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Pregnancy Hypertension Mar 2024Early diagnosis and efficient treatment of preeclampsia remains a medical challenge and etiological factors converge in a deficient placentation that triggers oxidative...
Early diagnosis and efficient treatment of preeclampsia remains a medical challenge and etiological factors converge in a deficient placentation that triggers oxidative stress. There is evidence that statins show antioxidant effects that can improve endothelial function without adverse perinatal effects. We aimed to compare early vs. late pravastatin treatment on the oxidative stress and cardiovascular features of an experimental model of preeclampsia. Female Wistar rats were randomly divided into preeclampsia phenotype rats (PEP) developed by sub renal aortic coarctation (SRAC) and healthy pregnant rats (C). Each group received pravastatin (5 mg/Kg) p.o. either for one week before and during the first week or during the last two weeks of gestation. Blood pressure was determined using the plethysmographic method. Phenylephrine (Phe)-induced contractility was evaluated in isolated thoracic and abdominal aortic rings with or without endothelium. Blood samples were obtained to determine anion superoxide concentration as indicator of NADPH activity. Two-way ANOVA and Bonferroni post hoc tests were used to define statistical significance. Early or late pravastatin treatment decreased hypertension of PEP animals but did not change BP of the healthy pregnant group. Thoracic and abdominal aorta from PEP rats showed increased contractility that was reverted by pravastatin early treatment in endothelium intact rings. Pravastatin did not significantly change contractility neither in the thoracic nor in the abdominal aorta segments from healthy pregnant control rats (C), and decrease anion superoxide concentration by NADPH activity. We conclude pravastatin can improve both blood pressure and endothelium-dependent Phe-induced contractility in an experimental model of preeclampsia by reducing oxidative stress.
Topics: Pregnancy; Humans; Rats; Female; Animals; Pravastatin; Pre-Eclampsia; Superoxides; NADP; Rats, Wistar; Oxidative Stress; Phenylephrine; Endothelium, Vascular
PubMed: 38306739
DOI: 10.1016/j.preghy.2024.01.131 -
Expert Review of Clinical Pharmacology Mar 2024Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the...
BACKGROUND
Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the association between statins and neurocognitive disorders using the FDA Adverse Event Reporting System (FAERS).
RESEARCH DESIGN AND METHODS
Data from 2004 to 2022 were obtained from the FAERS database. After deduplication and standardization of drug names, we extracted neurocognitive disorder event (NCDE) cases reported with statins as the suspected drugs. The significant association between statins and NCDE was evaluated using the reporting odds ratio (ROR) and information component.
RESULTS
In total, 6,959 NCDE cases with statins as the primary suspected drugs were identified. Signals were detected in pravastatin (ROR, 1.49; 95% CI: 1.32-1.67), atorvastatin (ROR, 1.39; 95% CI: 1.34-1.44), and simvastatin (ROR, 1.31; 95% CI: 1.25-1.38). Age-stratified analysis showed that (1) in the population aged 65 years and older, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin; and (2) in populations under 65 years of age, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, and lovastatin.
CONCLUSIONS
This study suggests a significant association between the NCDE and statins, including atorvastatin, simvastatin, and pravastatin. The intensity of the association increased with age.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Atorvastatin; Pravastatin; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Simvastatin; Lovastatin; Neurocognitive Disorders
PubMed: 38275183
DOI: 10.1080/17512433.2024.2311875 -
Journal of Affective Disorders Mar 2024Depression is a common mental disorder. Some studies have demonstrated that people with diabetes are more likely to suffer from depression. Statins are an everyday use...
BACKGROUND
Depression is a common mental disorder. Some studies have demonstrated that people with diabetes are more likely to suffer from depression. Statins are an everyday use for diabetes. Trials of statin therapy have had conflicting findings on the potential risk of depression.
METHODS
The National Health and Nutrition Examination Survey (NHANES) 2005-2018 was used to collect a representative sample. Weighted multivariate logistic regression models were used to evaluate odds ratios (ORs) and 95 % CIs for having depression symptoms. We performed stratified analyses to compare the effects of statins in subsamples with and without diabetes on depression symptoms.
RESULTS
Statin use showed a significant and strong decreasing effect on having depression symptoms in participants with diabetes (aOR (adjusted OR) 0.59, p = 0.014) compared with that in non-diabetics (aOR 0.78, p = 0.128). Diabetic individuals with statin use for >5 years had a lower risk of having depression symptoms (aOR 0.42, p = 0.002) than those with shorter-term statin use (1-5 years, aOR 0.69, p = 0.111; <1 year: aOR 0.83, p = 0.646). Atorvastatin was more effective in decreasing depression symptoms either in diabetes (aOR 0.49, p = 0.018) or in non-diabetes (aOR 0.58, p = 0.033).
LIMITATIONS
First, the dosage of statins cannot be obtained from NHANES datasets. Second, after being stratified, the number of participants for several statins was insufficient. Third, recall bias may exist in the survey.
CONCLUSIONS
Diabetics with depression symptoms may benefit from long-term statin therapy. Atorvastatin and pravastatin should be recommended for diabetic patients with depression.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Nutrition Surveys; Depression; Diabetes Mellitus
PubMed: 38199416
DOI: 10.1016/j.jad.2024.01.013 -
BMC Pregnancy and Childbirth Jan 2024Preeclampsia is a life-threatening disease of pregnancy that lacks effective pharmaceuticals which can target its pathogenesis. Since preeclampsia involves complex...
BACKGROUND
Preeclampsia is a life-threatening disease of pregnancy that lacks effective pharmaceuticals which can target its pathogenesis. Since preeclampsia involves complex pathological processes, including autophagy, this study aims to explore autophagy-related mechanisms of preeclampsia and to screen potential drugs.
METHODS
Firstly, the datasets GSE75010, GSE24129, GSE66273, and autophagic genes lists were downloaded from public databases. Then, a weighted gene co-expression network analysis (WGCNA) was applied to filter autophagic-related hub genes of preeclampsia. The differential expression levels of the hub genes were validated with datasets GSE24129 and GSE66273. Next, the GO and KEGG enrichment, protein-protein interacting (PPI) network, as well as the downstream pathways was analyzed via the starBase, STRING and Cytoscape to determine the functions and regulatory network of the hub genes. Additionally, the immune microenvironment of preeclampsia was investigated by the CIBERSORTX database. Finally, three herb ingredients, berberine, baicalein, and luteolin were screened by molecular docking in comparison to pravastatin, metformin, and aspirin, to predict potential drugs for treating preeclampsia.
RESULTS
A total of 54 autophagy-related genes were filtered by WGCNA. After filtering with |GS| > 0.5 and |MM| > 0.8, three hub genes, namely PKM, LEP, and HK2, were identified and validated. Among these genes, PKM and LEP were overexpressed in women older than 35 years old ( p<0.05; p<0.05); the expression of PKM, LEP, and HK2 differed remarkably in women with different BMI (all p<0.05); PKM overexpressed in women with hypertension (p<0.05). The regulatory network of hub genes demonstrated that they were mainly enriched in metabolic pathways, including the AMPK signaling pathway, glucagon signaling pathway, adipocytokine signaling pathway, and central carbon metabolism. Then, immune microenvironment analysis turned out that M2 macrophages were reduced in preeclampsia women (p<0.0001) and were negatively correlated with the expression of PKM (r=-0.2, p<0.05), LEP (r=-0.4, p<0.0001), and HK2 (r=-0.3, p<0.001). Lastly, molecular docking showed baicalein and luteolin could bind intimately to hub genes.
CONCLUSION
PKM, LEP, and HK2 could be promising biomarkers for preeclampsia, which might regulate the pathogenesis of preeclampsia via metabolism pathways and immune microenvironment. Baicalein and luteolin could be potential therapeutics for preeclampsia.
Topics: Adult; Female; Humans; Pregnancy; Autophagy; Biomarkers; Luteolin; Molecular Docking Simulation; Pre-Eclampsia
PubMed: 38166707
DOI: 10.1186/s12884-023-06211-2 -
Pharmacological Reports : PR Feb 2024Early-stage breast cancer is usually treated with breast-conserving surgery followed by adjuvant radiation therapy. Acute skin toxicity is a common radiation-induced...
BACKGROUND
Early-stage breast cancer is usually treated with breast-conserving surgery followed by adjuvant radiation therapy. Acute skin toxicity is a common radiation-induced side effect experienced by many patients. Recently, a combination of bisphosphonates (zoledronic acid) and statins (pravastatin), or ZOPRA, was shown to radio-protect normal tissues by enhancing DNA double-strand breaks (DSB) repair mechanism. However, there are no studies assessing the effect of ZOPRA on cancerous cells. The purpose of this study is to characterize the in vitro effect of the zoledronic acid (ZO), pravastatin (PRA), and ZOPRA treatment on the molecular and cellular radiosensitivity of breast cancer cell lines.
MATERIALS
Two breast cancer cell lines, MDA MB 231 and MCF-7, were tested. Cells were treated with different concentrations of pravastatin (PRA), zoledronate (ZO), as well as their ZOPRA combination, before irradiation. Anti-γH2AX and anti-pATM immunofluorescence were performed to study DNA DSB repair kinetics. MTT assay was performed to assess cell proliferation and viability, and flow cytometry was performed to analyze the effect of the drugs on the cell cycle distribution. The clonogenic assay was used to assess cell survival.
RESULTS
ZO, PRA, and ZOPRA treatments were shown to increase the residual number of γH2AX foci for both cell lines. ZOPRA treatment was also shown to reduce the activity of the ATM kinase in MCF-7. ZOPRA induced a significant decrease in cell survival for both cell lines.
CONCLUSIONS
Our findings show that pretreatment with ZOPRA can decrease the radioresistance of breast cancer cells at the molecular and cellular levels. The fact that ZOPRA was previously shown to radioprotect normal tissues, makes it a good candidate to become a therapeutic window-widening drug.
Topics: Humans; Female; MCF-7 Cells; DNA Repair; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Breast Neoplasms; Diphosphonates; Zoledronic Acid; Pravastatin; Radiation Tolerance; DNA; Cell Line, Tumor
PubMed: 38151641
DOI: 10.1007/s43440-023-00560-7 -
Contemporary Clinical Trials Feb 2024Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort.
AIMS
The aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD.
METHODS
One hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years.
OUTCOMES
The primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress.
CONCLUSION
This study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing.
REGISTRATION
This study is registered on Clinicaltrials.gov # NCT03273413.
Topics: Young Adult; Child; Humans; Adult; Polycystic Kidney, Autosomal Dominant; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Double-Blind Method; Disease Progression; Glomerular Filtration Rate
PubMed: 38151173
DOI: 10.1016/j.cct.2023.107423 -
Radiotherapy and Oncology : Journal of... Feb 2024This cohort study aimed to evaluate the impact of statin use on ischemic stroke risk in patients with advanced nasopharyngeal carcinoma (NPC) undergoing standard...
OBJECTIVE
This cohort study aimed to evaluate the impact of statin use on ischemic stroke risk in patients with advanced nasopharyngeal carcinoma (NPC) undergoing standard concurrent chemoradiotherapy (CCRT).
METHODS
Using data from the Taiwan Cancer Registry Database, we conducted an inverse probability of treatment-weighted Cox regression analysis to examine the association between statin use during CCRT and ischemic stroke risk.
RESULTS
The adjusted hazard ratio (aHR) for ischemic stroke in the statin group compared to the non-statin group was 0.70 (95 % CI: 0.54-0.92; P < 0.0107). This protective effect was observed across different statin classes, with hydrophilic statins such as pravastatin showing an aHR of 0.37 (95 % CI: 0.17-0.85) and lipophilic statins including atorvastatin displaying an aHR of 0.32 (95 % CI: 0.21-0.50) compared to non-statin use. Analysis of cumulative defined daily doses (cDDD) revealed a dose-response relationship, with lower stroke risk observed in higher quartiles of cDDD. Additionally, patients with a daily defined dose (DDD) > 1 had a reduced risk of stroke with an aHR of 0.49 (95 % CI: 0.31-0.63), while those with DDD ≤ 1 showed an aHR of 0.59 (95 % CI: 0.40-0.84).
CONCLUSIONS
Our study provides evidence supporting the beneficial effects of statin use during the CCRT period in reducing radiation-induced stroke risk among patients with advanced NPC undergoing definitive CCRT. Notably, pravastatin and atorvastatin demonstrated significant reductions in stroke occurrence. Furthermore, the findings suggest a dose-response relationship, where higher cumulative doses and greater daily dose intensity of statin use were associated with a lower risk of stroke.
Topics: Humans; Nasopharyngeal Carcinoma; Cohort Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Pravastatin; Stroke; Nasopharyngeal Neoplasms; Ischemic Stroke
PubMed: 38142934
DOI: 10.1016/j.radonc.2023.110067 -
Biomolecules Nov 2023Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of...
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, necroptosis with DNA damage, the absorption of the applied pharmaceuticals, and the functional activity of the ABCB1 drug transporter after administration of docetaxel or docetaxel with a selected hydrophobic statin were studied. Taxol-resistant human melanoma cells from three stages of development were used as a model: both A375P and WM239A metastatic lines and radial growth phase WM35 cells. An animal model ( SCID) was developed for the A375P cell line. The results show that hydrophobic statins administered with docetaxel increase the accumulation of the drug in the tumor cell a.o. by blocking the ABCB1 channel. They reduce taxol-induced drug resistance. The tumor size reduction was observed after the drug combination was administrated. It was shown that the structural similarity of statins is of secondary importance, e.g., pravastatin and simvastatin. Using cytostatics in the presence of hydrophobic statins increases their effectiveness while reducing their overall toxicity.
Topics: Animals; Mice; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Docetaxel; Melanoma; Drug Resistance, Neoplasm; Paclitaxel; Cell Line, Tumor
PubMed: 38136555
DOI: 10.3390/biom13121682 -
Journal of Diabetes Jun 2024Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but...
BACKGROUND
Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear.
METHODS
In this study, 16S rRNA sequencing and qRT-PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT-PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification.
RESULTS
We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5-trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA.
CONCLUSIONS
Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis.
Topics: Pravastatin; Animals; Vascular Calcification; Mice; Macrophages; Humans; Diabetes Mellitus, Type 2; Bacteroides fragilis; Male; Gastrointestinal Microbiome; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice, Inbred C57BL; Female
PubMed: 38112268
DOI: 10.1111/1753-0407.13514 -
American Journal of Obstetrics &... Feb 2024We aimed to perform a systematic review and meta-analysis of randomized controlled trials to evaluate the prophylactic use of pravastatin in pregnant women with... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
We aimed to perform a systematic review and meta-analysis of randomized controlled trials to evaluate the prophylactic use of pravastatin in pregnant women with high-risk of preeclampsia.
DATA SOURCES
PubMed, Embase, Cochrane Central, and Web of Science were searched from inception to August 2023 with no language or filters restriction. The references from included studies, previous systematic reviews, and meta-analyses were manually searched for any additional studies.
STUDY ELIGIBILITY CRITERIA
Randomized controlled trials comparing pravastatin in any dose with placebo or no treatment in pregnant women with high risk for preeclampsia and up to 20 weeks of gestation were included in this meta-analysis.
METHODS
We used RStudio version 4.2.2 with random effects models to compute pooled risk ratios for prespecified outcomes data. The quality assessment was conducted using version 2 of the Cochrane Risk of Bias Assessment Tool. We also performed a trial sequential analysis to evaluate the reliability of our findings.
RESULTS
We included 3 randomized controlled trials comprising 213 patients, of whom 106 (49.8%) were allocated to the pravastatin group. There was no significant effect of pravastatin on the incidence of preeclampsia (risk ratio, 0.62; 95% confidence interval, 0.33-1.14; P=.12).
CONCLUSION
Our study was unable to demonstrate the benefit of pravastatin for preventing preeclampsia in high-risk pregnant women. Nevertheless, these findings comprised only preliminary studies with a small number of subjects, highlighting the need of well-designed, and adequately powered clinical trials.
Topics: Pregnancy; Humans; Female; Pre-Eclampsia; Pravastatin; Pregnant Women; Reproducibility of Results
PubMed: 38109997
DOI: 10.1016/j.ajogmf.2023.101260