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Cell Death Discovery May 2024Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that poses significant challenges in terms of treatment and management. It is characterized by...
Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that poses significant challenges in terms of treatment and management. It is characterized by heightened endothelial apoptosis and impaired angiogenesis. In this study, we aimed to investigate the role of protein kinase Cδ (PKCδ) in regulating endothelial apoptosis in diabetic wounds by promoting cholesterol biosynthesis. The expression of PKCδ was increased in human umbilical vascular endothelial cells (HUVECs) cultivated in high glucose medium and skin tissue isolated from diabetic mice. High glucose-induced HUVECs apoptosis was reduced by PKCδ inhibition with siRNA or rottlerin. RNA-seq identified two enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), as the downstream of PKCδ. PKCδ knockdown or inhibition suppressed the expression of HMGCS1 and HMGCR and lowered free cholesterol (FC) levels. Cholesterol restored high glucose-induced apoptosis in siRNA- or rottlerin-treated HUVECs. In vivo use of rosuvastatin calcium, an inhibitor of HMGCR, downregulated free cholesterol levels and accelerated the wound healing process. In conclusion, PKCδ expression in endothelial cells was activated by high glucose, which subsequently upregulates the expression of two enzymes catalyzing cholesterol biosynthesis, HMGCS1 and HMGCR. Enhanced cholesterol biosynthesis raises free cholesterol levels, promotes endothelial apoptosis, and finally delays wound healing.
PubMed: 38811564
DOI: 10.1038/s41420-024-02030-2 -
Diabetes & Metabolism Journal May 2024
Topics: Humans; Rosuvastatin Calcium; Diabetes Mellitus, Type 2; Ezetimibe; Anticholesteremic Agents; Drug Therapy, Combination; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Blood Glucose; Azetidines; Sulfonamides; Pyrimidines
PubMed: 38802118
DOI: 10.4093/dmj.2024.0168 -
Medicine May 2024Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
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.
Topics: Humans; Rosuvastatin Calcium; Female; Atorvastatin; Middle Aged; Bone Remodeling; Postmenopause; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Biomarkers; Collagen Type I; Osteoporosis, Postmenopausal; Dyslipidemias
PubMed: 38728464
DOI: 10.1097/MD.0000000000038122 -
Biomedicine & Pharmacotherapy =... Jun 2024Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative...
Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1, Abcb1a/1b;Abcg2 and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2 << Slco1a/1b/2b1 < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1 and Abcb1a/1b;Abcg2 mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2 or Slco1a/1b/2b1 mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.
Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; Bilirubin; Mice; ATP Binding Cassette Transporter, Subfamily B; Mice, Knockout; Organic Anion Transporters; Liver-Specific Organic Anion Transporter 1; Terfenadine; Male; Biological Transport; Rosuvastatin Calcium; Mice, Inbred C57BL
PubMed: 38692057
DOI: 10.1016/j.biopha.2024.116644 -
Atherosclerosis Jun 2024Proper prescription and high adherence to intensive lipid lowering drugs (LLD) in patients with coronary heart disease (CHD) are crucial and strongly recommended. The...
BACKGROUND AND AIMS
Proper prescription and high adherence to intensive lipid lowering drugs (LLD) in patients with coronary heart disease (CHD) are crucial and strongly recommended. The aim of this study is to investigate long-term treatment patterns and adherence to LLD following hospitalization for a CHD event.
METHODS
Patients admitted to two Norwegian hospitals with a CHD event from 2011 to 2014 (N = 1094) attended clinical examination and completed a questionnaire, median 16 months later. Clinical data were linked to pharmacy dispensing data from 2010 to 2020. The proportions using high-intensity statin therapy (atorvastatin 40/80 mg or rosuvastatin 20/40 mg) and non-statin LLD after the CHD event were assessed. Adherence was evaluated by proportion of days covered (PDC) and gaps in treatment.
RESULTS
Median age at hospitalization was 63 (IQR 12) years, 21 % were female. Altogether, 1054 patients (96 %) were discharged with a statin prescription, while treatment was dispensed in 85 % within the following 90 days. During median 8 (SD 2.5) years follow-up, the proportion using high-intensity statin therapy ranged 62-68 %, whereas the use of ezetimibe increased from 4 to 26 %. PDC <0.8 was found in 22 % of statin users and 26 % of ezetimibe users. The proportions with a treatment gap exceeding 180 days were 22 % for statins and 28 % for ezetimibe. Smoking at hospitalization and negative affectivity were significantly associated with reduced statin adherence, regardless of adherence measure.
CONCLUSIONS
In this long-term follow-up of patients with CHD, less than 70 % used high-intensity statin therapy with only small changes over time, and only 25 % used additional treatment with ezetimibe. We identified factors associated with reduced statin adherence that may be target for interventions.
Topics: Humans; Female; Male; Middle Aged; Medication Adherence; Coronary Disease; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Norway; Follow-Up Studies; Time Factors; Ezetimibe; Treatment Outcome; Hospitalization; Practice Patterns, Physicians'; Dyslipidemias; Hypolipidemic Agents; Rosuvastatin Calcium
PubMed: 38657552
DOI: 10.1016/j.atherosclerosis.2024.117550 -
Clinical and Translational Science Apr 2024Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with...
Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (C), area under the concentration-time curve (AUC), time to reach C, and half-life. The increase in momelotinib (23% C, 14% AUC) or M21 (30% C, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% C, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% C, 46% AUC) and increase in M21 (31% C, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (C no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% C, 16% AUC decreases) or 1'-hydroxymidazolam (14% C, 16% AUC decreases) but increased rosuvastatin C by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.
Topics: Adult; Humans; Ritonavir; Cytochrome P-450 CYP3A; Rifampin; Midazolam; ATP Binding Cassette Transporter, Subfamily G, Member 2; Rosuvastatin Calcium; Neoplasm Proteins; Drug Interactions; Membrane Transport Proteins; Benzamides; Pyrimidines
PubMed: 38634429
DOI: 10.1111/cts.13799 -
International Journal of Cardiology Jul 2024Secreted glycoproteins of the Dickkopf (DKK) family modify Wnt signaling and may influence plaque destabilization but their modulation by statins in MI patients is not...
BACKGROUND
Secreted glycoproteins of the Dickkopf (DKK) family modify Wnt signaling and may influence plaque destabilization but their modulation by statins in MI patients is not known.
METHODS
We measured plasma DKK-1 and DKK-3 in patients with acute ST-segment elevation MI (STEMI) before percutaneous coronary intervention (PCI) and after 2 and 7 days and 2 months in patients receiving short-term high-dose (40 mg rosuvastatin, given before PCI; n = 25) and moderate dose (20 mg simvastatin, given the day after PCI; n = 34). In vitro modulation of DKK-1 in human umbilical vein endothelial cells (HUVECs) by statins were assessed.
RESULTS
(i) Patients receiving high dose rosuvastatin had a marked decline in DKK-1 at day 2 which was maintained throughout the study period. However, a more prevalent use of β-blockers in the simvastatin group, that could have contributed to higher DKK-1 levels in these patients. (ii) There was a strong correlation between baseline DKK-1 levels and change in DKK-1 from baseline to day 2 in patients receiving high dose rosuvastatin treatment. (iii) DKK-3 increased at day 2 but returned to baseline levels at 2 months in both treatment groups. (iv) Statin treatment dose-dependently decreased DKK-1 mRNA and protein levels in HUVEC.
CONCLUSIONS
Our findings suggest that high dose statin treatment with 40 mg rosuvastatin could persistently down-regulate DKK-1 levels, even at 2 months after the initial event in STEMI patients.
Topics: Humans; Male; Female; Rosuvastatin Calcium; Middle Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Aged; Intercellular Signaling Peptides and Proteins; Dose-Response Relationship, Drug; Simvastatin; Human Umbilical Vein Endothelial Cells; Myocardial Infarction; Biomarkers; ST Elevation Myocardial Infarction; Cells, Cultured; Adaptor Proteins, Signal Transducing
PubMed: 38604450
DOI: 10.1016/j.ijcard.2024.132035 -
BMC Cardiovascular Disorders Apr 2024The latest evidence indicates that ATP-binding cassette superfamily G member 2 (ABCG2) is critical in regulating lipid metabolism and mediating statin or cholesterol... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The latest evidence indicates that ATP-binding cassette superfamily G member 2 (ABCG2) is critical in regulating lipid metabolism and mediating statin or cholesterol efflux. This study investigates whether the function variant loss within ABCG2 (rs2231142) impacts lipid levels and statin efficiency.
METHODS
PubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until November 18, 2023.
RESULTS
Fifteen studies (34,150 individuals) were included in the analysis. The A allele [Glu141Lys amino acid substitution was formed by a transversion from cytosine (C) to adenine (A)] of rs2231142 was linked to lower levels of high-density lipoprotein cholesterol (HDL-C), and higher levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). In addition, the A allele of rs2231142 substantially increased the lipid-lowering efficiency of rosuvastatin in Asian individuals with dyslipidemia. Subgroup analysis indicated that the impacts of rs2231142 on lipid levels and statin response were primarily in Asian individuals.
CONCLUSIONS
The ABCG2 rs2231142 loss of function variant significantly impacts lipid levels and statin efficiency. Preventive use of rosuvastatin may prevent the onset of coronary artery disease (CAD) in Asian individuals with dyslipidemia.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Genetic Predisposition to Disease; Cholesterol, LDL; Dyslipidemias; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins
PubMed: 38589776
DOI: 10.1186/s12872-024-03821-2 -
Frontiers in Endocrinology 2024Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is... (Randomized Controlled Trial)
Randomized Controlled Trial
Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial.
OBJECTIVES
Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers.
METHODS
In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication.
RESULTS
The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (T) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, =0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, =0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (=0.314) or LDL-C (=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (=0.011), but not in the rosuvastatin group (=0.339).
CONCLUSIONS
We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.
Topics: Humans; Rosuvastatin Calcium; Ezetimibe; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Anticholesteremic Agents; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Leukocytes, Mononuclear; Hypercholesterolemia; Azetidines; Fluorobenzenes; Pyrimidines; Sulfonamides; Drug Therapy, Combination; Treatment Outcome; Inflammation; T-Lymphocytes
PubMed: 38586464
DOI: 10.3389/fendo.2024.1336357 -
Journal of Analytical Methods in... 2024Rosuvastatin calcium is a widely used 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. To establish a control...
Rosuvastatin calcium is a widely used 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. To establish a control strategy for the elemental impurities, a new digestion method combined with an inductively coupled plasma-mass spectrometer (ICP-MS) was developed and validated by our team to determine elements Cd, Pb, As, Hg, Co, V, and Ni in rosuvastatin calcium tablets, which digest the sample perfectly even in the presence of a large number of excipients, especially titanium dioxide. The measurement mode was collision cell mode with kinetic energy discrimination (KED). 209Bi, 115In, and 89Y were chosen as internal standard elements. The recoveries of the limit of quantitation (LOQ) ranged from 90.5% to 106.4%, concentrations of the abovementioned elements in LOQ were 0.25 g·L, 0.25 g·L, 0.75 g·L, 1.5 g·L, 2.5 g·L, 5 g·L, and 8 g·L , respectively, linear correlation coefficients were above 0.9997, the recoveries in accuracy item ranged from 91.8% to 103.6%, and relative standard deviations (RSDs) of recovery in precision were not more than 1.8%, reflecting a reliable method of high sensitivity, strong anti-interference capacity, and good precision, and that it was suitable for the determination of elemental impurities in drugs.
PubMed: 38567381
DOI: 10.1155/2024/9952318