Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation.

BACKGROUND: Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown. METHODS: We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery. RESULTS: We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis. CONCLUSIONS: Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG.

Effect of Daridorexant on the Pharmacokinetics of P-Glycoprotein Substrate Dabigatran Etexilate and Breast Cancer Resistance Protein Substrate Rosuvastatin in Healthy Subjects.

BACKGROUND AND OBJECTIVE: The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively. METHODS: This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2. RESULTS: Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated. CONCLUSIONS: A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected. CLINICAL TRIAL REGISTRATION: NCT05480475; date of registration: 29 July, 2022.

Rosuvastatin Improves Endothelial Dysfunction in Diabetes by Normalizing Endoplasmic Reticulum Stress via Calpain-1 Inhibition.

BACKGROUND: Rosuvastatin contributes to the improvement of vascular complications in diabetes, but the protective mechanisms remain unclear. The aim of the present study was to investigate the effect and mechanism of rosuvastatin on endothelial dysfunction induced by diabetes. METHODS: Calpain-1 knockout (Capn1 EK684-/-) and C57BL/6 mice were intraperitoneally injected with STZ to induce type 1 diabetes. Human umbilical vein endothelial cells (HUVECs) were incubated with high glucose in this study. The function of isolated vascular rings, apoptosis, and endoplasmic reticulum stress (ERS) indicators were measured in this experiment. RESULTS: The results showed that rosuvastatin (5 mg/kg/d) and calpain-1 knockout improved impaired vasodilation in an endothelial-dependent manner, and this effect was abolished by an ERS inducer. Rosuvastatin administration inhibited calpain-1 activation and ERS induced by high glucose, as well as apoptosis and oxidative stress both in vivo and in vitro. In addition, an ERS inducer (tunicamycin) offset the beneficial effect of rosuvastatin on endothelial dysfunction and ERS, which was accompanied by increased calpain-1 expression. The ERS inhibitor showed a similar improvement in endothelial dysfunction with rosuvastatin but could not increase the improvement in endothelial function of rosuvastatin. CONCLUSION: These results suggested that rosuvastatin improves endothelial dysfunction by suppressing calpain- 1 and normalizing ERS, subsequently decreasing apoptosis and oxidative stress.

Exploring synergy between azole antifungal drugs and statins for Candida auris.

BACKGROUND: Global emergence of rapidly developing resistance to multiple antifungal drugs and high mortality pose challenges to the treatment of invasive Candida auris infections. New therapeutic approaches are needed, such as repurposing drugs including combination with antifungals. Statins have been reported to exert antifungal effects against various Candida species. OBJECTIVES: Our study investigated potential synergy between the statins (rosuvastatin and fluvastatin) and azoles (voriconazole, posaconazole and isavuconazole) on clinical isolates of C. auris. METHODS: Twenty-one clinical isolates of C. auris were obtained. Chequerboard assays based on the CLSI broth microdilution method were used to assess synergy based on FIC index (FICI) calculations of MICs of individual drugs and in combinations. RESULTS: Single drug geometric mean (GM) MICs of fluvastatin and rosuvastatin were ≥128 mg/L in all 21 isolates. GM (range) MICs of posaconazole, voriconazole and isavuconazole were 0.259 (0.016-1 mg/L), 0.469 (0.016-2 mg/L) and 0.085 (0.004-1 mg/L), respectively. Combination of azoles with fluvastatin showed synergy in 70%-90% of C. auris isolates. In particular, voriconazole/fluvastatin resulted in 16-fold reduction in voriconazole MIC and synergy in 14/21 (67%) isolates. Posaconazole/fluvastatin resulted in 8-fold reduction in posaconazole MIC and synergy in 19/21 (90%) isolates.Combining rosuvastatin with the azoles also showed synergy against C. auris in 40%-60% of the isolates and additive effect in 40%-50%. None of the combinations was antagonistic. CONCLUSIONS: Our results provide a rationale for pursuing in vivo synergy tests as well as clinical studies to explore tolerability, treatment outcomes, optimal dose and exposure targets.

Effect of sequential release of sirolimus and rosuvastatin using silk fibroin microneedle to prevent intimal hyperplasia.

Intimal hyperplasia (IH) is a major cause of vascular restenosis after bypass surgery, which progresses as a series of processes from the acute to chronic stage in response to endothelial damage during bypass grafting. A strategic localized drug delivery system that reflects the pathophysiology of IH and minimizes systemic side effects is necessary. In this study, the sequential release of sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, and statin, an HMG-COA inhibitor, was realized as a silk fibroin-based microneedle device in vivo. The released sirolimus in the acute stage reduced neointima (NI) and vascular fibrosis through mTOR inhibition. Furthermore, rosuvastatin, which was continuously released from the acute to chronic stage, reduced vascular stiffness and apoptosis through the inactivation of Yes-associated protein (YAP). The sequential release of sirolimus and rosuvastatin confirmed the synergistic treatment effects on vascular inflammation, VSMC proliferation, and ECM degradation remodeling through the inhibition of transforming growth factor (TGF)-beta/NF-κB pathway. These results demonstrate the therapeutic effect on preventing restenosis with sufficient vascular elasticity and significantly reduced IH in response to endothelial damage. Therefore, this study suggests a promising strategy for treating coronary artery disease through localized drug delivery of customized drug combinations.

Utilization of response surface design for development and optimization of rosuvastatin calcium-loaded nano-squarticles for hair growth stimulating VEGF and IGF production: in-vitro and in-vivo evaluation.

INTRODUCTION: Countless individuals experience negative emotions as hair loss pattern affects their self-esteem and well-being. Rosuvastatin calcium (Ca-RUV) was reported to stimulate the growth of the hair in the applied area, hence, it was selected as a potential hair loss treatment drug. SIGNIFICANCE: This study aims to develop and optimize (Ca-RUV) loaded squarticles (SQRs) and assess their ability to deliver and release Ca-RUV in the hair follicle for the promotion of hair growth. METHODS: A response surface design was utilized to study the effect of varying Pluronic® F68 (PF68) and the percentage of liquid lipids within the core of the SQRs and the effects of particle size, entrapment efficiency, and drug released percentage after 24 h (%Q24) were assessed. The optimized formula was subjected to DSC, XRD, and in-vivo evaluation in rats. RESULTS: SQRs stabilized by 0.8% PF68 and contained 37.5% liquid lipids showed an acceptable particle size (250 nm), drug entrapment efficiency (75%), and %Q24 (100%). The in-vivo studies illustrated the ability of the formula to regrow hair in animals after 10 days due to the elevation of the vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) to their normal values and by 9% and 54%, respectively, relative to standard therapy minoxidil (5%). CONCLUSION: Thus, it can be concluded that the optimized formula of Ca-RUV loaded SQRs showed superior in-vivo results in the promotion of hair growth in a shorter period relative to the marketed product. Therefore, the formula can offer a viable option for the treatment of hair loss.

Rosuvastatin and Simvastatin potentiate antihypertensive effect of amlodipine through vasorelaxation phenomenon.

This study is carried out to assess the effects of rosuvastatin and simvastatin on blood vessels for possible vasorelaxant effect. The study is also translating the possible vasorelaxant effect in Wistar rats for a subsequent fall in systolic blood pressure. It is evident from the EC50, that rosuvastatin is more effective on relaxing N.E induced contractions, while simvastatin is more effective on relaxing KCL induced contractions. Simvastatin is equipotent when compared to effects of amlodipine on KCl induced contractions in denuded aortae. Simvastatin produced significant right shift in test concentration 1.1× 10-6M with its respective EC50 -1.85logCa++M as compared to its respective control EC50 -3logCa++M. Rosuvastatin also produced significant right shift in the EC50. In conclusion, it is stated that rosuvastatin and simvastatin relax the aortic strips preparations through inhibition of voltage gated calcium channels and inhibition of N.E induced contractions. Rosuvastatin and simvastatin have additive effects when used in the presence of a standard vaso-relaxant drug like amlodipine, which further confirms its additive effect on decreasing the systolic blood pressure of hypertensive rats (P<0.05).

Rosuvastatin enhances alterations caused by Toxoplasma gondii in the duodenum of mice.

Infection by Toxoplasma gondii may compromise the intestinal histoarchitecture through the tissue reaction triggered by the parasite. Thus, this study evaluated whether treatment with rosuvastatin modifies duodenal changes caused by the chronic infection induced by cysts of T. gondii. For this, female Swiss mice were distributed into infected and treated group (ITG), infected group (IG), group treated with 40 mg/kg rosuvastatin (TG) and control group (CG). After 72 days of infection, the animals were euthanized, the duodenum was collected and processed for histopathological analysis. We observed an increase in immune cell infiltration in the IG, TG and ITG groups, with injury to the Brunner glands. The infection led to a reduction in collagen fibers and mast cells. Infected and treated animals showed an increase in collagen fibers, acidic mucin-producing goblet cells, intraepithelial lymphocytes and mast cells, in addition to the reduction of muscle, neutral mucin-producing and Paneth cells. While treatment with rosuvastatin alone led to increased muscle layer, proportion of neutral mucin-producing goblet cells, Paneth cells, and reduction of collagen fibers. These findings indicate that the infection and treatment caused changes in the homeostasis of the intestinal wall and treatment with rosuvastatin potentiated most parameters indicative of inflammation.

Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity.

PURPOSE: Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. METHODS: In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. RESULTS: In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. CONCLUSION: Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.

Some pleiotropic effects of statins on hepatocellular carcinoma cells: Comparative study on atorvastatin, rosuvastatin and simvastatin.

PURPOSE: For many years, statins have been the most commonly used drugs in cholesterol-lowering therapy. In addition to these therapeutic effects, statins exhibit other, pleiotropic effects that can be beneficial, but also harmful to cells and tissues. The aim of this research was to determine and compare the pleiotropic effects of structurally different statins: atorvastatin, simvastatin and rosuvastatin at different concentrations on hepatocellular carcinoma (HepG2) cells. MATERIALS AND METHODS: The MTT assay was used to determine the cytotoxic effects of statins. The influence of statins on the production of reactive oxygen species (ROS) was determined by measuring fluorescent response of 2,7-dichlorofluorescein diacetate (DCFH-DA). The effect of statins on glucose production and excretion was determined with glucose production assay. RESULTS: The obtained results confirmed that all tested statins exhibit cytotoxic effects, increase the production of ROS as well as the production and excretion of glucose from HepG2 cells. It was observed that all the mentioned effects are more pronounced with lipophilic statins, atorvastatin and simvastatin compared to hydrophilic rosuvastatin. CONCLUSION: The less pronounced pleiotropic effects of rosuvastatin on HepG2 cells are probably due to differences in structure and solubility compared to atorvastatin and simvastatin. Transporter-dependent and a slower influx of rosuvastatin into cells compared to the tested lipophilic statins probably lead to a weaker accumulation of rosuvastatin in HepG2 cells, which results in less pronounced pleiotropic effects compared to lipophilic atorvastatin and simvastatin.

Atorvastatin Exerts More Selective Inhibitory Effects on hMCT2 than on hMCT1 and hMCT4.

BACKGROUND/AIM: Human monocarboxylate transporter 1 (hMCT1), hMCT2, and hMCT4 transport monocarboxylates, such as L-lactate and pyruvate, with pH dependency. They are often over-expressed in various cancer cells and mediate the energy balance and pH homeostasis. Therefore, hMCT inhibitors can potentially be used as anticancer drugs. However, isoform-selective inhibitors have not yet been well-characterized. In addition, several statins and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors have been reported to inhibit hMCTs, but their selectivity has not yet been evaluated. In this study, we aimed to determine whether statins could inhibit hMCT1, hMCT2, and hMCT4. MATERIALS AND METHODS: We expressed hMCT1, hMCT2, and hMCT4 in a heterologous expression system of Xenopus oocytes and performed inhibitory experiments with various statins (fluvastatin, atorvastatin, simvastatin, rosuvastatin, pravastatin, and pitavastatin). As the three-dimensional structure of hMCT2 has been recently reported, docking simulations of statins and their structures were also performed to estimate the inhibition site. RESULTS: All statins inhibited the transport activities of hMCT1, hMCT2, and hMCT4. In addition, atorvastatin was found to be a potent isoform-selective inhibitor of hMCT2. Docking simulation indicated that atorvastatin could interact with a site surrounded by transmembrane (TM)-2, TM11, and intracellular helix in the TM6/7loop. Therefore, targeting this site may lead to the discovery of more potent hMCT2-selective inhibitors. CONCLUSION: Atorvastatin exerts selective inhibitory effects on hMCT2. These findings provide insights into the inhibitory mechanism of statins against hMCT1, hMCT2, and hMCT4 and may aid in the development of novel anticancer agents.

The Effect of Statins on Male Reproductive Parameters: A Mechanism Involving Dysregulation of Gonadal Hormone Receptors and TRPV1.

Statins have been shown to cause diverse male reproductive function impairment, and in some cases, orchialgia. Therefore, the current study investigated the possible mechanisms through which statins may alter male reproductive parameters. Thirty adult male Wistar rats (200-250 g) were divided into three groups. The animals were orally administered rosuvastatin (50 mg/kg), simvastatin (50 mg/kg), or 0.5% carboxy methyl cellulose (control), for a 30-day period. Spermatozoa were retrieved from the caudal epididymis for sperm analysis. The testis was used for all biochemical assays and immunofluorescent localization of biomarkers of interest. Rosuvastatin-treated animals presented with a significant decrease in sperm concentration when compared to both the control and simvastatin groups (p < 0.005). While no significant difference was observed between the simvastatin and the control group. The Sertoli cells, Leydig cells and whole testicular tissue homogenate expressed transcripts of solute carrier organic anion transporters (SLCO1B1 and SLCO1B3). There was a significant decrease in the testicular protein expression of the luteinizing hormone receptor, follicle stimulating hormone receptor, and transient receptor potential vanilloid 1 in the rosuvastatin and simvastatin-treated animals compared to the control. The expression of SLCO1B1, SLCO1B2, and SLCO1B3 in the different spermatogenic cells portray that un-bio transformed statin can be transported into the testicular microenvironment, which can subsequently alter the regulation of the gonadal hormone receptors, dysregulate pain-inflammatory biomarkers, and consequently impair sperm concentration.

MYD88 and Proinflammatory Chemokines in Aortic Atheromatosis: Exploring Novel Statin Effects.

Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate proatherogenic inflammation. 48 male New Zealand rabbits were divided into eight groups, each including 6 animals. The control groups received normal chow for 90 and 120 days. Three groups underwent a hypercholesterolemic diet (HCD) for 30, 60, and 90 days. Another three groups underwent HCD for 3 months, followed by normal chow for one month, with or without rosuvastatin or fluvastatin. The cytokine and chemokine expressions were assessed in the samples of thoracic and abdominal aorta. Rosuvastatin significantly reduced MYD88, CCL4, CCL20, CCR2, TNF-α, IFN-ß, IL-1b, IL-2, IL-4, IL-8, and IL-10, both in the thoracic and abdominal aorta. Fluvastatin also downregulated MYD88, CCR2, IFN-ß, IFN-γ, IL-1b, IL-2, IL-4, and IL-10 in both aortic segments. Rosuvastatin curtailed the expression of CCL4, IFN-ß, IL-2, IL-4, and IL-10 more effectively than fluvastatin in both types of tissue. MYD88, TNF-α, IL-1b, and IL-8 showed a stronger downregulation with rosuvastatin compared to fluvastatin only in the thoracic aorta. The CCL20 and CCR2 levels reduced more extensively with rosuvastatin treatment only in abdominal aortic tissue. In conclusion, statin therapy can halt proatherogenic inflammation in hyperlipidemic animals. Rosuvastatin may be more effective in downregulating MYD88 in atherosclerotic thoracic aortas.

Rosuvastatin suppresses TNF-α-induced matrix catabolism, pyroptosis and senescence via the HMGB1/NF-κB signaling pathway in nucleus pulposus cells.

Intervertebral disc degeneration is mainly caused by irregular matrix metabolism in nucleus pulposus cells and involves inflammatory factors such as TNF-α. Rosuvastatin, which is widely used in the clinic to reduce cholesterol levels, exerts anti-inflammatory effects, but whether rosuvastatin participates in IDD remains unclear. The current study aims to investigate the regulatory effect of rosuvastatin on IDD and the potential mechanism. In vitro experiments demonstrate that rosuvastatin promotes matrix anabolism and suppresses catabolism in response to TNF-α stimulation. In addition, rosuvastatin inhibits cell pyroptosis and senescence induced by TNF-α. These results demonstrate the therapeutic effect of rosuvastatin on IDD. We further find that HMGB1, a gene closely related to cholesterol metabolism and the inflammatory response, is upregulated in response to TNF-α stimulation. HMGB1 inhibition or knockdown successfully alleviates TNF-α-induced ECM degradation, senescence and pyroptosis. Subsequently, we find that HMGB1 is regulated by rosuvastatin and that its overexpression abrogates the protective effect of rosuvastatin. We then verify that the NF-κB pathway is the underlying pathway regulated by rosuvastatin and HMGB1. In vivo experiments also reveal that rosuvastatin inhibits IDD progression by alleviating pyroptosis and senescence and downregulating HMGB1 and p65. This study might provide new insight into therapeutic strategies for IDD.

Rosuvastatin Attenuates Progression of Atherosclerosis and Reduces Serum IL6 and CCL2 Levels in Apolipoprotein-E-deficient Mice.

BACKGROUND/AIM: Apolipoprotein E-deficient (Apoe-/-) mice develop atherosclerotic lesions that closely resemble metabolic syndrome in humans. We sought to investigate how rosuvastatin mitigates the atherosclerotic profile of Apoe-/- mice over time and its effects on certain inflammatory chemokines. MATERIALS AND METHODS: Eighteen Apoe-/- mice were allocated into three groups of six mice each receiving: standard chow diet (SCD; control group); high-fat diet (HFD); and HFD and rosuvastatin at 5 mg/kg/d orally via gavage for 20 weeks. Analysis of aortic plaques and lipid deposition was conducted by means of en face Sudan IV staining and Oil Red O staining. Serum cholesterol, low-density lipoprotein, high-density lipoprotein, plasma glucose and triglyceride levels were determined at baseline and after 20 weeks of treatment. Serum interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor-α (TNFα) levels were measured by enzyme-linked immunosorbent assay at the time of euthanasia. RESULTS: The lipidemic profile of Apoe-/- mice on HFD deteriorated over time. Apoe-/- mice on HFD developed atherosclerotic lesions over time. Sudan IV and Oil Red O-stained sections of the aorta revealed increased plaque formation and plaque lipid deposition in HFD-fed mice compared with SCD-fed mice and reduced plaque development in HFD-fed mice treated with rosuvastatin compared with mice not receiving statin treatment. Serum analysis revealed reduced metabolic parameters in HFD-fed mice on rosuvastatin compared with non-statin, HFD-fed mice. At the time of euthanasia, HFD-fed mice treated with rosuvastatin had significantly lower IL6 as well as CCL2 levels when compared with HFD-fed mice not receiving rosuvastatin. TNFα levels were comparable among all groups of mice, irrespective of treatment. IL6 and CCL2 positively correlated with the extent of atherosclerotic lesions and lipid deposition in atherosclerotic plaques. CONCLUSION: Serum IL6 and CCL2 levels might potentially be used as clinical markers of progression of atherosclerosis during statin treatment for hypercholesterolemia.

Insights into the role of PHLPP2/Akt/GSK3ß/Fyn kinase/Nrf2 trajectory in the reno-protective effect of rosuvastatin against colistin-induced acute kidney injury in rats.

OBJECTIVES: Oxidative stress-mediated colistin's nephrotoxicity is associated with the diminished activity of nuclear factor erythroid 2-related factor 2 (Nrf2) that is primarily correlated with cellular PH domain and leucine-rich repeat protein phosphatase (PHLPP2) levels. This study investigated the possible modulation of PHLPP2/protein kinase B (Akt) trajectory as a critical regulator of Nrf2 stability by rosuvastatin (RST) to guard against colistin-induced oxidative renal damage in rats. METHODS: Colistin (300,000 IU/kg/day; i.p.) was injected for 6 consecutive days, and rats were treated simultaneously with RST orally at 10 or 20 mg/kg. KEY FINDINGS: RST enhanced renal nuclear Nrf2 translocation as revealed by immunohistochemical staining to boost the renal antioxidants, superoxide dismutase (SOD) and reduced glutathione (GSH) along with a marked reduction in caspase-3. Accordingly, rats treated with RST showed significant restoration of normal renal function and histological features. On the molecular level, RST effectively decreased the mRNA expression of PHLPP2 to promote Akt phosphorylation. Consequently, it deactivated GSK-3ß and reduced the gene expression of Fyn kinase in renal tissues. CONCLUSIONS: RST could attenuate colistin-induced oxidative acute kidney injury via its suppressive effect on PHLPP2 to endorse Nrf2 activity through modulating Akt/GSK3 ß/Fyn kinase trajectory.

A pharmacokinetic drug-drug interaction study between rosuvastatin and emvododstat, a potent anti-SARS-CoV-2 (COVID-19) DHODH (dihydroorotate dehydrogenase) inhibitor.

A therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) management. Emvododstat (PTC299) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by the inhibition of dihydroorotate dehydrogenase (DHODH) to reduce SARS-CoV-2 replication. DHODH is the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. This drug interaction study was performed to determine whether emvododstat was an inhibitor of breast cancer resistance protein (BCRP) transporters in humans. Potential drug-drug interactions (DDIs) between emvododstat and a BCRP transporter substrate (rosuvastatin) were investigated by measuring plasma rosuvastatin concentrations before and after emvododstat administration. There was no apparent difference in rosuvastatin plasma exposure. The geometric means of maximum plasma rosuvastatin concentrations (Cmax ) were 4369 (rosuvastatin) and 5141 pg/mL (rosuvastatin + emvododstat) at 4 h postdose. Geometric mean rosuvastatin area under the concentration-time curve (AUC) from time 0 to the last measurable plasma concentration was 45 616 and 48 975 h·pg/mL when administered alone and after 7 days of b.i.d. emvododstat dosing, respectively. Geometric least squares mean ratios for Cmax and AUC were approximately equal to 1. Overall, administration of multiple doses of 100 mg emvododstat b.i.d. for 7 days in combination with a single dose of rosuvastatin was safe and well tolerated. Emvododstat can be safely administered with other BCRP substrate drugs. Hence, pharmacokinetic DDI mediated via BCRP inhibition is not expected when emvododstat and BCRP substrates are coadministered.

[Rosuvastatin acts on the lymphatic system to improve atherosclerosis].

Objective: To investigate whether rosuvastatin acts on lymphatic system and influences lymphatic system-mediated reverse cholesterol transport to play an anti-atherosclerosis role. Methods: Forty-eight apolipoprotein E-/- mice fed a high fat diet were used to construct the atherosclerosis model. They were randomly divided into 4 groups with 12 rats in each group. They were treated with rosuvastatin, vascular endothelial growth factor-C (VEGF-C) and rosuvastatin+VEGF-C inhibitors as experimental group, and no intervention measures were given in control group. After 8 weeks, aortic plaque area, high density lipoprotein cholesterol (HDL-C) content in lymph fluid, the function of popliteal lymphatic drainage of peripheral Evans blue, and the ability of lymphatic system to transport peripheral cell membrane red fluorescent probes to label high-density lipoprotein (HDL) were detected. Subsequently, the effects of rosuvastatin on proliferation, migration and tubular function of lymphoendothelial cells and the expression of scavenger receptor class B type 1 (SR-B1) on lymphoendothelial cells at different concentrations were detected. Results: Compared with the control group, Rosuvastatin and VEGF-C could reduce the area of aortic atherosclerotic plaque (P<0.05). In addition to rosuvastatin plus VEGF-C inhibitor, the intra-aortic plaque area increased (P<0.05). Compared with the control group, Rosuvastatin could increase the content of HDL-C in lymphatic fluid (P<0.05), enhance the drainage function of lymphatic vessels, and enhance the capacity of HDL in the transport tissue fluid of lymphatic system. Compared with the control group, VEGF-C increased the content of HDL-C in mouse lymph fluid (P<0.01), enhanced the drainage function of popliteal lymphatic canal, and enhanced the ability of lymphatic system to transport HDL. With the addition of VEGF-C inhibitor on the basis of rosuvastatin, the content of HDL-C in lymph fluid was reduced, the drainage of popliteal lymphatic canal was interrupted, and the ability of lymphatic system to transport HDL was reduced. Western blotting showed that rosuvastatin increased the protein expression of SR-B1. Conclusion: Rosuvastatin can promote the proliferation, migration and tube formation of lymphatic endothelial cells. At the same time, SR-B1 expression on lymphatic endothelial cells is promoted, thus enhancing the lymphatic system mediated cholesterol reversal transport and playing the role of anti-atherosclerosis.

Rosuvastatin promotes survival of random skin flaps through AMPK-mTOR pathway-induced autophagy.

Plastic surgery frequently employs random skin flaps. However, its clinical applicability is constrained by flap necrosis brought on by ischemia-reperfusion damage. Flap survival is aided by rosuvastatin, a naturally occurring flavonoid primarily obtained from plants. In this research, we looked into the processes mediating the effects of rosuvastatin on flap survival. All experimental mice were randomly assigned to three groups: control, rosuvastatin, and 3-methyladenine (3MA) plus rosuvastatin. These groups were, respectively, treated with dimethyl sulfoxide solution, rosuvastatin, and rosuvastatin combined with 3MA. After that, the animals were euthanized so that histology and protein analyses could determine the extent of angiogenesis, pyroptosis, oxidative stress, and autophagy. In addition to lessening tissue edema, rosuvastatin promoted the survival of the skin flap. Rosuvastatin also promoted angiogenesis, reduced oxidative stress, induced autophagy, and reduced pyroptosis. According to the study's findings, rosuvastatin increases angiogenesis, prevents pyroptosis, and reduces oxidative stress by inducing autophagy, which improves the survival rate of random skin flaps.

Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials.

BACKGROUND: Two acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins. METHODS: Secondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile (< 69 mg/dL in SAILS, < 44 mg/dL in HARP-2) versus all other quartiles for association with 60-day mortality and medication effect. Fisher's exact test, logistic regression, and Cox Proportional Hazards were used to assess mortality. RESULTS: There were 678 subjects with cholesterol measured in SAILS and 509 subjects in HARP-2, of whom 384 had sepsis. Median cholesterol at enrollment was 97 mg/dL in both SAILS and HARP-2. Low cholesterol was associated with higher APACHE III and shock prevalence in SAILS, and higher Sequential Organ Failure Assessment score and vasopressor use in HARP-2. Importantly, the effect of statins differed in these trials. In SAILS, patients with low cholesterol who received rosuvastatin were more likely to die (odds ratio (OR) 2.23, 95% confidence interval (95% CI) 1.06-4.77, p = 0.02; interaction p = 0.02). In contrast, in HARP-2, low cholesterol patients had lower mortality if randomized to simvastatin, though this did not reach statistical significance in the smaller cohort (OR 0.44, 95% CI 0.17-1.07, p = 0.06; interaction p = 0.22). CONCLUSIONS: Cholesterol levels are low in two cohorts with sepsis-related ARDS, and those in the lowest cholesterol quartile are sicker. Despite the very low levels of cholesterol, simvastatin therapy seems safe and may reduce mortality in this group, though rosuvastatin was associated with harm.