusions: Clinicians should remain vigilant about the possibility of statin-induced headache, even in long-term users. Early recognition can prevent unnecessary diagnostic investigations, expedite symptom resolution, and support optimal management of both cardiovascular risk and treatment-related adverse effects. Full article

Citri grandis exocarpium (Citri grandis) has been consumed by human beings for fifteen hundred years. It is commonly consumed as a health drink and dietary supplement in China. However, its nutritional and healthcare functions are still not fully understood. Objective: Our previous study found that oral administration of Citri grandis extract can significantly decrease the blood lipid levels of hyperlipidemic mice fed a high-fat diet. The aim of this study was to confirm the preventative effects of Citri grandis extract against atherosclerosis. Methods: Atherosclerotic lesion models were induced in HUVECs and apoE^−/− C57BL/6J mice. ApoE^−/− mice fed a high-fat diet were orally administered Citri grandis extract (0.4, 0.8, and 1.6 g/kg/d BW) and Simvastatin (1 mg/kg/d BW) on the first day of model establishment. After a 16-week treatment, serum samples and aorta and liver tissues were collected. Observation of pathological changes in aortic and liver tissues was performed using a light microscope with oil red O, H&E, Masson’s trichrome staining, and TEM. Biochemical detection was employed to determine the serum levels of TC, TG, LDL-C, and HDL-C as well as the activities of AST and ALT. In addition, expression studies of TGF-β, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1 were performed via qPCR and Western blot analysis. Results: Compared with cholesterol-induced HUVECs, Citri grandis extract significantly enhanced cell viability, attenuated the morphological changes in HUVECs, and reduced LDH release. Furthermore, after treatment with Citri grandis extract, the levels of TC, TG, and LDL-C significantly decreased in the atherosclerosis model apoE^−/− mice after 16 weeks, and aortic plaque, lipid deposition, and endothelial injury were obviously ameliorated. The mRNA and protein expression of TGF-β, PPAR-γ, LXR-α, and ABCA1 in aortic and liver of atherosclerosis apoE^−/− mice were upregulated (p < 0.05, p < 0.01), while those of PI3K and Akt1 were suppressed (p < 0.05, p < 0.01). Conclusions: Citri grandis extract can significantly decrease the high circulating lipid levels and the liver lipid deposition of high-fat-diet-fed apoE^−/− mice and reduce aorta lipid accumulation and atherosclerotic plaques by regulating the expression of TGF-β1, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1. Citri grandis extract can be used as a healthcare dietary supplement for the prevention of abnormal lipid metabolism and atherosclerosis. Full article

Osteoporotic vertebrae are a uniquely challenging tissue for local delivery due to the complex geometry of cancellous bone, the proximity of the spinal cord, and the need for reliable site retention. These challenges can be met with the use of stimuli responsive, state transiting formulations by leveraging their unique capacity for minimally invasive implantation as a liquid, sol–gel transition in response to stimuli, and finally, release of a loaded therapeutic. Here, we present the formulation development of a thermosensitive methylcellulose–collagen hydrogel, functionalised with controlled release simvastatin, recently shown to enhance osteogenesis while also impeding osteoclast activity. We first optimised a formulation with collagen content of 0.4% w/v to achieve a thermosensitive system with sol–gel transition at 29 °C, shear-thinning/injectable properties, low cytotoxicity, and high biocompatibility. Incorporation of nano-hydroxyapatite for enhanced bone tissue mimicry revealed optimal performance at 100% w/collagen content, showing long-term hydrolytic stability, maintaining more than 100% of its mass after 28 days. A loading concentration of 1 mg of simvastatin to 1 g of hydrogel displayed sustained release of simvastatin over 35 days. Finally, the release of simvastatin from the hydrogel into in vitro conditions prevented the formation of osteoclasts but failed to boost osteogenesis. Together these findings reveal a series of desirable stimuli-responsive hydrogel properties, achieving minimally invasive application coupled with sustained release of a hydrophobic compound, which is potentially useful for spatially complex bone regeneration. Further this work demonstrates the challenge of dosing sustained release systems to achieve simultaneous osteogenesis and anti-osteoclastogenic effects. Full article

Background/Objectives: While furcation involvement is a known predictor for tooth loss, the role of systemic medications is understudied. This study aimed to investigate the association between common systemic medications and both the presence and severity of furcation involvement in a large patient cohort. Methods: This retrospective cross-sectional study analyzed electronic health records from 15,881 patients within the BigMouth Dental Data Repository. The association between demographics, medication use (ACE inhibitors, statins, anti-coagulants, antidepressants, bisphosphonates, proton pump inhibitors), and the presence of furcation involvement was assessed using Chi-Square tests and multivariate logistic regression. The statistically significant relationship between medications and furcation severity (Grades 1–4) was analyzed using multinomial logistic regression. Results: Being male (OR: 1.34) and of non-Hispanic ethnicity (OR: 1.36) were significant demographic predictors for furcation involvement. After adjusting for demographics, use of ACE inhibitors (OR: 1.40), anti-coagulants (OR: 1.19), and statins (OR: 1.14) were significantly associated with higher odds of furcation involvement. Specifically, Lisinopril (OR: 1.48), Enalapril (OR: 1.83), and Atorvastatin (OR: 1.27) were significant predictors. Furthermore, patients taking Lisinopril, Aspirin, Atorvastatin, or Simvastatin had approximately 1.5 times the odds of having Grade 3 involvement compared to Grade 1 (p ≤ 0.001). Conclusions: The use of certain systemic medications, particularly for cardiovascular conditions, is independently associated with both a higher likelihood and increased severity of furcation involvement, highlighting the critical need for dental professionals to consider a patient’s medication profile as an integral part of periodontal risk assessment. Full article

Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy. Full article

Oxidative stress and mitochondrial dysfunction play a key role in the early stage of Doxorubicin (Doxo)-induced cardiotoxicity. Our study investigated the potential cardioprotective role of Simvastatin (Sim), widely known for its antioxidant properties, in an in vitro model of Doxo-induced acute cardiotoxicity. Human Cardiomyocytes (HCMs) were treated with Sim (10 µM, 4 h) and then co-exposed to Doxo (1 µM) and Sim for 20 h. Our data showed that Sim co-treatment significantly (p < 0.05) reduced both cytosolic and mitochondrial Doxo-induced reactive oxygen species overproduction. In Sim co-treated cells, significant reductions in nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression (p < 0.01) and catalase (CAT), heme-oxygenase 1 (HO-1), and superoxide dismutase 2 (SOD2) levels (p < 0.05) compared to Doxo-treated cells were also demonstrated, suggesting a decreased need for compensatory antioxidant defense responses. Moreover, significant reductions in Doxo-induced mitochondrial calcium overload, mitochondrial membrane depolarization (p < 0.005), and apoptosis (p < 0.005) confirmed the protective effects of Sim co-treatment on cardiomyocytes. These data confirm that Sim could be a valuable therapeutic strategy for reducing Doxo-induced HCM damage, preventing the development of dilated cardiomyopathy and long-term heart damage, which are the main limitations of anthracycline use. Finally, real-time PCR analysis revealed that Sim co-treatment significantly reduced (p < 0.001) the Doxo-induced overexpression of MAP4K4, a mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) involved in oxidative stress-induced cell death, thus suggesting the involvement of other molecular mechanisms in Sim-mediated cardioprotection. Full article

Objectives: The aim of the current in vitro study was to assess the effect of simvastatin on the early-stage differentiation of human dental pulp stem cells (hDPSCs) in an odontogenic pattern by evaluating the expression of specific odontogenic-related genes. Methods: hDPSCs were cultured in the presence of different concentrations of simvastatin (0.1, 0.5, 1, 5, and 10 µM) to evaluate cytotoxicity. Moreover, osteogenic differentiation was assessed by Alkaline Phosphatase (ALP) activity and alizarin red staining (ARS) after 7 days of culture. Finally, odontogenic-related gene (OCN, MEPE, DSPP, and DMP-1) expression analysis was performed. Results: Three days after treatment, higher concentrations of simvastatin (1, 5, and 10 µM) significantly limited cell viability. Upregulation of ALP activity and odontoblastic cell-related genes (OCN and MEPE) was observed in the presence of 1 µM simvastatin. The expression was statistically higher for ALP (p = 0.0001) and OCN (p = 0.0231). On the other hand, comparable or slightly less effect concerning mineralization ability with respect to the control group, as well as in the expression of DSPP and DMP-1, was observed. Conclusions: Simvastatin demonstrated a positive influence on dentinogenesis by improving the expression of specific markers such as MEPE and OCN. However, its effect on inflammation reduction and the potential to be used in combination with other materials should be further assessed. Simvastatin might be successfully applied in the regeneration of damaged dental pulp tissues and promotion of reparative dentinogenesis. Additional studies should be carried out to support the obtained outcomes. Full article

Natural product-derived drugs represent a cornerstone of modern pharmacotherapy, with many serving as essential therapeutic agents across diverse medical conditions. Recent advances in structural biology have provided unprecedented insights into the molecular mechanisms underlying their biological activities. This review presents a comprehensive structural analysis of five representative natural product-derived drugs: digoxin, simvastatin, morphine, paclitaxel, and penicillin. Through an examination of high-resolution crystal structures and cryo-electron microscopy (cryo-EM) data, we elucidate how these compounds interact with their respective protein targets and modulate biological functions. The structural data reveal diverse binding mechanisms—ranging from competitive inhibition and covalent modification to allosteric modulation via conformational selection and induced fit—demonstrating how natural products achieve their therapeutic effects through precise molecular recognition. These structural insights provide a molecular foundation for understanding natural product pharmacology and offer valuable guidance for structure-based drug design approaches in developing next-generation therapeutics. Full article

Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in the metabolism of nearly half of all clinically used drugs, including widely prescribed statins and antidiabetic agents. Dietary constituents can modulate CYP3A4 expression and activity through various mechanisms, thereby altering drug pharmacokinetics and potentially leading to therapeutic failure or toxicity. This narrative review compiles current evidence on dietary modulation of CYP3A4, with a particular focus on pharmacological and clinical implications for lipid-lowering and glucose-lowering drugs. Literature was identified through a comprehensive search in PubMed, Scopus, and Web of Science, including preclinical and clinical studies addressing food–drug interactions involving CYP3A4 substrates. Numerous dietary compounds, such as citrus furanocoumarins, polyphenols, herbal extracts, and vitamins, act as CYP3A4 inhibitors or inducers through competitive, mechanism-based, or nuclear receptor-mediated pathways. Specific examples include simvastatin, atorvastatin, repaglinide, and saxagliptin, whose systemic exposure can be significantly altered by dietary factors. Moreover, interindividual variability in CYP3A4 activity may be shaped by genetic polymorphisms, microbiota-derived metabolites, and epigenetic regulation, further influencing drug response. Understanding these interactions is crucial, especially in polymedicated patients or those receiving drugs with a narrow therapeutic index. Clinicians should remain aware of potential CYP3A4-related food–drug interactions and consider dietary habits and supplement use in therapeutic decision-making. Future research should aim to integrate pharmacogenomics, gut microbiome profiling, and personalized nutrition in order to improve the prediction and prevention of clinically significant interactions. Full article