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Introduction: Atorvastatin (ATV), a medication used to reduce cholesterol levels, possesses properties that can counteract the damaging effects of free radicals and reduce inflammation. However, the administration of ATV orally is associated with low systemic bioavailability due to its limited capacity to dissolve in water and significant first-pass effect. This study aimed to assess the appropriateness of employing nano-vesicles for transdermal administration of ATV in order to enhance its anti-inflammatory effects., Methods: ATV-loaded transethosomes (ATV-TEs) were optimized using the 3 3 Box-Behnken design. The ATV-TEs that were created were evaluated for their vesicle size, encapsulation efficiency (% EE), and percent release of drug. The optimum formulation was integrated into a hydroxypropyl methylcellulose (HPMC) emulsion-based gel (ATV-TEs emulgel) using jojoba oil. ATV-TEs emulgel was examined for its physical characteristics, ex vivo permeability, histological, and anti-inflammatory effect in a rat model of inflamed paw edema., Results: The optimized transethosomes exhibited a vesicle size of 158.00 nm and an encapsulation efficiency of 80.14 ± 1.42%. Furthermore, the use of transethosomal vesicles effectively prolonged the release of ATV for a duration of 24 hours, in contrast to the pure drug suspension. In addition, the transethosomal emulgel loaded with ATV exhibited a 3.8-fold increase in the transdermal flow of ATV, in comparison to the pure drug suspension. ATV-TEs emulgel demonstrated a strong anti-inflammatory impact in the carrageenan-induced paw edema model., Discussion: This was evident from the significant reduction in paw edema, which was equivalent to the effect of the standard anti-inflammatory medicine, Diclofenac sodium., Conclusion: In summary, transethosomes, as a whole, might potentially serve as an effective method for delivering drugs via the skin. This could improve the ability of ATV to reduce inflammation by increasing its absorption through the skin., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Abdallah et al.)

Research Question: Can atorvastatin, with its antioxidant, anti-inflammatory and anti-apoptotic properties, improve ovarian function and follicular reserve in rats with cyclophosphamide-induced premature ovarian insufficiency (POI)?, Design: In this experimental study, 24 adult female Wistar rats were divided into four groups: control; POI; POI + atorvastatin; and atorvastatin. After treatment with atorvastatin, serum concentrations of total antioxidant capacity, glutathione, malondialdehyde, FSH, oestradiol, anti-Müllerian hormone, tumour necrosis factor-alpha and interleukin-6 were evaluated. Additionally, mRNA and protein expression of Bax, Bcl-2 and VEGF-A; number of follicles; and total volume of the ovary, and volumes of the cortex and medulla were examined., Results: The results showed that serum concentrations of total antioxidant capacity (P < 0.001), glutathione, oestradiol and anti-Müllerian hormone (P < 0.05); mRNA and protein expression of Bcl-2 and VEGF-A (P < 0.05); number of primordial and primary follicles (P < 0.001), and preantral and antral follicles (P < 0.01); and total volume of the ovary, and volume of the cortex (P < 0.05) increased significantly in the POI + atorvastatin group compared with the POI group. Serum concentrations of malondialdehyde, FSH, tumour necrosis factor-alpha and interleukin-6; and mRNA and protein expression of Bax decreased significantly in the POI + atorvastatin group compared with the POI group (P < 0.05)., Conclusions: Atorvastatin reduces the detrimental effects of cyclophosphamide in the POI model significantly by reducing oxidative stress and pro-inflammatory cytokines; regulating the expression of Bax, Bcl-2 and VEGF-A; and improving ovarian function and follicular reserve., (Copyright © 2024 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus developed for the treatment of chronic plaque psoriasis. Cedirogant induces cytochrome P450 (CYP) 3A4 while inhibiting P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3 in vitro. Static drug-drug interactions (DDIs) predictions suggested possible clinical induction of CYP3A4, and inhibition of P-gp, BCRP, and OATP1B1, leading to challenges in interpreting DDI studies between cedirogant and substrates of CYP3A, P-gp, BCRP, and OATP1B1/3. Here the effects of cedirogant on the pharmacokinetics of two statin drugs were investigated in healthy participants. Coproporphyrin-I (CP-I), a selective endogenous OATP1B biomarker, was used to assess the impact of cedirogant on OATP1B. Cedirogant (375 mg once daily) increased rosuvastatin maximum plasma concentration (C max ) and area under the plasma concentration curve (AUC tau ) by 141% and 55%, respectively when co-administered, whereas atorvastatin C max increased by 40% with no effect on its AUC tau compared with administration of rosuvastatin/atorvastatin alone. Cedirogant did not increase CP-I exposures, indicating no clinical OATP1B inhibition. The increased rosuvastatin exposure and minimal change in atorvastatin exposure with co-administration of cedirogant is attributed to BCRP inhibition and interplay between P-gp/BCRP inhibition and CYP3A induction, respectively. Correlation analysis with data from two investigational drugs (glecaprevir and flubentylosin) demonstrated that OATP1B1 R-value of > 1.5 and [C max,u ]/[OATP1B1 IC 50 ] of > 0.1 are associated with > 1.25-fold increase in CP-I C max ratio. This demonstrates the utility of CP-I in disentangling mechanisms underlying a complex DDI involving multiple transporters and enzymes and proposes refined criteria for static OATP1B inhibition predictions., (© 2024 AbbVie Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Neutrophil extracellular trap (NET) formation is involved in atherothrombosis., Objectives: We sought to investigate whether statins affect neutrophil extracellular traps activation and release (NETosis) in coronary artery disease (CAD), and whether such changes show associations with statin‑induced additional effects., Patients and Methods: We studied 130 patients with advanced CAD before and at least 6 months after initiation of high‑dose statin therapy with rosuvastatin 40 mg/d or atorvastatin 80 mg/d. The levels of circulating citrullinated histone H3 (H3cit), myeloperoxidase (MPO), and neutrophil elastase (NE) were assessed as proteins associated with NETosis along with thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis inhibitors., Results: Following statin therapy intensification, we observed reduced accumulation of H3cit (-30.4%), MPO (-28.1%), and NE (-25.5%; all P <0.001), all not associated with low‑density lipoprotein cholesterol (LDL‑C) lowering (-25%). However, H3cit level was lower in 50 patients (38.5%) who achieved the target LDL‑C below 1.8 mmol/l (-16.5%; P = 0.004), and in 19 patients (14.6%) with LDL‑C below 1.4 mmol/l (-25.5%; P = 0.001), as compared with the remaining individuals. The reductions in H3cit and MPO levels were associated with a 42.9% decrease in C‑reactive protein (CRP) level on high‑dose statins (R = 0.855; P <0.001 and R = 0.25; P = 0.004, respectively), along with increases in Ks and reduction in thrombin activatable fibrinolysis inhibitor (TAFI) activity, but not with CLT or thrombin generation (all |R|, 0.24-0.4; P <0.01). In multivariable analysis, changes in CRP (β = 0.771; P <0.001), TAFI activity (β = 0.125; P = 0.013), and fibrinogen level (β = 0.106; P = 0.034) were independently associated with a decrease in H3cit concentration., Conclusions: We showed for the first time that high‑dose statins can reduce the level of NET‑related proteins in association with anti‑inflammatory and antithrombotic actions in CAD patients.

Periodontal bone loss is potentiated by diabetes. Despite the beneficial anti-inflammatory and antiresorptive effects of Atorvastatin (ATV) on periodontitis, it has been reported to increase the risk of diabetes, which may modify the course of periodontal disease. Therefore, this study aimed to evaluate the effect of ATV on alveolar bone in rats with periodontitis and diabetes. For this, 72 Wistar rats were divided into groups: Naïve (N) not submitted to any procedure; Experimental periodontitis (EP) group submitted to ligature-induced periodontitis; diabetes mellitus (DM), submitted to EP and receiving single dose of streptozotocin (60 mg/kg, i.p.) after 12 hours of fasting; and ATV DM, submitted to EP and DM and receiving orally 27 mg/kg of ATV, 30 minutes before ligature placement, and continued daily until the 11th day. Animals from EP and DM received saline solution 0.9% as placebo. Glycemic levels measured in all animals and then were euthanized. Maxillae were collected for macroscopic, micro-tomographic, and microscopic analyses. DM caused intense bone loss (60%), characterized by a reduction in trabecular thickness and bone volume. DM reduced osteoblasts, increasing osteoclast counts, and induced an inflammatory infiltrate in the periodontium. ATV was found ineffective in protecting bone in diabetic rats, exacerbating bone loss by 21%. Additionally, ATV significantly increased blood glucose levels. In summary, ATV did not prevent alveolar bone loss or modulate inflammation in DM animals undergoing EP. ATV also increased blood glucose levels in these animals. Therefore, the systemic use of ATV in uncontrolled diabetic conditions should be carefully evaluated.

This study aimed to evaluate the impact of atorvastatin, administered both locally and systemically, on critical defects in the calvaria of rats. Thirty-six adult rats were randomly assigned to three groups, with all bone defects covered by a collagen membrane. The groups received different treatments: distilled water (GAD), where membranes were soaked in distilled water; systemic application of atorvastatin (GAS) at a dosage of 3.6mg/kg/day through gavage; and local application of atorvastatin (GAL). After 14 and 28 days, all animals were euthanized, and various assessments were conducted, including histometric analysis, measurement of linear residual defect, evaluation of newly formed bone area, determination of membrane and soft tissue area, cell count, and immunohistochemical analysis. Group GAS exhibited a significant reduction in residual defect compared to the other groups (p<0.05) and a lower number of osteocytes (p<0.05) in comparison with other groups. On day 28, both GAL and GAS groups showed a higher number of inflammatory cells compared to GAD (p<0.05). Immunolabeling of CD31 was similar for both groups, but in the case of osteocalcin, there was a significant increase in labeling for groups GAS and GAL between days 14 and 28 postoperative (p<0.05). In conclusion, systemic atorvastatin demonstrated enhanced osteogenesis in critical calvaria defects in rats, suggesting its efficacy in promoting bone regeneration without exerting a notable anti-inflammatory effect.

Background: One of the probable causes of statin myotoxicity is an imbalance between protein synthesis and degradation. These processes are regulated by the PI3K/Akt/mTOR pathway and the ubiquitin‒proteasome system (UPS). The aim of this study was to assess whether the effects of atorvastatin on PI3K/Akt/mTOR pathway downstream proteins, the FoxO3a transcription factor and the UPS genes, i.e., MuRF-1 and MAFbx, depend on muscle fibre type., Methods and Results: Atorvastatin (50 mg/kg) was administered to Wistar rats. The levels of selected PI3K/Akt/mTOR pathway proteins were assayed via Western blotting, whereas MuRF-1, MAFbx and FoxO3a mRNA levels were measured using reverse transcription quantitative polymerase chain reaction (RT‒qPCR). Gomöri trichrome staining was performed to assess skeletal muscle pathology. A decrease in the P-Akt/Akt ratio was observed in the gastrocnemius muscle (MG), whereas an increase in the P-Akt/Akt ratio was observed in the soleus muscle (SOL). FoxO3a gene expression increased in the SOL and extensor digitorum longus (EDL) muscles. MuRF-1 gene expression increased in the MG, and MAFbx expression increased in the EDL. No histopathological changes were observed in any of the tested muscles., Conclusions: In the absence of overt muscle damage, atorvastatin decreased the P-Akt/Akt ratio in the MG, indicating an increase in inactive Akt. Consistent with the decrease in Akt activation, rpS6 phosphorylation decreased. In SOL, atorvastatin increased the P-Akt/Akt ratio, indicating Akt activation. P-FoxO3a and the P-FoxO3a/FoxO3a ratio increased, suggesting that FoxO3a inactivation occurred. Moreover, in the SOL, atorvastatin did not affect the expression of atrophy-related genes. These findings indicate that atorvastatin has no adverse effect on the Akt pathway in the SOL. Our results showed that the effects of atorvastatin on the Akt signalling pathway and atrophy-related gene expression depend on muscle type., (© 2024. The Author(s).)

The repair of critical bone defects caused by various clinical conditions needs to be addressed urgently, and the regeneration of large bone defects depends on early vascularization. Therefore, enhanced vascularization of artificial bone grafts may be a promising strategy for the regeneration of critical-sized bone defects. Taking into account the importance of rapid angiogenesis during bone repair and the potential of piezoelectric stimulation in promoting bone regeneration, novel coaxial electrospun mats coupled with piezoelectric materials and angiogenic drugs were fabricated in this study using coaxial electrospinning technology, with a shell layer loaded with atorvastatin (AVT) and a core layer loaded with zinc oxide (ZnO). AVT was used as an angiogenesis inducer, and piezoelectric stimulation generated by the zinc oxide was used as an osteogenesis enhancer. The multifunctional mats were characterized in terms of morphology, core-shell structure, piezoelectric properties, drug release, and mechanical properties, and their osteogenic and angiogenic capabilities were validated in vivo and ex vivo . The results revealed that the coaxial electrospun mats exhibit a porous surface morphology and nanofibers with a core-shell structure, and the piezoelectricity of the mats improved with increasing ZnO content. Excellent biocompatibility, hydrophilicity and cell adhesion were observed in the multifunctional mats. Early and rapid release of AVT in the fibrous shell layer of the mat promoted angiogenesis in human umbilical vascular endothelial cells (HUVECs), whereas ZnO in the fibrous core layer harvested bioenergy and converted it into electrical energy to enhance osteogenic differentiation of rat bone mesenchymal stem cells (BMSCs), and both modalities synergistically promoted osteogenesis and angiogenesis. Furthermore, optimal bone regeneration was achieved in a model of critical bone defects in the rat mandible. This osteogenesis-promoting effect was induced by electrical stimulation via activation of the calcium signaling pathway. This multifunctional mat coupling piezoelectric stimulation and atorvastatin promotes angiogenesis and bone regeneration, and shows great potential in the treatment of large bone defects.

Kawasaki disease (KD) causes vascular injury and lifelong remodeling. Excessive intimal proliferation has been observed, resulting in coronary artery lesions (CALs). However, the mechanisms underlying vascular remodeling in CAL and statin treatment have not been comprehensively elucidated. This study aimed to investigate the effects of statins on vascular remodeling using a KD mouse model. Candida albicans water-soluble substance (CAWS) was intraperitoneally injected in 5-week-old male apolipoprotein-E-deficient mice. They were categorized as follows (n = 4): control, CAWS, CAWS+statin, and late-statin groups. The mice were euthanized at 6 or 10 weeks after injection. Statins (atorvastatin) were initiated after CAWS injection, except for the late-statin group, for which statins were internally administered 6 weeks after injection. Elastica van Gieson staining and immunostaining were performed for evaluation. Statins substantially suppressed the marked neointimal hyperplasia induced by CAWS. Additionally, CAWS induced TGFβ receptor II and MAC-2 expression around the coronary arteries, which was suppressed by the statins. KD-like vasculitis might promote the formation of aneurysm by destroying elastic laminae and inducing vascular stenosis by neointimal proliferation. The anti-inflammatory effects of statins might inhibit neointimal proliferation. Therefore, statin therapy might be effective in adult patients with KD with CAL by inhibiting vascular remodeling., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Trichinosis is a common parasitic disease that affects the striated skeletal muscles, causing apoptotic and degenerative changes associated with myogenin expression in the affected myocytes. Hence, this study aimed to assess the ameliorative effects of stem cells and atorvastatin added to ivermectin on the infected myocytes during the muscular phase of murine trichinosis. 120 laboratory Swiss albino male mice were divided into 10 groups, and each group was subdivided into intestinal and muscular phases (each n = 6); uninfected control; untreated infected control; infected received ivermectin monotherapy; infected received atorvastatin monotherapy; infected received stem cells monotherapy; infected received ivermectin and atorvastatin dual therapy; infected received ivermectin and stem cells dual therapy; infected received atorvastatin and stem cells dual therapy; infected received ivermectin 0.2, atorvastatin 40, and stem cells triple therapy; and infected received ivermectin 0.1, atorvastatin 20, and stem cells triple therapy. Intestinal phase mice were sacrificed on the 5th day post-infection, while those of the muscular phase were sacrificed on the 35th day post-infection. Parasitological, histopathological, ultrastructural, histochemical, biochemical, and myogenin gene expression assessments were performed. The results revealed that mice that received ivermectin, atorvastatin, and stem cell triple therapies showed the maximum reduction in the adult worm and larvae burden, marked improvement in the underlying muscular degenerative changes (as was noticed by histopathological, ultrastructural, and histochemical Feulgen stain assessment), lower biochemical levels of serum NK-κB and tissue NO, and lower myogenin expression. Accordingly, the combination of stem cells, atorvastatin, and ivermectin affords a potential synergistic activity against trichinosis with considerable healing of the underlying degenerative sequel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism., Methods: On gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed., Results: Male offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group., Conclusions: The research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD., (© 2024. The Author(s).)

Benzo[a]pyrene (BaP) is a contaminant that is generated in the environment through processes such as smoke, incomplete combustion of fossil fuels, vehicle exhaust emissions, entry into the body is through inhalation, and consumption of contaminated food. It is an omnipresent environmental pollutant with unavoidable exposure. BaP metabolites are observed in the male reproductive system, especially in the testes and epididymis of animals, and are responsible for reduced testicular and epididymal function. The protective effect of atorvastatin (ATV) on testicular damage was investigated previously. The aim of the present study was to investigate the protective effect of ATV on testicular toxicity induced by benzo[a]pyrene (BaP) during pregnancy in Wistar rats. This experimental laboratory study involved 40 adult rats, divided into seven groups and maintained under standard environmental conditions. The groups received different diets [control, corn oil, ATV (10 mg/kg), BaP (10 and 20 mg/kg), and ATV + BaP (10 and 20 mg/kg)] at gestation Days 7-16, orally. Male offspring were examined 10 weeks after birth. Testis and serum samples were collected, and testosterone level, malondialdehyde (MDA), and glutathione (GSH) were measured. Histological and immunohistochemical assays were performed under a light microscope. Statistical analysis was conducted using SPSS, with analysis of variance and Tukey tests to assess significant differences between groups. ATV significantly reduced MDA, a marker of lipid peroxidation and oxidative stress in rat testes following BaP administration. Treatment with ATV at doses of 10 mg/kg increased GSH levels, correcting disruptions in the antioxidant system caused by BaP. Testosterone concentration in rats treated with ATV and BaP substantially prevented the decrease induced by BaP. Histomorphometry revealed that ATV significantly prevented the detrimental effects of BaP on the thickness of spermatogenic epithelium and the diameter of seminiferous tubules. Under ATV treatment, testicular tissue histopathology improved, and spermatogenesis returned to a almost back to normal state. Caspase-3 expression decreased, and apoptosis activity in testicular tissue improved under ATV treatment, indicating a positive effect of ATV in reducing apoptotic damage caused by BaP. In conclusion, exposure to BaP can induce oxidative stress-related damage to testicular tissue, as evidenced by an increase in MDA levels, which ATV treatment can mitigate. Additionally, ATV enhances intracellular antioxidant GSH and protects the testes against BaP-induced damage while increasing testosterone levels, which are reduced due to exposure to BaP., (© 2024 Wiley Periodicals LLC.)

Preincubation with inhibitor in organic anion transporting polypeptide (OATP) in vitro assays may increase the inhibition potency of inhibitors compared to conventional inhibition assays with only short inhibitor coincubation with substrate. The decrease in IC 50 may affect prediction of drug-drug interactions (DDI) involving these transporters and inhibitors. Only few drugs, however, have been assessed for the preincubation-dependent inhibition of the OATP2B1 transporter. Therefore, we studied the effect of preincubation on OATP2B1 inhibition with five known OATP2B1 inhibitors (atorvastatin, erlotinib, ezetimibe, ticagrelor and simeprevir) in HEK293 cells transiently overexpressing OATP2B1. IC 50 values were determined with and without inhibitor preincubation for 20 min with three different OATP2B1 substrates (dibromofluorescein, DBF; 5-carboxyfluorescein, 5-CF; estrone sulfate). Atorvastatin, ezetimibe, and simeprevir displayed more than 2-fold lower IC 50 values after preincubation with at least one of the tested substrates. Altogether, 4 out of 15 inhibitor/substrate combinations exhibited more than 2-fold potentiation of IC 50 after inhibitor preincubation. In addition, preincubation by itself, without inhibitor present with the substrate, resulted in more than 50% inhibition of OATP2B1-mediated uptake of DBF and/or 5-CF by atorvastatin, ticagrelor and simeprevir. Thus, erlotinib was the only inhibitor with no indication of potentiation of inhibition by preincubation with any of the tested substrates. In conclusion, preincubation resulted in inhibitor- and substrate-dependent inhibition of OATP2B1. These results support the conclusion that to reduce the risk of false negative DDI prediction, preincubation should be considered also in OATP2B1 inhibition assays., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Canine haemangiosarcoma (HSA) is a highly aggressive cancer often associated with coagulation abnormalities. Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) clinically prescribed for hypercholesterolemia, are also believed to possess antitumour and anticoagulant properties by inhibiting downstream Akt activation. Akt phosphorylation is involved in the mechanism of the antitumour and tissue factor (TF)-lowering effects of statins. In the present study, we aimed to investigate whether statins could inhibit cell viability while concurrently inducing anticoagulant properties by regulating the expression of TFs in canine HSA cells. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), we initially exclusively detected HMGCR mRNA expression in canine HSA tissues and cell lines but not in normal cephalic vein and spleen tissues. Moreover, treatment with lipophilic statins, including atorvastatin, fluvastatin, and simvastatin, inhibited cell viability in a concentration-dependent manner and decreased TF expression both at the mRNA and protein levels, as evidenced by cell viability assays, RT-qPCR, and immunoblotting, respectively. Further investigation using cell viability assays and flow cytometry revealed that simvastatin decreased Akt phosphorylation, and MK-2206, a specific Akt inhibitor, mirrored the effect of simvastatin on cell viability and cell cycle arrest. However, MK-2206 exhibited different effects on TF expression depending on the cell type, indicating that Akt phosphorylation may not consistently regulate TF expression. Overall, this study provides insights into the potential therapeutic use of statins in targeting tumour growth and coagulation abnormalities in canine HSA. Further research is warranted to fully elucidate the underlying mechanisms and clinical applications of statins in canine HSA treatment., (© 2024 John Wiley & Sons Ltd.)

Post-traumatic epilepsy (PTE) is a recurrent and often drug-refractory seizure disorder caused by traumatic brain injury (TBI). No single drug treatment prevents PTE, but preventive drug combinations that may prophylax against PTE have not been studied. Based on a systematic evaluation of rationally chosen drug combinations in the intrahippocampal kainate (IHK) mouse model of acquired epilepsy, we identified two multi-targeted drug cocktails that exert strong antiepileptogenic effects. The first, a combination of levetiracetam (LEV) and topiramate, only partially prevented spontaneous recurrent seizures in the model. We therefore added atorvastatin (ATV) to the therapeutic cocktail (TC) to increase efficacy, forming "TC-001". The second cocktail - a combination of LEV, ATV, and ceftriaxone, termed "TC-002" - completely prevented epilepsy in the mouse IHK model. In the present proof-of-concept study, we tested whether the two drug cocktails prevent epilepsy in a rat PTE model in which recurrent electrographic seizures develop after severe rostral parasagittal fluid percussion injury (FPI). Following FPI, rats were either treated over 3-4 weeks with vehicle or drug cocktails, starting either 1 or 4-6 h after the injury. Using mouse doses of TC-001 and TC-002, no significant antiepileptogenic effect was obtained in the rat PTE model. However, when using allometric scaling of drug doses to consider the differences in body surface area between mice and rats, PTE was prevented by TC-002. Furthermore, the latter drug cocktail partially prevented the loss of perilesional cortical parvalbumin-positive GABAergic interneurons. Plasma and brain drug analysis showed that these effects of TC-002 occurred at clinically relevant levels of the individual TC-002 drug components. In silico analysis of drug-drug brain protein interactions by the STITCH database indicated that TC-002 impacts a larger functional network of epilepsy-relevant brain proteins than each drug alone, providing a potential network pharmacology explanation for the observed antiepileptogenic and neuroprotective effects observed with this combination., Competing Interests: Declaration of competing interest PK, CR, WL, and AR are co-founders and have equity in PrevEp Inc., Bethesda, MD. The other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To elucidate the therapeutic mechanism of Qingxin Jieyu Granule (QXJYG) against atherosclerosis (AS) based on network pharmacology., Methods: The major targets and pathways of QXJYG against AS were analyzed using network pharmacology. Rat models of AS established by high-fat feeding combined with intraperitoneal vitamin D3 injection were treated daily with normal saline, atorvastatin (13.15 mg/kg), or QXJYG at 0.99, 1.98, and 3.96 g/kg for 8 weeks ( n =6). Ultrasound and HE staining were used to assess the function and pathologies of the abdominal aorta. Blood lipids and serum levels of Ang Ⅱ, ET-1, TXA2, PGI2, and ox-LDL of the rats were detected using an automatic biochemical analyzer or ELISA. The expressions of LOX-1, PPARγ, RXRα, p-P65, VCAM-1 and ICAM-1 in the abdominal aorta were detected with immunohistochemistry., Results: The rat models of AS showed obvious abdominal aorta wall thickening, increased pulse wave velocity and pulse index, decreased inner diameter of the abdominal aorta, elevated levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and lowered levels of HDL-C and PGI2. QXJYG and atorvastatin treatment of the rat models significantly alleviated histopathological changes of the abdominal aorta, decreased serum levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and increased the levels of HDL-C and PGI2. Network pharmacology study suggested the therapeutic effect of QXJYG against AS was mediated by regulating lipid metabolism, PPAR and NF-κB pathways. Consistently, treatments with QXJYG were found to significantly decrease ox-LDL level and LOX-1, P-P65, VCAM-1 and ICAM-1 protein expressions while increasing PPARγ and RXRα expressions in the aorta of AS rats., Conclusion: QXJYG alleviates lipid metabolism disorder and improves histopathological changes of the abdominal aorta of AS rats possibly by lowering ox-LDL level, reducing LOX-1 expression, activating PPAR γ and RXR α , and inhibiting P65 phosphorylation to reduce VCAM-1 and ICAM-1 expression in the aorta.

Aims: Atorvastatin is a commonly used cholesterol-lowering drug that possesses non-canonical anti-inflammatory properties. However, the precise mechanism underlying its anti-inflammatory effects remains unclear., Materials and Methods: The acute phase of ulcerative colitis (UC) was induced using a 5 % dextran sulfate sodium (DSS) solution for 7 consecutive days and administrated with atorvastatin (10 mg/kg) from day 3 to day 7. mRNA-seq, histological pathology, and inflammatory response were determined. Intestinal microbiota alteration, tryptophan, and its metabolites were analyzed through 16S rRNA sequencing and untargeted metabolomics., Key Findings: Atorvastatin relieved the DSS-induced UC in mice, as evidenced by colon length, body weight, disease activity index score and pathological staining. Atorvastatin treatment reduced the level of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Atorvastatin also relieved the intestinal microbiota disorder caused by UC and decreased the proliferation of pernicious microbiota such as Akkermansia and Bacteroides. Atorvastatin dramatically altered tryptophan metabolism and increased the fecal contents of tryptophan, indolelactic acid (ILA), and indole-3-acetic acid (IAA). Furthermore, atorvastatin enhanced the expression level of aryl hydrocarbon receptor (AhR) and interleukin-22 (IL-22) and further promoted the expression level of intestinal tight junction proteins, such as ZO-1 and occludin, in colitis mice., Significance: These findings indicated that atorvastatin could alleviate UC by regulating intestinal flora disorders, promoting microbial tryptophan metabolism, and repairing the intestinal barrier., Competing Interests: Declaration of competing interest The all authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to explore the differential effects of varying doses of atorvastatin on antagonizing lipopolysaccharide (LPS)-induced endothelial inflammation based on heme oxygenase 1 (HO-1) expression., Method: Vascular endothelial inflammatory injury was induced in 40 Sprague-Dawley rats by intraperitoneal injection of LPS. These rats were randomly divided into control, low-dose atorvastatin, high-dose atorvastatin, and HO-1 blocking groups. Seven days after treatment, all rats were sacrificed, and heart-derived peripheral blood was collected to measure the serum concentrations of bilirubin, alanine aminotransferase (ALT), total cholesterol, malondialdehyde, endothelial cell protein C receptor, endothelin-1, von Willebrand factor, and soluble thrombomodulin. Meanwhile, the number of circulating endothelial cells was determined using flow cytometry. Vascular tissues from descending aorta of rats from each group were extracted to detect the expression level of HO-1., Results: After different doses of atorvastatin intervention, the above inflammatory indices were decreased, and HO-1 expression and ALT concentration were increased in the atorvastatin-treated group of rats compared with the control group. These changes were more pronounced in the high-dose statin group (P < 0.05). Conversely, no significant decrease in the above inflammatory indices and no significant increase in HO-1 expression were observed in rats in the blocking group (P > 0.05)., Conclusion: For LPS-induced vascular inflammation, high-dose atorvastatin exerts potent anti-inflammatory and vascular endothelial protection effects by inducing HO-1 expression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Luo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor 1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX 4 ), nuclear factor erythroid 2-related factor (NRF 2 ) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe 2+ accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF 2 , GPX 4 and FTH in HK 2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe 2+ accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK 2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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

Adjustment of the cellular metabolism of pro-inflammatory macrophages is essential for their bactericidal function; however, it underlies the development of many human diseases if induced chronically. Therefore, intervention of macrophage metabolic polarisation has been recognised as a potent strategy for their treatment. Although many small-molecule inhibitors affecting macrophage metabolism have been identified, their in vivo administration requires a tool for macrophage-specific delivery to limit their potential side effects. Here, we establish Drosophila melanogaster as a simple experimental model for in vivo testing of macrophage-specific delivery tools. We found that yeast-derived glucan particles (GPs) are suitable for macrophage-specific delivery of small-molecule inhibitors. Systemic administration of GPs loaded with atorvastatin, the inhibitor of hydroxy-methyl-glutaryl-CoA reductase (Hmgcr), leads to intervention of mevalonate pathway specifically in macrophages, without affecting HMGCR activity in other tissues. Using this tool, we demonstrate that mevalonate pathway is essential for macrophage pro-inflammatory polarisation and individual's survival of infection., (© 2024 The Authors. Insect Molecular Biology published by John Wiley & Sons Ltd on behalf of Royal Entomological Society.)

Intracerebral hemorrhage (ICH), for which there are currently no effective preventive or treatment methods, has a very high fatality rate. Statins, such as atorvastatin (ATV), are the first-line drugs for regulating blood lipids and treating hyperlipidemia-related cardiovascular diseases. However, ATV-associated ICH has been reported, although its incidence is rare. In this study, we aimed to investigate the protective action and mechanisms of berberine (BBR) against ATV-induced brain hemorrhage. We established an ICH model in zebrafish induced by ATV (2 μM) and demonstrated the effects of BBR (10, 50, and 100 μM) on ICH via protecting the vascular network using hemocyte staining and three transgenic zebrafish. BBR was found to reduce brain inflammation and locomotion injury in ICH-zebrafish. Mechanism research showed that ATV increased the levels of VE-cadherin and occludin proteins but disturbed their localization at the cell membrane by abnormal phosphorylation, which decreased the number of intercellular junctions between vascular endothelial cells (VECs), disrupting the integrity of vascular walls. BBR reversed the effects of ATV by promoting autophagic degradation of phosphorylated VE-cadherin and occludin in ATV-induced VECs examined by co-immunoprecipitation (co-IP). These findings provide crucial insights into understanding the BBR mechanisms involved in the maintenance of vascular integrity and in mitigating adverse reactions to ATV., (© 2024 John Wiley & Sons Ltd.)

Diabetes mellitus (DM) has substantial global implications and contributes to vascular inflammation and the onset of atherosclerotic cardiovascular diseases. However, translating the findings from animal models to humans has inherent limitations, necessitating a novel platform. Therefore, herein, an arterial model is established using a microphysiological system. This model successfully replicates the stratified characteristics of human arteries by integrating collagen, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs). Perfusion via a peristaltic pump shows dynamic characteristics distinct from those of static culture models. High glucose, advanced glycation end products (AGEs), and interleukin-1 beta are employed to stimulate diabetic conditions, resulting in notable cellular changes and different levels of cytokines and nitric oxide. Additionally, the interactions between the disease models and oxidized low-density lipoproteins (LDL) are examined. Finally, the potential therapeutic effects of metformin, atorvastatin, and diphenyleneiodonium are investigated. Metformin and diphenyleneiodonium mitigate high-glucose- and AGE-associated pathological changes, whereas atorvastatin affects only the morphology of ECs. Altogether, the arterial model represents a pivotal advancement, offering a robust and insightful platform for investigating cardiovascular diseases and their corresponding drug development., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background and Aims: Activation of vascular smooth muscle cell inflammation is recognised as an important early driver of vascular disease. We have previously identified the let-7 miRNA family as important regulators of inflammation in in vitro and in vivo models of atherosclerosis. Here we investigated a dual statin/let-7d-5p miRNA combination therapy approach to target human aortic SMC (HAoSMC) activation and inflammation., Methods: In vitro studies using primary HAoSMCs were performed to investigate the effects of let-7d-5p miRNA overexpression and inhibition. HAoSMCs were treated with combinations of the inflammatory cytokine tumor necrosis factor-α (TNF-α), and atorvastatin or lovastatin. HAoSMC Bulk RNA-seq transcriptomics of HAoSMCs revealed downstream regulatory networks modulated by let-7d-5p miRNA overexpression and statins. Proteome profiler cytokine array, Western blotting and quantitative PCR analyses were performed on HAoSMCs to validate key findings., Results: Let-7d-5p overexpression significantly attenuated TNF-α-induced upregulation of IL-6, ICAM1, VCAM1, CCL2, CD68, MYOCD gene expression in HAoSMCs (p<0.05). Statins (atorvastatin, lovastatin) significantly attenuated inflammatory gene expression and upregulated Let-7d levels in HAoSMCs (p<0.05). Bulk RNA-seq analysis of a dual Let-7d-5p overexpression/statin therapy in HAoSMCs revealed that let-7d-5p activation and statins converge on key inflammatory pathways (IL-6, IL-1β, TNF-α, IFN-γ). Let-7d-5p overexpression led to reduced expression of the ox-LDL receptor OLR1, and this was associated with lower ox-LDL uptake in HAoSMCs. In silico analysis of smooth muscle cell phenotypic switching shows that overexpression of let-7d-5p in HAoSMCs maintains a contractile phenotype., Conclusions: Targeting the Let-7 network alongside statins can modulate HAoSMC activation and attenuate key inflammatory pathway signals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sepsis is a systemic inflammatory response syndrome caused by the invasion of pathogenic microorganisms. Despite major advances in diagnosis and technology, morbidity and mortality remain high. The level of neutrophil extracellular traps (NETs) is closely associated with the progression and prognosis of sepsis, suggesting the regulation of NET formation as a new strategy in sepsis treatment. Owing to its pleiotropic effects, atorvastatin, a clinical lipid-lowering drug, affects various aspects of sepsis-related inflammation and immune responses. To align closely with clinical practice, we combined it with imipenem for the treatment of sepsis. In this study, we used a cecum ligation and puncture-induced lung injury mouse model and employed techniques including western blot, immunofluorescence, and enzyme-linked immunosorbent assay to measure the levels of NETs and other sepsis-related lung injury indicators. Our findings indicate that atorvastatin effectively inhibited the formation of NETs. When combined with imipenem, it significantly alleviated lung injury, reduced systemic inflammation, and improved the 7-day survival rate of septic mice. Additionally, we explored the inhibitory mechanism of atorvastatin on NET formation in vitro, revealing its potential action through the ERK/NOX2 pathway. Therefore, atorvastatin is a potential immunomodulatory agent that may offer new treatment strategies for patients with sepsis in clinical settings., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Breast cancer remains a significant health challenge with complex molecular mechanisms. While many studies have explored genetic markers in breast carcinogenesis, few have studied the potential impact of pharmacological interventions such as Atorvastatin on its genetic landscape. This study aimed to elucidate the molecular distinctions between normal and tumor-adjacent tissues in breast cancer and to investigate the potential protective role of atorvastatin, primarily known for its lipid-lowering effects, against breast cancer. Searching the Gene Expression Omnibus database identified two datasets, GSE9574 and GSE20437, comparing normal breast tissues with tumor-adjacent samples, which were merged, and one dataset, GSE63427, comparing paired pre- and post-treated patients with atorvastatin. Post-ComBat application showed merged datasets' consistency, revealing 116 DEGs between normal and tumor-adjacent tissues. Although initial GSE63427 data analysis suggested a minimal impact of atorvastatin, 105 DEGs post-treatment were discovered. Thirteen genes emerged as key players, both affected by Atorvastatin and dysregulated in tumor-adjacent tissues. Pathway analysis spotlighted the significance of these genes in processes like inflammation, oxidative stress, apoptosis, and cell cycle control. Moreover, there was a noticeable interaction between these genes and the immunological microenvironment in tumor-adjacent tissues, with Atorvastatin potentially altering the suppressive immune landscape to favor anti-tumor immunity. Survival analysis further highlighted the prognostic potential of the 13-gene panel, with 12 genes associated with improved survival outcomes. The 13-gene signature offers promising insights into breast cancer's molecular mechanisms and atorvastatin's potential therapeutic role. The preliminary findings advocate for an in-depth exploration of atorvastatin's impact on., (© 2024. The Author(s).)

Aim: The study explores the synergistic potential of atorvastatin (ATR) and quercetin (QUER)- loaded solid lipid nanoparticles (SLN) in combating breast cancer. Materials & methods: SLNs were synthesized using a high-shear homogenization method and optimized using Box-Behnken design. The SLNs were characterized and evaluated for their in vitro anticancer activity. Results: The optimized SLN exhibited narrow size distribution (PDI = 0.338 ± 0.034), a particle size of 72.5 ± 6.5 nm, higher entrapment efficiency (<90%), sustained release and spherical surface particles. The in vitro cytotoxicity studies showed a significant reduction in IC 50 values on MDA-MB-231 cell lines. Conclusion: We report a novel strategy of repurposing well-known drugs and encapsulating them into SLNs as a promising drug-delivery system against breast cancer.

Triple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer., Competing Interests: The authors declare that they have no competing interests., (© 2024 Gao et al.)

Atherosclerosis (AS), as the main pathophysiological basis of coronary heart disease, can develop into carotid atherosclerotic plaque (CAP) through intimal inflammation, necrosis, fibrosis and calcification. However, there are few reports on the clinical drug selection of CAP. The aim of this study was to explore the effects of atorvastatin and ezetimibe on CD147, HIF-1, MMP-2 and VEGF in CAP under the guidance of IVUS, so as to provide basis for CAP of the best drug. 32 male New Zealand rabbits were divided into the control group, the model group, the atorvastatin group and the ezetimibe group randomly. The levels of serum LDL-C and MMP-2 have a significant decrease in atorvastatin group and ezetimibe group (P <0.05). The level of serum CD147 has a significant decrease in ezetimibe group (P <0.05). The average OD value of HIF-1 in atorvastatin group decreased significantly (P <0.05). The relative expression of CD147 and VEGF decreased significantly in atorvastatin group (P <0.05). There were different degrees of fibrous plaque and lipid plaque in model group, atorvastatin group and ezetimibe group. There exists a significant decline of CD147, HIF-1, MMP-2 and VEGF by atorvastatin in plaque, but the effect of ezetimibe is not obvious.

Background: Obesity has become a prevalent issue worldwide, leading to various complications such as hyperlipidemia, diabetes, and cardiovascular problems. Statins, as FDA approved anti-hyperlipidemic drugs, still pose some concerns upon their administration. Recently, researchers have looked for natural products as an alternative to manage hyperlipidemia and obesity., Aim: This work aimed to study the hypolipidemic effect of Lepidium sativum garden cress (GC) from different preparations; orally administered seeds, and hydrogel, in comparison to atorvastatin., Methods: GC hydrogel was prepared from the GC aqueous extract and pharmaceutically evaluated for its pH, spreadability, seeds content, homogeneity, rheology, and in vitro release. The rat's body weight, blood glucose levels, total lipid profile, and liver biomarkers were evaluated on obese rats for one month. In addition, the histopathology study was also performed., Results: GC hydrogel had acceptable pharmaceutical properties and showed a sustained release performance over 24 h. Oral and topical GC significantly reduced the lipid profiles, blood sugar and ALT, AST levels more than the negative control group and comparable to atorvastatin. It was found that oral GC showed a significant effect on the percentage decrease in the rat's body weight than the applied hydrogel. Histopathology study revealed a better outcome in the histological structure of pancreas and liver compared with rats feed on high fat diet post-treatment for one month., Conclusion: GC orally administered, or topically applied hydrogel could be a promising, safe alternative formulation to atorvastatin in managing hyperlipidemia and normalizing body weight of obese rats.

Free radicals and reactive oxygen species initiate when the oxidative stress arises. (1) Background: The effect of natural molecules on oxidative stress in hyperlipidemic rats, taking statins, was observed. (2) Methods: One hundred and twelve white Wistar rats, males and females, were divided into seven: Group I received 20 mg of atorvastatin while groups II and III received a combination of 20 mg of atorvastatin and 100 mg of Sea buckthorn and grape extract. Groups IV and V received 100 mg of Sea buckthorn and grape extract, while groups VI and VII received only high-fat diet (HFD) and normal rodents' fodder. After two and six months, rats were euthanized, and blood was gathered to measure the main paraclinical values and total antioxidant capacity (TAC). Also, the liver and kidney were stored for the organs' cytoarchitecture. For statistics, two-way analysis of variance (ANOVA), was performed. (3) Results: HFD produced hyperlipidemia, accompanied by augmented serum and hepatic oxidative stress markers, in addition to a reduction in antioxidant enzyme activities and glutathione levels. Polyphenolic substances proven efficient against HFD caused oxidative stress. (4) Conclusions: Atorvastatin heightened the histological injuries caused by the fatty diet, but these were diminished by taking atorvastatin in combination with 100 mg/kg of plant extracts.

Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE - / - mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG ( p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG ( p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG ( p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE - / - mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

Purpose: Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT., Patients and Methods: Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine-nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF., Results: Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05)., Conclusions: Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial., (©2024 American Association for Cancer Research.)

Background/aim: Pancreatic cancer is an aggressive type of cancer, with a dismally low survival rate of <5%. FDA-approved drugs like gemcitabine have shown little therapeutic success, prolonging survival by a mere six months. Isoflavones, such as biochanin A and daidzein, are known to exhibit anti-cancer activity, whereas statins reportedly have anti-proliferative effects. This study investigated the effects of combination treatment of biochanin A and atorvastatin on pancreatic cancer cells., Materials and Methods: Pancreatic cancer cells AsPC-1, PANC-1, and MIA PaCa-2 were procured from ATCC. The cell viability studies were carried out using MTT & cell count assays. Flow cytometry was used to study cell apoptosis whereas cell metabolism studies were carried out using the Seahorse Mito stress test and XF-PMP assay. The effects of treatment on cell signaling pathways & cell cycle associated proteins were investigated using western blot whereas invasiveness of cancer cells was evaluated using gelatin zymography., Results: The combination treatment decreased the survival and enhanced pro-apoptotic responses compared to single treatments in the pancreatic cancer cells. In PANC-1 cells, the combination treatment decreased invasiveness, reduced expression of activated STAT3 and expression of critical mediators of cell cycle progression. Furthermore, the combination treatment induced a differential inhibition of respiratory complexes in the pancreatic cancer cells., Conclusion: The combination treatment of biochanin A and atorvastatin exerts enhanced anti-cancer effects, inducing apoptosis, down-regulating cell cycle associated proteins and invasiveness in pancreatic cancer cells and merits further investigation for new, improved treatments for pancreatic cancer., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Due to the limited success in the treatment of lung adenocarcinomas, new treatment protocols are urgently needed to increase the curability rate and the survival of lung cancer patients., Objectives: Although statins, like atorvastatin (Ator), and metformin (Met) are widely accepted as hypolipidemic and hypoglycemic drugs, respectively, there are many predictions about their enhancing antitumor effect when they are combined with traditional chemotherapeutics., Methods: The individual and combined antiproliferative potential of Ator and Met was tested by MTT-assay in non-small cell lung cancer (NSCLC) A549 cell line, compared to the corresponding effect of Gemcitabine (Gem) with implication on the mechanisms of action., Results: Initially, both drugs demonstrated concentration-dependent cytotoxicity in A549 cells. Also, their combination index (CI) indicated their synergistic effect at equi-IC50 concentration (CI = 0.00984). Moreover, Ator and/or Met-treated cells revealed disrupted patterns of SOD, CAT, GSH, MDA, and TAC, developed apoptosis, and larger fractions of the cell population were arrested in G0/G1 phase, particularly in cells dually-treated both Ator and Met. These observations were accompanied by downregulation in the expression of iNOS, HO-1, and the angiogenic marker VEGF, meanwhile, an altered expression of MAPK and AMPK was observed., Conclusion: Conclusively, these data suggest that repurposing of Ator and Met demonstrates their individual and combined antiproliferative effect in non-small cell lung cancer and they may adopt a similar mechanism of action., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

The level of cytokine expression was measured in human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells exposed to 500 ng/ml alkylating mutagen mitomycin C (MMC) and 5 μM atorvastatin. It was found that treatment of MMC-exposed HCAEC with atorvastatin decreased secretion of macrophage migration inhibitory factor (MIF), IL-8, and IL8 gene expression, but increased the expression of SERPINE1 gene encoding the PAI-1 protein. In atorvastatin-treated HITAEC, the concentration of MIF protein and the expression of the IL8 and SERPINE1 genes were reduced. We can conclude that atorvastatin prevents proinflammatory activation of endothelial cells cultured under conditions of genotoxic load. However, the molecular mechanisms of this effect require further research., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

It has been reported that lipophilic statins such as atorvastatin can more readily penetrate into β-cells and reach the mitochondria, resulting in mitochondrial dysfunction, oxidative stress, decrease in insulin release. Many studies have shown that natural products can protect mitochondrial dysfunction induced by drug in different tissue. We aimed to explore mitochondrial protection potency of hesperidin, vanillic acid, and sinapic acid as natural compounds against mitochondrial dysfunction induced by atorvastatin in pancreas isolated mitochondria. Mitochondria were isolated form rat pancreas and directly treated with toxic concentration of atorvastatin (500 µM) in presence of various concentrations hesperidin, vanillic acid, and sinapic acid (1, 10, and 100 µM) separately. Mitochondrial toxicity parameters such as the reactive oxygen species (ROS) formation, succinate dehydrogenases (SDH) activity, mitochondrial swelling, depletion of glutathione (GSH), mitochondrial membrane potential (MMP) collapse, and malondialdehyde (MDA) production were measured. Our findings demonstrated that atorvastatin directly induced mitochondrial toxicity at concentration of 500 μM and higher in pancreatic mitochondria. Except MDA, atorvastatin caused significantly reduction in SDH activity, mitochondrial swelling, ROS formation, depletion of GSH, and collapse of MMP. While, our data showed that all three protective compounds at low concentrations ameliorated atorvastatin-induced mitochondrial dysfunction with the increase of SDH activity, improvement of mitochondrial swelling, MMP collapse and mitochondrial GSH, and reduction of ROS formation. We can conclude that hesperidin, vanillic acid, and sinapic acid can directly reverse the toxic of atorvastatin in rat pancreas isolated mitochondria, which may be beneficial for protection against diabetogenic-induced mitochondrial dysfunction in pancreatic β-cells., (© 2024 Wiley Periodicals LLC.)

Inflammatory reaction plays a key role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonates. Microglia are resident innate immune cells in the central nervous system and are profoundly involved in neuroinflammation. Studies have revealed that atorvastatin exerts a neuroprotective effect by regulating neuroinflammation in adult animal models of brain stroke and traumatic brain injury, but its role regarding damage to the developing brain remains unclear. This study aimed to clarify the effect and mechanism of atorvastatin on the regulation of microglia function in neonatal hypoxic-ischemic brain damage (HIBD). The oxygen glucose deprivation (OGD) of microglia and neonatal rat HIBD model was established. Atorvastatin, recombinant sclerostin protein (SOST), and XAV939 (degradation of β-catenin) were administered to OGD microglia and HIBD rats. The pathological changes of brain tissue, cerebral infarction volume, learning and memory ability of rats, pro-inflammatory (CD16 + /Iba1 + ) and anti-inflammatory (CD206 + /Iba1 + ) microglia markers, inflammation-related indicators (Inos, Tnfα, Il6, Arg1, Tgfb, and Mrc1), and Wnt/β-catenin signaling molecules were examined. Atorvastatin reduced OGD-induced pro-inflammatory microglia and pro-inflammatory factors, while increasing anti-inflammatory microglia and anti-inflammatory factors. In vivo, atorvastatin attenuated hypoxia-ischemia (HI)-induced neuroinflammation and brain damage. Mechanistically, atorvastatin decreased SOST expression and activated the Wnt/β-catenin signaling pathway, and the administration of recombinant SOST protein or XAV939 inhibited Wnt/β-catenin signaling and attenuated the anti-inflammatory effect of atorvastatin. Atorvastatin promotes the pro/anti-inflammatory phenotypic transformation of microglia via the Wnt/β-catenin pathway in HI neonatal rats. Atorvastatin may be developed as a potent agent for the treatment of HIE in neonates., (© 2023. The Author(s).)

Proliferative vitreoretinopathy (PVR) develops after an unsuccessful or complicated recovery from rhegmatogenous retinal detachment (RRD) surgery. Intraocular scar formation with the contribution of epithelial-mesenchymal transition (EMT) in RPE cells is prominent in the pathology of PVR. In the present study, the EMT process was experimentally induced in human retinal pigment epithelium (RPE; ARPE-19) cells, and the effect of atorvastatin on the process was studied. The mRNA and protein levels of mesenchymal markers actin alpha 2 (ACTA2) / alpha-smooth muscle actin (α-SMA) and fibronectin (FN), and epithelial markers occludin (OCLN) and zonula occludens-1 (ZO-1) were measured using quantitative real-time PCR (qRT-PCR) and western blot methods, respectively. In addition, α-SMA and FN were visualized using immunofluorescence staining. Cells were photographed under a phase contrast light microscope. Changes in the functionality of cells following the EMT process were studied using the IncuCyte scratch wound cell migration assay and the collagen cell invasion assay with confocal microscopy. The induction of EMT in ARPE-19 cells increased the expression of mesenchymal markers ACTA2/α-SMA and fibronectin and reduced the expression of epithelial marker OCLN both at mRNA and protein levels. The mRNA levels of ZO-1 were lower after EMT, as well. Increased levels of α-SMA and FN were confirmed by immunofluorescence staining. Atorvastatin further increased the mRNA levels of mesenchymal markers ACTA2 and FN as well as the protein levels of α-SMA and reduced the mRNA levels of epithelial markers OCLN and ZO-1 under the EMT process. EMT promoted wound closure and cell invasion into the 3D collagen matrix when compared to untreated control cells. These data present cellular changes upon the induction of the EMT process in ARPE-19 cells and the propensity of atorvastatin to complement the effect. More studies are needed to confirm the exact influence of the EMT process and atorvastatin treatment on the PVR development after RRD surgery., (© 2024. The Author(s).)

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg -1 ·d -1 ) and fenofibrate (100 mg·kg -1 ·d -1 ). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity., Methods: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-β1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed., Results: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-β1, IL-1β, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-β1 over-expressed transgenic mice with normal diet., Conclusions: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity., (© 2024. The Author(s).)

Background: Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in addition to the beneficial lipid-lowering effect, statins also exhibit a number of pleiotropic effects that may find application in other diseases, including osteoporosis. This study aimed to assess the effect of statins on bone turnover, as measured by the concentration of bone turnover markers, and to compare the effect of atorvastatin as a lipophilic statin and rosuvastatin as a hydrophilic statin., Methods: This study included 34 postmenopausal women aged < 65 years with newly diagnosed dyslipidemia requiring statin therapy. Patients were randomly assigned to receive a statin drug. Statins were initiated at standard doses of 5 to 10 mg of rosuvastatin and 20 mg of atorvastatin. The levels of C-terminal telopeptide of type I collagen as a bone resorption marker and N-terminal propeptide of procollagen type I as a marker of bone formation, lipid concentrations and other biochemical parameters were assessed at baseline and after 6 and twelve months of treatment., Results: There were no statistically significant differences between the levels of bone turnover markers before and 6 months after statin implementation (P > .05) - for all patients or subgroups according to statin use. Analysis of the results showed that after 12 months, there was a statistically significant decrease in N-terminal propeptide of procollagen type I concentration in all subjects (P = .004). By statin subgroup, a statistically significant decrease in N-terminal propeptide of procollagen type I was observed only in patients receiving rosuvastatin (P = .012) and not in those receiving atorvastatin (P = .25). Moreover, changes in bone turnover markers did not correlate with changes in lipid concentrations., Conclusions: These results may indicate the superiority of atorvastatin over rosuvastatin in inhibiting adverse changes in bone turnover in postmenopausal women. Confirmed by studies involving a larger population, the observed differences might find particular applications in clinical practice, and the choice of atorvastatin over rosuvastatin for women could be considered in the early postmenopausal period to reduce the risk of osteoporosis and subsequent osteoporotic fractures., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

In environmental risk assessment of substances, the 14-day growth inhibition test following OECD test guideline 239 is employed to assess toxicity in the macrophyte Myriophyllum spicatum. Currently, this test evaluates physiological parameters and does not allow the identification of the mode of action (MoA) by which adverse effects are induced. However, for an improved ecotoxicity assessment of substances, knowledge about their ecotoxic MoA in non-target organisms is required. It has previously been suggested that the identification of gene expression changes can contribute to MoA identification. Therefore, we developed a shortened three-day assay for M. spicatum including the transcriptomic assessment of global gene expression changes and applied this assay to two model substances, the herbicide and photosynthesis inhibitor bentazone and the pharmaceutical and HMG-CoA reductase inhibitor atorvastatin. Due to the lack of a reference genome for M. spicatum we performed a de novo transcriptome assembly followed by a functional annotation to use the toxicogenomic results for MoA discrimination. The gene expression changes induced by low effect concentrations of these substances were used to identify differentially expressed genes (DEGs) and impaired biological functions for the respective MoA. We observed both concentration-dependent numbers and differentiated patterns of DEGs for both substances. While bentazone impaired genes involved in the response to reactive oxygen species as well as light response, and also genes involved in developmental processes, atorvastatin exposure led to a differential regulation of genes related to brassinosteroid response as well as potential metabolic shifts between the mevalonate and methyl erythritol 4-phosphate pathway. Based on these responses, we identified biomarker candidates for the assessment of MoA in M. spicatum. Utilizing the shortened assay developed in this study, the investigation of the identified biomarker candidates may contribute to the development of future MoA-specific screening approaches in the ecotoxicological hazard prediction using aquatic non-standard model organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ischemia stroke is one of the leading causes of death and disability worldwide. Owing to the limited delivery efficiency to the brain caused by the blood-brain barrier (BBB) and off-target effects of systemic treatment, it is crucial to develop an in situ drug delivery system to improve the therapeutic effect in ischemic stroke. Briefly, we report a multifunctional in situ hydrogel delivery system for the co-delivery of reactive oxygen species (ROS)-responsive nanoparticles loaded with atorvastatin calcium (DSPE-se-se-PEG@AC NPs) and β-nerve growth factor (NGF), which is expected to remodel pathological microenvironment for improving cerebral ischemia injury. The in vitro results exhibited the multifunctional hydrogel scavenged oxygen-glucose deprivation (OGD)-induced free radical, rescued the mitochondrial function, and maintained the survival and function of neurons, hence reducing neuronal apoptosis and neuroinflammation, consequently relieving ischemia injury in hippocampal neurons cell line (HT22). In the rat ischemia stroke model, the hydrogel significantly minified cerebral infarction by regulating inflammatory response, saving apoptotic neurons, and promoting angiogenesis and neurogenesis. Besides, the hydrogel distinctly improved the rats' neurological deficits after cerebral ischemia injury over the long-term observation. In conclusion, the in-situ hydrogel platform has demonstrated promising therapeutic effects in both in vitro and in vivo studies, indicating its potential as a new and effective therapy., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Diabetic nephropathy is a type of kidney disorder that develops as a complication of multifactorial diabetes. Diabetic nephropathy is characterized by microangiopathy, resulting from glucose metabolism, oxidative stress, and changes in renal hemodynamics. This study strived to evaluate the in vitro cytoprotective activity of atorvastatin (ATR), and quercetin (QCT) alone and in combination against diabetic nephropathy., Methods: The MTT assay was utilized to analyze the effects of the test compounds on NRK-52E rat kidney epithelial cells. The detection of apoptosis and ability to scavenge free radicals was assessed via acridine orange-ethidium bromide (AO-EB) dual fluorescence staining, and 2,2-diphenyl-1-picrylhydrazyfree assay (DPPH), respectively. The ability of anti-inflammatory effect of the test compounds and western blot analysis against TGF-β, TNF-α, and IL-6 further assessed to determine the combinatorial efficacy., Results: Atorvastatin and quercetin treatment significantly lowered the expression of TGF-β, TNF-α, and IL-6 indicating the protective role in Streptozotocin-induced nephrotoxicity. The kidney cells treated with a combination of atorvastatin and quercetin showed green fluorescing nuclei in the AO-EB staining assay, indicating that the combination treatment restored cell viability. Quercetin, both alone and in combination with atorvastatin, demonstrated strong DPPH free radical scavenging activity and further encountered an anti-oxidant and anti-inflammatory effect on the combination of these drugs., Conclusion: Nevertheless, there is currently no existing literature that reports on the role of QCT as a combination renoprotective drug with statins in the context of diabetic nephropathy. Hence, these findings suggest that atorvastatin and quercetin may have clinical potential in treating diabetic nephropathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis. We designed and tested a treatment protocol to minimize atorvastatin- and acetaminophen-induced hepatotoxicity. Last, we documented circadian-dependent induction of pro-inflammatory cytokines when triggered by LPS, IFN-β, or Plasmodium infection in human hepatocytes. Collectively, our findings emphasize that the phase of the circadian cycle has a robust impact on the efficacy and toxicity of drugs, and we provide a test bed to study the timing and magnitude of inflammatory responses over the course of infection in human liver.

Atorvastatin (ATO), as a cholesterol-lowering drug, was the world's best-selling drug in the early 2000s. However, ATO overdose-induced liver or muscle injury is a threat to many patients, which restricts its application. Previous studies suggest that ATO overdose is accompanied with ROS accumulation and increased lipid peroxidation, which are the leading causes of ATO-induced liver damage. This study is, therefore, carried out to investigate the roles of anti-oxidant pathways and enzymes in protection against ATO-induced hepatotoxicity. Here we show that in ATO-challenged HepG2 cells, the expression levels of transcription factor NFE2L2/Nrf2 (nuclear factor erythroid 2 p45-related factor 2) are significantly upregulated. When Nrf2 is pharmacologically inhibited or genetically inactivated, ATO-induced cytotoxicity is significantly aggravated. Aldo-keto reductase-7A (AKR7A) enzymes, transcriptionally regulated by Nrf2, are important for bioactivation and biodetoxification. Here, we reveal that in response to ATO exposure, mRNA levels of human AKR7A2 are significantly upregulated in HepG2 cells. Furthermore, knockdown of AKR7A2 exacerbates ATO-induced hepatotoxicity, suggesting that AKR7A2 is essential for cellular adaptive response to ATO-induced cell damage. In addition, overexpression of AKR7A2 in HepG2 cells can significantly mitigate ATO-induced cytotoxicity and this process is Nrf2-dependent. Taken together, these findings indicate that Nrf2-mediated AKR7A2 is responsive to high concentrations of ATO and contributes to protection against ATO-induced hepatotoxicity, making it a good candidate for mitigating ATO-induced side effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dan Li reports financial support was provided by National Natural Science Foundation of China., (Copyright © 2024. Published by Elsevier B.V.)