Search Results (294)

Objective: Uncovering the renoprotective and anti-inflammatory effects of atorvastatin treatment in diabetic-and-obese rats by employing traditional renal function indicators (urea and creatinine) and four prototypical cytokines (IL-1β, il-6, IL-17α, TNFα). Method: Twenty-eight male Wistar rats, aged 6 months, 350–400 g, were randomized into four groups. The first group, G-I, the denominated control, were fed standard chow over the whole course of the experiments. The rodents in G-II were exposed to a High-Fat Diet. The last two groups were exposed to Streptozotocin peritoneal injection (35 mg/kg of body weight). A short biochemical assessment was performed before diabetes model induction to ensure appropriate glucose metabolism before experiments. Following model induction, only rodents in group G-IV were gradually introduced to the same High-Fat Diet as received by G-II. Model confirmation 10 days after injections marked the start of statin treatment in group G-IV, by daily gavage of atorvastatin 20 mg/kg of body weight/day for 21 days. At the end of the experiments, the biochemical profile of interest comprised typical renal retention byproducts (urea and creatinine) and the inflammatory profile described using plasma levels of TNFα, IL-17α, IL-6, and IL-1β. Results: Treatment with Atorvastatin was associated with a statistically significant improvement in renal function in G-IV compared to untreated diabetic rodents in G-III. Changes in inflammatory activity showed partial association with statin therapy, TNFα and IL-17α mirroring the trend in urea and creatinine values. Conclusions: Our results indicate that atorvastatin treatment yields a myriad of pleiotropic activities, among which renal protection was clearly demonstrated in this model of diabetic-and-obese rodents. The statin impact on inflammation regulation may not be as clear-cut, but the potential synergy of renal function preservation and partial tapering of inflammatory activity requires further research in severely metabolically challenged models. Full article

Background/Objectives: Immune-mediated necrotizing myopathy (IMNM) is a severe inflammatory myopathy marked by proximal muscle weakness, elevated creatine kinase (CK), and the presence of anti-HMGCR antibodies. Statin exposure is a recognized trigger for anti-HMGCR-positive IMNM, which may persist despite statin withdrawal. This pilot case series explores, for the first time, the use of bempedoic acid—a liver-specific lipid-lowering agent with minimal muscle toxicity—as an alternative to statins in these patients. Methods: We report 10 anti-HMGCR-antibody-positive IMNM patients (6 females, 4 males) previously on statins for primary prevention (8 on atorvastatin, 2 on simvastatin) without prior cardiovascular events. Statins were discontinued at myositis onset. All patients received prednisone and immunosuppressants (methotrexate in 7, mycophenolate in 3), plus bempedoic acid. Anti-HMGCR antibodies were measured using a chemiluminescence method. Results: Their mean anti-HMGCR antibody levels decreased significantly from 390.93 ± 275.22 to 220.89 ± 113.37 CU/L (p = 0.027) after 6 months of treatment. Their CK levels dropped from 1278.9 ± 769.39 to 315.1 ± 157.72 IU/L (p = 0.001), and aldolase dropped from 11.63 ± 2.18 to 6.61 ± 1.22 U/L (p = 0.0001). The mean LDL-C value was 96.1 ± 8.16 mg/dL. No disease recurrence was observed. Autoimmune panels were negative for other myositis-associated and/or -specific antibodies. Conclusions: Bempedoic acid appears to be a safe, effective, and cost-efficient lipid-lowering alternative in statin-intolerant IMNM patients. Larger studies are warranted to confirm its efficacy across different subgroups and to optimize dyslipidemia management in this setting. Full article

Stability assessments of drug substances and the detection of crystalline forms are critical for ensuring drug quality and medication safety. Atorvastatin calcium drug substance samples were characterized using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). DSC results demonstrated a precise discrimination of the stability of samples. An analysis of PXRD characteristic peaks and DSC melting data suggested that instability likely stems from the presence of the amorphous phase. To validate this hypothesis, blended samples containing controlled ratios of amorphous phase and crystalline Form I were prepared. Quantitative models based on PXRD, DSC, and near-infrared spectroscopy (NIRS) data were developed to predict amorphous content, and classification accuracy was evaluated. Experimental results confirmed that all three models achieved classification accuracy values exceeding 70% in the stability prediction of the two groups of samples, which included “stable” and “unstable” samples, substantiating the hypothesis. Among them, the modeling method based on NIRS data was not only non-destructive and rapid but also demonstrates a superior discrimination accuracy value reaching 100% (n = 11), showing potential for promotion and application in industrial sample detection. The quantitative correlation between amorphous content and stability was successfully established in this study, offering a novel method for a quality stability assessment of atorvastatin calcium drug substances. Full article

Cancer remains one of the most formidable challenges to human health; hence, developing effective treatments is critical for saving lives. An important strategy involves reactivating tumor suppressor genes, particularly p53, by targeting their negative regulator MDM2, which is essential in promoting cell cycle arrest and apoptosis. Leveraging a drug repurposing approach, we screened over 24,000 clinically tested molecules to identify new MDM2 inhibitors. A key innovation of this work is the development and application of a selective cleaning algorithm that systematically filters assay data to mitigate noise and inconsistencies inherent in large-scale bioactivity datasets. This approach significantly improved the predictive accuracy of our machine learning model for pIC₅₀ values, reducing RMSE by 21.6% and achieving state-of-the-art performance (R² = 0.87)—a substantial improvement over standard data preprocessing pipelines. The optimized model was integrated with structure-based virtual screening via molecular docking to prioritize repurposing candidate compounds. We identified two clinical CB1 antagonists, MePPEP and otenabant, and the statin drug atorvastatin as promising repurposing candidates based on their high predicted potency and binding affinity toward MDM2. Interactions with the related proteins MDM4 and BCL2 suggest these compounds may enhance p53 restoration through multi-target mechanisms. Quantum mechanical (ONIOM) optimizations and molecular dynamics simulations confirmed the stability and favorable interaction profiles of the selected protein–ligand complexes, resembling that of navtemadlin, a known MDM2 inhibitor. This multiscale, accuracy-boosted workflow introduces a novel data-curation strategy that substantially enhances AI model performance and enables efficient drug repurposing against challenging cancer targets. Full article

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. Full article

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs—including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)—have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN. Full article

Background/Objectives: This study aimed to enhance the oral delivery and therapeutic synergy of atorvastatin (AT) and docetaxel (DT) through a metronomic schedule using a transporter-targeted nanoemulsion (NE), with the goal of improving antitumor efficacy and immune modulation. Methods: AT and DT were co-encapsulated in a NE system (AT/DT-NE#E) incorporating deoxycholic acid–DOTAP (D-TAP), biotin-conjugated phospholipid (Biotin-PE), and d-α-tocopherol polyethylene glycol succinate (TPGS) to exploit bile acid and multivitamin transport pathways and inhibit P-glycoprotein efflux. The optimized NE was characterized physicochemically and evaluated for permeability in artificial membranes and Caco-2/HT29-MTX-E12 monolayers. Pharmacokinetics, tumor suppression, and immune cell infiltration were assessed in vivo using rat and CT26.CL25 mouse models. Results: AT/DT-NE#E showed enhanced permeability of AT and DT by 45.7- and 43.1-fold, respectively, across intestinal cell models and improved oral bioavailability by 118% and 376% compared to free drugs. In vivo, oral metronomic AT/DT-NE#E reduced tumor volume by 65.2%, outperforming intravenous AT/DT. Combination with anti-PD1 therapy achieved a 942% increase in tumor suppression over the control, accompanied by marked increases in tumor-infiltrating CD45⁺, CD4⁺CD3⁺, and CD8⁺CD3⁺ T cells. Conclusions: Oral metronomic administration of AT/DT via a dual-transporter-targeted NE significantly improves drug absorption, tumor inhibition, and immune response. This strategy presents a safe and effective approach for colon cancer therapy, particularly when combined with immunotherapy. Full article

Shallow lakes are highly vulnerable to pollution due to their small water volume. Those that receive effluent from the drainfields of onsite wastewater treatment systems (septic tanks) may contain pharmaceuticals and personal care products (PPCPs) that escaped removal during treatment. This study examined the effects of seasonal rainfall variability on the assemblages and concentrations of fourteen PPCPs in two shallow lakes in West–Central Florida, USA: one surrounded by residents equipped with septic tanks and the other located within a nature preserve. Water samples were collected weekly during an 18-week interval from April to August 2021. Liquid chromatography–mass spectrometry analyses revealed the omnipresence of five PPCPs: theophylline, caffeine, cotinine, DEET, and testosterone, although acetaminophen, ibuprofen, and sulfamethoxazole were also common. Of all the PPCPs detected, theophylline, DEET, and acetaminophen concentrations were higher during the wet season in the septic tank-influenced lake, while caffeine, cotinine, and testosterone concentrations decreased. In the lake located in the nature preserve, theophylline, caffeine, and acetaminophen levels increased in the wet season. In contrast, cotinine, DEET, and testosterone levels decreased. Overall, more compounds were detected during the wet season, with highly hydrophobic PPCPs (fluoxetine, atorvastatin, and octocrylene) only present during this period. Full article

Background: Topical statin therapy holds promise for ocular diseases, such as age-related macular degeneration, but the effective delivery to the posterior segment is limited by poor aqueous solubility, chemical instability, and ocular barriers. Cyclodextrins (CDs) can enhance statin solubility and stability; however, the behavior of CD–statin complexes in aqueous eye drops—particularly their influence on the equilibrium between the inactive lactone (ring closed) and active hydroxyacid forms (ring open)—remains unclear. This study aimed to (i) investigate how 5% and 10% (w/v) concentrations of selected CDs affect the lactone/acid equilibrium of simvastatin and atorvastatin and (ii) define formulation parameters (statin form, CD type and concentration, and pH range) for stable eye drop development. Methods: Simvastatin or atorvastatin was added to buffered solutions (pH 2.0 to pH 9.5) of RMβCD, HPβCD, γ-CD, or SBEβCD at 0%, 5%, and 10% (w/v), incubated at 23 ± 1 °C, and sampled over time for UPLC quantification of lactone and hydroxyacid forms, and rate constants for the forward and reverse reaction were calculated. Phase solubility studies were also conducted to further characterize equilibrium behavior in aqueous CD systems. Results: The lactone form was most stable at a pH of 4.5, while the hydroxyacid form prevailed at a pH ≥ 7. γ-CD and HPβCD accelerated lactone hydrolysis for both statins, whereas RMβCD exerted a stabilizing effect. Increasing the CD concentration from 5% to 10% provided minimal additional stabilization. Conclusions: These findings highlight that the precise control of the pH, an appropriate cyclodextrin choice, and the selection of the statin form are critical to developing chemically stable eye drops. Full article

Background: Lipid metabolism disturbances are common in end-stage renal disease (ESRD) patients on hemodialysis (HD), leading to dyslipidemia, which is characterized by abnormal plasma lipids and lipoproteins. Although large randomized controlled trials have generally not demonstrated a survival benefit associated with statin therapy among patients receiving hemodialysis, limited observational studies have reported potential associations with improved clinical outcomes in this population. Methods: This retrospective cohort study investigated the clinical and safety outcomes of statin use in ESRD patients on HD with documented dyslipidemia over a two-year period from 1 January 2018 to 30 December 2019. The primary endpoints evaluated the clinical outcomes of statins by assessing changes in specific lipid parameters, including low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). The secondary endpoints assessed safety by monitoring liver enzymes and creatine kinase (CK) levels. Results: Among 179 participants, diabetes mellitus was present in 134 patients (74.9%), while 168 patients (93.9%) had hypertension. Cardiovascular events occurred in 95 patients (53.1%). Statin therapy was administered to 146 patients (82.0%), with atorvastatin being the most frequently prescribed statin (69.3%). Modest reductions in LDL-C levels were observed in the rosuvastatin and atorvastatin groups, whereas slight increases were noted in the simvastatin and non-statin groups. None of these within-group changes were statistically significant. In the atorvastatin group, LDL-C decreased slightly from 2.058 to 2.003 mmol/L. The rosuvastatin group experienced a more pronounced LDL-C reduction from 2.607 to 2.113 mmol/L. Conversely, the simvastatin group showed an LDL-C increase from 1.550 to 1.901 mmol/L. Among the non-statin group, LDL-C increased from 2.678 to 2.820 mmol/L. Liver enzyme and CK levels fluctuated slightly but remained within normal ranges. Conclusions: This study evaluated statin therapy in hemodialysis patients with dyslipidemia. Although modest reductions in LDL-C levels were observed in the atorvastatin and rosuvastatin groups, statin therapy did not reduce the incidence of atherosclerotic events in hemodialysis patients with dyslipidemia. Additionally, statin use was not associated with any clinically or statistically significant effects. Full article

Background: Colorectal cancer (CRC) is the third most common cancer globally. Atorvastatin (ATR), a lipid-lowering drug, has shown promise as a repurposed therapeutic agent for CRC. However, its clinical application is limited by poor solubility and low oral bioavailability. This study aimed to optimize ATR-loaded chitosan-coated cubosomes using a Box–Behnken design and evaluate their potential in CRC treatment through physicochemical characterization and cell viability studies on HCT116 human CRC cells. Methods: Optimized cubosomes were characterized for particle size, zeta potential, polydispersity index (PDI), drug content, entrapment efficiency, compatibility using Fourier transform infrared spectroscopy, and in vitro release in various pH media. Cytotoxic effects were assessed using sulforhodamine B and trypan blue viability assays. Results: Uncoated cubosomes exhibited a particle size of 120.0 ± 1.66 nm, a zeta potential of −22.2 ± 1.05 mV, and a PDI of 0.136 ± 0.01. The chitosan-coated cubosomes displayed a size of 169.3 ± 4.14 nm, a zeta potential of 29.7 ± 0.814 mV, and a PDI of 0.245 ± 0.015. Entrapment efficiency and drug content were 92.1 ± 2.46% and 64.5 ± 1.58%, respectively. The ATR-loaded cubosomes demonstrated pH-dependent release, negligible at pH 1.2 and 4.5, but pronounced at pH 6.8 and 7.4, supporting colon-targeted delivery. Cell viability studies showed significant inhibition of HCT116 cells at ATR concentrations of 1 and 5 µM, with complete inhibition at higher doses. Conclusions: Chitosan-coated ATR-loaded cubosomes are promising for targeting ATR delivery to the colon. They offer enhanced anticancer activity by bypassing gastric degradation and systemic circulation, making an efficient approach to CRC treatment. Full article

A phytochemical study of Ganoderma applanatum identified four predominant triterpenoids, with ganoapplanilactone C (GATC) exhibiting the most significant lipid-reducing effects in high-fat diet-fed zebrafish, surpassing atorvastatin at 5 μM. Histopathological analysis confirmed GATC’s protective effects on the liver against high-fat diet-induced damage. The Enzyme-Linked Immunosorbent Assay (ELISA) results showed a positive correlation between GATC treatment and liver health markers, as well as antioxidant enzymes, while they revealed a negative correlation with triglycerides and inflammatory cytokines. Metabolomic profiling demonstrates GATC’s impact on metabolites such as amino acids, fatty acids, and the mechanistic Target of Rapamycin (mTOR) signaling pathway, suggesting its role in regulating multiple metabolic processes. The increase in Adenosine Monophosphate-activated protein kinase (AMPK) phosphorylation in the GATC-treated groups indicates the activation of the AMPK/mTOR pathway, a key mechanism in lipid metabolism and liver protection. Molecular docking studies highlighted the importance of GATC’s spirocyclic ketone system and hydroxyl group in binding to target proteins. These findings underscore GATC’s potential as a therapeutic agent for metabolic dysfunction-associated steatotic liver disease (MASLD), emphasizing its superior efficacy compared to other triterpenoids due to its unique C-23 spiro 5/7 system. This study provides valuable insights into the prevention and treatment of MASLD using G. applanatum-derived compounds. Full article

SH-SY5Y neuroblastoma cells can be effectively differentiated into a neuronal phenotype using retinoic acid (RA) and brain-derived neurotrophic factor (BDNF), making them a valuable in vitro model for studying neuronal differentiation. This study aimed to investigate the electrophysiological properties of SH-SY5Y cells following prolonged differentiation, with a focus on membrane characteristics, evoked action potentials, and the functionality of cellular components such as N-methyl-D-aspartate (NMDA) receptor. Whole-cell patch-clamp recordings were employed to evaluate ionic currents and action potentials in embryonic mouse cortical neurons (mCNs) and in both differentiated and undifferentiated SH-SY5Y neuroblastoma cells. Differentiated SH-SY5Y cells exhibited neurite outgrowth, evoked action potential firing, and functional NMDA receptor-mediated currents. Notably, atorvastatin significantly modulated the duration and firing of action potentials as well as NMDA receptor-mediated currents in differentiated SH-SY5Y cells. These findings highlight that neuronally differentiated SH-SY5Y cells expressing functional NMDA receptor-mediated currents serve as a robust and convenient model for investigating the molecular mechanisms of NMDA receptor function and for screening pharmacological agents targeting these receptors. Full article

This study analyzed 97 pharmaceuticals in samples of surface water, as well as influent and effluent from various wastewater treatment plants (WWTPs), during winter 2022 and spring 2023. Approximately 40% of the tested compounds were detected, at amounts ranging from below the methods’ detection limits to 5623 ng/L (2-hydroxyibuprofen in surface water) and 12,664 ng/L (caffeine in wastewater). Twelve compounds (acetaminophen, ampicillin, azithromycin, caffeine, fluoxetine, gemfibrozil, 2-hydroxyibuprofen, ibuprofen, ketoprofen, mazindol, naproxen, and salicylic acid) were detected with a 100% frequency in both surface water and wastewater samples. The observed high detection frequency of pharmaceuticals within the nonsteroidal anti-inflammatory drugs/analgesics, antibiotics, and psychiatric drug classes aligns with their high consumption. Caffeine was both the compound with the highest concentration and the most prevalent compound detected. Seasonal differences were observed, with higher concentrations detected during winter. Six of the eleven targeted metabolites and degradation products were detected in at least one sample. Risk quotient assessment revealed potential ecological risks, particularly for atorvastatin, caffeine, carbamazepine, and venlafaxine, exceeding risk thresholds for various trophic levels. The studied WWTPs showed limited removal efficiencies, with some compounds presenting higher concentrations in effluent than in influent, emphasizing the need for enhanced treatment to mitigate micropollutant risks. Full article

Statins, in addition to their main beneficial lipid-lowering effects (lowering cholesterol and LDL levels), have many additional adverse effects. Among them, the most common is skeletal myopathy. Mitochondria not only play a pivotal role in statin-induced adverse skeletal muscle effects but also seem to be involved in the adverse effects of statins on human cardiac function. However, given that similar oxidative phosphorylation pathways are relevant in skeletal and cardiac muscles, whether long-term statin treatment may alter cardiac muscle is currently unknown. Natural products have been widely employed in skeletal muscle disorders thanks to their antioxidant and anti-inflammatory properties. The purpose of this study was to evaluate the effects of a novel phytotherapic formulation (PF) composed of Curcuma and Boswellia essential oils, Harpagophytum procumbens root, and Bromelain on the human AC16 cell line in an in vitro model of atorvastatin-induced cardiomyopathy. Our results showed that atorvastatin decreased cell viability by approximately 50% and induced ROS production and mitochondrial structural damage. Interestingly, supplementation of cells with PF reduced oxidative stress by 20%, improved mitochondrial reshape and function, and restored the expression of the Nrf2/HO-1/GPX4 axis. These results provide new insights into statin-induced cardiomyopathy and suggest the employment of PF as a promising agent in the recovery of cardiac function. Full article