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Cell Communication and Signaling : CCS May 2023Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in...
BACKGROUND
Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in adults. Like other flaviviruses, ZIKV depends on cholesterol to facilitate its replication; thus, cholesterol has been proposed as a therapeutic target to treat the infection using FDA-approved statins. Cholesterol is stored in intracellular lipid droplets (LD) in the form of cholesterol esters and can be regulated by autophagy. We hypothesize that the virus hijacks autophagy machinery as an early step to increase the formation of LD and viral replication, and that interference with this pathway will limit reproduction of virus.
METHODS
We pretreated MDCK cells with atorvastatin or other inhibitors of autophagy prior to infection with ZIKV. We measured viral expression by qPCR for NS1 RNA and immunofluorescence for Zika E protein.
RESULTS
Autophagy increases in virus-infected cells as early as 6 h post infection (hpi). In the presence of atorvastatin, LD are decreased, and cholesterol is reduced, targeting key steps in viral replication, resulting in suppression of replication of ZIKV is suppressed. Other both early- and late-acting autophagy inhibitors decrease both the number of LD and viral replication. Bafilomycin renders cholesterol is inaccessible to ZIKV. We also confirm previous reports of a bystander effect, in which neighboring uninfected cells have higher LD counts compared to infected cells.
CONCLUSIONS
We conclude that atorvastatin and inhibitors of autophagy lead to lower availability of LD, decreasing viral replication. We conclude that bafilomycin A1 inhibits viral expression by blocking cholesterol esterification to form LD. Video Abstract.
Topics: Humans; Atorvastatin; Autophagy; Lipid Metabolism; Virus Replication; Zika Virus; Zika Virus Infection; Madin Darby Canine Kidney Cells; Animals; Dogs
PubMed: 37208782
DOI: 10.1186/s12964-022-01026-8 -
Journal of the American Medical... Oct 2021Ulcerative colitis (UC) is a chronic inflammatory disorder with limited effective therapeutic options for long-term treatment and disease maintenance. We hypothesized...
OBJECTIVE
Ulcerative colitis (UC) is a chronic inflammatory disorder with limited effective therapeutic options for long-term treatment and disease maintenance. We hypothesized that a multi-cohort analysis of independent cohorts representing real-world heterogeneity of UC would identify a robust transcriptomic signature to improve identification of FDA-approved drugs that can be repurposed to treat patients with UC.
MATERIALS AND METHODS
We performed a multi-cohort analysis of 272 colon biopsy transcriptome samples across 11 publicly available datasets to identify a robust UC disease gene signature. We compared the gene signature to in vitro transcriptomic profiles induced by 781 FDA-approved drugs to identify potential drug targets. We used a retrospective cohort study design modeled after a target trial to evaluate the protective effect of predicted drugs on colectomy risk in patients with UC from the Stanford Research Repository (STARR) database and Optum Clinformatics DataMart.
RESULTS
Atorvastatin treatment had the highest inverse-correlation with the UC gene signature among non-oncolytic FDA-approved therapies. In both STARR (n = 827) and Optum (n = 7821), atorvastatin intake was significantly associated with a decreased risk of colectomy, a marker of treatment-refractory disease, compared to patients prescribed a comparator drug (STARR: HR = 0.47, P = .03; Optum: HR = 0.66, P = .03), irrespective of age and length of atorvastatin treatment.
DISCUSSION & CONCLUSION
These findings suggest that atorvastatin may serve as a novel therapeutic option for ameliorating disease in patients with UC. Importantly, we provide a systematic framework for integrating publicly available heterogeneous molecular data with clinical data at a large scale to repurpose existing FDA-approved drugs for a wide range of human diseases.
Topics: Atorvastatin; Colectomy; Colitis, Ulcerative; Drug Repositioning; Humans; Retrospective Studies
PubMed: 34529084
DOI: 10.1093/jamia/ocab165 -
International Journal of Molecular... Apr 2022The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in...
The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.
Topics: Atorvastatin; Down-Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; MicroRNAs
PubMed: 35563413
DOI: 10.3390/ijms23095022 -
Antimicrobial Agents and Chemotherapy Feb 2017Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1... (Clinical Trial)
Clinical Trial
Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.
Topics: Adult; Area Under Curve; Atorvastatin; Drug Interactions; Female; Humans; Male; Middle Aged; Pyridones; Reverse Transcriptase Inhibitors; Triazoles
PubMed: 27872071
DOI: 10.1128/AAC.01364-16 -
Cell and Tissue Banking Dec 2022Recent studies have demonstrated inhibitory effects of mesenchymal stem cells on breast tumors. Likewise, the emerging interest in statins as anticancer agents is based...
Recent studies have demonstrated inhibitory effects of mesenchymal stem cells on breast tumors. Likewise, the emerging interest in statins as anticancer agents is based on their pleiotropic effects. In the present study, we investigated whether atorvastatin and umbilical cord matrix derived mesenchymal stem cells-conditioned medium affect the MCF7 cancer cells viability and interactions. We measured the viability of MCF7 cancer cells by MTT assay, flow cytometry, and quantitative real-time PCR. Two-dimensional culture and hanging drop aggregation assay illustrated the morphological changes. We traced the MCF7 migration via scratch-wound healing test and trans-well assay. The results showed the inhibition of cancer cell viability in all treated groups compared to the control group. The effect of atorvastatin and conditioned medium combination was significantly more than each substance separately. The morphological changes indicated apoptosis in treated cells. The annexin V/PI flow cytometry especially in the combination-treated group displayed decreasing in DNA synthesis and cell cycle arrest in G1 and G2/M phases. As well, the mRNA expressions of caspases 3, 8, 9, and Bcl-2 genes were along with extrinsic and intrinsic apoptosis pathways. Conditioned medium disrupted the connections between cancer cells, so the spheroids in three-dimensional configuration lost their order and dispersed. The migration of treated cells across the wound area and trans-well diminished, particularly by the conditioned medium and atorvastatin combination. There fore, the synergistic anti-proliferative and anti-motility effect of atorvastatin along with human umbilical cord mesenchymal stem cells-derived conditioned medium on MCF7 breast cancer cells have been proved. The results might lead the development of novel adjuvant anticancer therapeutics based on targeting or modifying the extracellular matrix to increase chemotherapy results or to prevent metastatic colonization. Schematic representation of "Synergistic Inhibitory Effect of Human Umbilical Cord Matrix Mesenchymal Stem Cells-Conditioned Medium and Atorvastatin on MCF7 Cancer Cells Viablity and Migration" by: Dr. Reyhaneh Abolghasemi, Dr. Somayeh Ebrahimi-barough, Proffesor. Jafar Ai.
Topics: Humans; Culture Media, Conditioned; Atorvastatin; Cell Proliferation; Mesenchymal Stem Cells; Umbilical Cord; Neoplasms
PubMed: 34988840
DOI: 10.1007/s10561-021-09984-y -
Pharmacology Research & Perspectives May 2021Atorvastatin and direct oral factor Xa inhibitors (xabans) are frequently co-administrated in patients with atrial fibrillation (AF). However, no studies investigating... (Observational Study)
Observational Study
Atorvastatin and direct oral factor Xa inhibitors (xabans) are frequently co-administrated in patients with atrial fibrillation (AF). However, no studies investigating the possibility of the pharmacologic interaction between these agents have been conducted. The aim of this prospective observational study was to determine the impact of atorvastatin therapy on anti-Xa activity in xabans-treated patients with AF. We enrolled 115 AF patients on long-term rivaroxaban (52 patients) and long-term apixaban (63 patients) therapy. Long-term atorvastatin (40 mg once daily) was administrated to 28 rivaroxaban-treated patients and to 28 apixaban-treated patients. Trough and peak samples were tested for anti-Xa activity with drug-specific anti-Xa chromogenic analysis. For rivaroxaban, there were no significant differences in trough activity (45.5 ± 39.5 ng/ml vs. 46.2 ± 30.1 ng/ml; p = .34) and peak anti-Xa activity (179.2 ± 108.8 ng/ml vs. 208.1 ± 104.1 ng/ml; p = .94) between atorvastatin-treated patients and those without atorvastatin. Similarly, atorvastatin did not impact the trough activity (127.7 ± 71.1 ng/ml vs. 100.8 ± 61.1 ng/ml; p = .12) or peak anti-Xa activity (213.8 ± 103.6 ng/ml vs. 179.3 ± 72.9 ng/ml; p = .14) among apixaban-treated patients with AF. This observational study did not show a significant impact of atorvastatin on trough and peak anti-Xa activity in xabans-treated patients with AF.
Topics: Aged; Aged, 80 and over; Atorvastatin; Atrial Fibrillation; Drug Interactions; Factor Xa Inhibitors; Female; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thrombosis
PubMed: 33984191
DOI: 10.1002/prp2.730 -
AAPS PharmSciTech Feb 2014A dissolution method to analyze atorvastatin tablets using in vivo data for RP and test pilot (PB) was developed and validated. The appropriate conditions were...
A dissolution method to analyze atorvastatin tablets using in vivo data for RP and test pilot (PB) was developed and validated. The appropriate conditions were determined after solubility tests using different media, and sink conditions were established. The conditions used were equipment paddle at 50 rpm and 900 mL of potassium phosphate buffer pH 6.0 as dissolution medium. In vivo release profiles were obtained from the bioequivalence study of RP and the generic candidate PB. The fraction of dose absorbed was calculated using the Loo-Riegelman method. It was necessary to use a scale factor of time similar to 6.0, to associate the values of absorbed fraction and dissolved fraction, obtaining an in vivo-in vitro correlation level A. The dissolution method to quantify the amount of drug dissolved was validated using high-performance liquid chromatography and ultraviolet spectrophotometry, and validated according to the USP protocol. The discriminative power of dissolution conditions was assessed using two different pilot batches of atorvastatin tablets (PA and PB) and RP. The dissolution test was validated and may be used as a discriminating method in quality control and in the development of the new formulations.
Topics: Atorvastatin; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Heptanoic Acids; Pyrroles; Quality Control; Solubility; Spectrophotometry, Ultraviolet; Tablets
PubMed: 24265014
DOI: 10.1208/s12249-013-0053-z -
Journal of Translational Medicine Mar 2018Medical therapeutic options remain quite limited for uterine fibroids treatment. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have...
BACKGROUND
Medical therapeutic options remain quite limited for uterine fibroids treatment. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have anti-tumoral effects on multiple cancer types, however, little is known about their effects on uterine fibroids.
METHODS
Initially, we conducted a retrospective study of 120 patients with uterine fibroids and hyperlipidemia from the Second Affiliated Hospital of Wenzhou Medical University. Then, we evaluated the effect of atorvastatin on proliferation and apoptosis both in immortalized uterine fibroids cells and primary uterine fibroids cells. Furthermore, the molecular mechanism by which atorvastatin suppressed uterine fibroids cell growth was explored.
RESULTS
Our results showed that atorvastatin use for 1 or 2 years significantly suppressed growth of uterine fibroids. Atorvastatin inhibited the proliferation of immortalized and primary uterine fibroids cells in a dose and time-dependent manner and stimulated apoptosis of uterine fibroids cells by inducing caspase-3 activation, up-regulating Bim and down-regulating Bcl-2. Additionally, atorvastatin treatment suppressed phosphorylation of ERK1/2 and JNK. Furthermore, GGPP, a downstream lipid isoprenoid intermediate, significantly rescued the effect of atorvastatin.
CONCLUSIONS
These results suggest that atorvastatin exerts anti-tumoral effects on uterine fibroids through inhibition of cell proliferation and induction of apoptosis in HMG-CoA-dependent pathway. Our results provide the first clinical and preclinical data on the use of atorvastatin as a promising nonsurgical treatment option for uterine fibroids.
Topics: Adult; Apoptosis; Atorvastatin; Cell Proliferation; Female; Humans; Hyperlipidemias; Leiomyoma; MAP Kinase Signaling System; Middle Aged; Phenotype; Phosphorylation; Polyisoprenyl Phosphates; Sesquiterpenes; Uterine Neoplasms
PubMed: 29523174
DOI: 10.1186/s12967-018-1430-x -
International Journal of Molecular... Mar 2022Calcium oxalate (CaOx) is the major constituent of kidney stones. Growing evidence shows a close connection between hyperlipidemia, cardiovascular disease (CVD), and the...
Calcium oxalate (CaOx) is the major constituent of kidney stones. Growing evidence shows a close connection between hyperlipidemia, cardiovascular disease (CVD), and the formation of kidney stones. Owing to their antioxidant properties, statins control hyperlipidemia and may ameliorate CaOx stone formation. The present study was designed to investigate the suppressive effects of statins on CaOx urolithiasis and their potential mechanism. We used rats fed a high-fat diet (HFD) to achieve hyperlipidemia (HL) and hydroxyproline (HP) water to establish a hyperoxaluric CaOx nephrolithiasis model; the animals were administered statins (A) for 28 days. The rats were divided into eight groups treated or not with A, i.e., Control, HP, HL, HL + HP. HL aggravated urinary calcium crystallization compared to the control. Due to increased expression of renal osteopontin (OPN), a key anti-lithic protein, and reduced free radical production, the calcium crystals in the urinary bladder increased as renal calcium deposition decreased. The levels of the ion activity product of CaOx (AP(CaOx)) decreased after statins administration, and AP(Calcium phosphate) (CaP) increased, which suggested the dominant calcium crystal composition changed from CaOx to CaP after statin administration. In conclusion, atorvastatin decreases renal CaOx stone deposits by restoring OPN expression in hyperoxaluric rats fed a HFD.
Topics: Animals; Atorvastatin; Calcium; Calcium Oxalate; Diet, High-Fat; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxyproline; Hyperoxaluria; Kidney Calculi; Nephrolithiasis; Osteopontin; Rats; Rats, Sprague-Dawley
PubMed: 35328466
DOI: 10.3390/ijms23063048 -
Journal of the American Heart... Dec 2023Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid-activated...
Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease.
BACKGROUND
Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid-activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown.
METHODS AND RESULTS
Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and , , and dual mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking and / display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by and gene ablation. In apolipoprotein E and wild-type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low-density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti-inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists.
CONCLUSIONS
FXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.
Topics: Animals; Humans; Mice; Atorvastatin; Bile Acids and Salts; Dysbiosis; GTP-Binding Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Non-alcoholic Fatty Liver Disease; Receptors, G-Protein-Coupled
PubMed: 37996988
DOI: 10.1161/JAHA.123.031241