Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family. ZIKV infection has been associated with neurological complications such as microcephaly in newborns and Guillain-Barré ...syndrome in adults; thus, therapeutic agents are urgently needed. Statins are clinically approved for lowering cholesterol levels to prevent cardiovascular disease but have shown potential as antiviral drugs. In this study, we explored the possibility of utilizing statins as anti-ZIKV drugs. We found that, generally, lipophilic statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, and simvastatin) could reduce ZIKV production in vitro and result in smaller foci of infection. Time-of-drug-addition assay revealed that early treatment with statins is more beneficial than late treatment; however, statins could not completely inhibit the entry stage of ZIKV infection. Furthermore, individual lipophilic statins differed in anti-ZIKV capacity, with fluvastatin being the most efficient at low concentrations. Taken together, this study shows that statins or their derivatives have the potential to be used as anti-ZIKV therapeutic agents.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin.
Chemerin was ...determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries.
Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release.
Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.
Triple-negative breast cancer is more common among younger than older women and is associated with the poorest survival outcomes of all breast cancer types. Fluvastatin inhibits tumour progression ...and induces the autophagy of breast cancer cells; however, the role of autophagy in fluvastatin-induced inhibition of breast cancer metastasis is unknown. Therefore, this study aimed to determine this mechanism. The effect of fluvastatin on human hormone receptor-negative breast cancer cells was evaluated in vitro via migration and wound healing assays, western blotting, and morphological measurements, as well as in vivo using a mouse xenograft model. Chloroquine, a prophylactic medication used to prevent malaria in humans was used as an autophagy inhibitor. We found that fluvastatin administration effectively prevented the migration/invasion of triple-negative breast cancer cells, an effect that was largely dependent on the induction of autophagy. Administration of the autophagy inhibitor chloroquine prevented the fluvastatin-induced suppression of lung metastasis in the nude mouse model. Furthermore, fluvastatin increased Ras homolog family member B (RhoB) expression, and the autophagy and anti-metastatic activity induced by fluvastatin were predominantly dependent on the regulation of RhoB through the protein kinase B-mammalian target of rapamycin (Akt-mTOR) signaling pathway. These results suggest that fluvastatin inhibits the metastasis of triple-negative breast cancer cells by modulating autophagy via the up regulation of RhoB through the AKT-mTOR signaling pathway. Fluvastatin may be a promising therapeutic option for patients with triple-negative breast cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The objective of present study was to develop hydrogel based nanoemulsion (NE) drug delivery system for transdermal delivery and evaluate its potential in in vivo anti-osteoporotic activity. NE was ...prepared using aqueous phase titration method and characterized for droplet size, zeta potential and morphology. It was then formulated into hydrogel based NE gel using carbopol 940 as gelling agent. NE gel was evaluated for pH, viscosity, in vitro/ex vivo permeation studies and in vivo anti-osteoporotic activity. The results indicated formation of spherical, nano sized globules of NE ranging from 11.17 ± 0.24 to 128.8 ± 0.16 nm with polydispersity of <0.5. In vitro and ex vivo permeation studies showed significantly higher permeation of NE as well as NE gel in comparison to fluvastatin solution indicating that NE gel can effectively penetrate through skin layers. In vivo anti-osteoporotic results demonstrated formation of new bone in trabecular region of osteoporotic rat femurs through micro-CT scanning radiographs. Biomechanical strength testing demonstrated greater load bearing capacity of rat femurs in the treated animals in comparison with the osteoporotic group. Thus, developed NE gel formulation of fluvastatin demonstrated greater potential for transdermal delivery and in the treatment of osteoporosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Fluvastatin and atorvastatin are inhibitors of hydroxy-methylglutaryl-CoA (HMG-CoA) reductase, the enzyme that converts HMG-CoA to mevalonic acid (MVA). The present study reports for the first time ...the analysis of mevalonolactone (MVL) in plasma samples by UPLC-MS/MS as well as the use of MVA, analyzed as MVL, as a pharmacodynamics parameter of fluvastatin in multiple oral doses (20, 40 or 80 mg/day for 7 days) and atorvastatin in a single oral dose (20, 40 or 80 mg) in healthy female volunteers. this study presents the use of MVL exposure as a pharmacodynamics biomarker of fluvastatin in multiple oral doses (20, 40 or 80 mg/day for 7 days) or atorvastatin in a single oral dose (20, 40 or 80 mg) in healthy volunteers (n = 30). The administration of multiple doses of fluvastatin (n = 15) does not alter the values (geometric mean and 95 % CI) of AUC0–24 h of MVL 72.00 (57.49–90.18) vs 65.57 (51.73–83.12) ng∙h/mL, but reduces AUC0–6 h 15.33 (11.85–19.83) vs 8.15 (6.18–10.75) ng∙h/mL by approximately 47 %, whereas single oral dose administration of atorvastatin (n = 15) reduces both AUC0–24 h 75.79 (65.10–88.24) vs 32.88 (27.05–39.96) ng∙h/mL and AUC0–6 h 17.07 (13.87–21.01) vs 7.01 (5.99–8.22) ng∙h/mL values by approximately 57 % and 59 %, respectively. In conclusion, the data show that the plasma exposure of MVL represents a reliable pharmacodynamic parameter for PK-PD (pharmacokinetic-pharmacodynamic) studies of fluvastatin in multiple doses and atorvastatin in a single dose.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Novel magnetic MOFs-Starch hydrogel has been synthesized.•High surface area (528.39 m2/g) of the MOFs-Starch hydrogel was confirmed.•Maximum swelling ratio (1000.0 %) of the hydrogel at pH 10, 180 ...min and 25 °C.•Adsorptive removal of Fluvastatin statin drug was optimized.•Adsorption was best fitted with Langmuir isotherm and pseudo-second models.
Growing interests and efforts have been recently focused on design and assembly of novel hydrogel nanosorbents for removal of drugs from wastewater. Therefore, this work is aimed to immobilize and encapsulate starch hydrogel matrix onto metal organic frameworks (MOFs) and dope with nanomagnetite. The magnetic MOFs-Starch hydrogel (NFe3O4@Zn(GA)/Starch-Hydrogel) was synthesized via microwave irradiation process and characterized with high surface area (528.39 m2/g), mesoporous with pore size 2.90 nm and highly crystalline structure. The maximum swelling ratio (1000.0 %) was optimized at pH 10, 180 min and 25 °C. The validity of NFe3O4@Zn(GA)/Starch-Hydrogel for adsorptive removal of Fluvastatin statin drug provided maximum equilibrium adsorption capacity 782.05 mg g−1. The Langmuir isotherm and pseudo-second kinetics models were correlated well with the computed correlation coefficient values 0.9991 and 0.9997, respectively. The validity of NFe3O4@Zn(GA)/Starch-Hydrogel for removal of FLV statin drug from real water matrices was confirmed in the range 96.15–99.99 %.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from limitations.
We searched in ...PubMed for existing systematic reviews and individual open-label or double-blinded randomized controlled trials that compared a statin with a placebo or another, which were published in English until January 01, 2018. We performed a random-effect pairwise meta-analysis of all statins as a class and network meta-analysis for the specific statins on different benefit and harm outcomes.
In the pairwise meta-analyses, statins as a class showed statistically significant risk reductions on non-fatal MI (risk ratio RR 0.62, 95% CI 0.53-0.72), CVD mortality (RR 0.80, 0.71-0.91), all-cause mortality (RR 0.89, 0.85-0.93), non-fatal stroke (RR 0.83, 0.75-0.92), unstable angina (RR 0.75, 0.63-0.91), and composite major cardiovascular events (RR 0.74, 0.67-0.81). Statins increased statistically significantly relative and absolute risks of myopathy (RR 1.08, 1.01-1.15; Risk difference RD 13, 2-24 per 10,000 person-years); renal dysfunction (RR 1.12, 1.00-1.26; RD 16, 0-36 per 10,000 person-years); and hepatic dysfunction (RR 1.16, 1.02-1.31; RD 8, 1-16 per 10,000 person-years). The drug-level network meta-analyses showed that atorvastatin and rosuvastatin were most effective in reducing CVD events while atorvastatin appeared to have the best safety profile.
All statins showed statistically significant risk reduction of CVD and all-cause mortality in primary prevention populations while increasing the risk for some harm risks. However, the benefit-harm profile differed by statin type. A quantitative assessment of the benefit-harm balance is thus needed since meta-analyses alone are insufficient to inform whether statins provide net benefit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA‐dependent RNA polymerase that plays a key role in HCV replication, and, hence, NS5B is an attractive target for hepatitis C drug ...discovery. Hepatitis C is a chronic liver disease affecting the global population significantly. Many NS5B inhibitors targeting active site were launched in recent years, however, still there exists a pressing need for cost‐effective therapies with pan genotypic activity and therapies targeting niche HCV population with comorbities and resistant to earlier therapies. The objective of the current study is to identify potential anti‐HCV agents from FDA approved drugs that are already in the market for a different disease—Drug repurposing approach. A combination of computational chemistry and computational biology techniques was used to discover potential therapies for hepatitis C targeting the NS5B Thumb I allosteric site. Computational chemistry analysis emphasized the fact that fluvastatin, a lipid lowering agent, and olopatadine, an antihistamine, exhibited good binding affinity to NS5B. In addition, gene set enrichment analysis brought to light the significant overlap between disease characteristic features and the mechanism of action of fluvastatin and olopatadine. The current study concludes the potentially beneficial use of fluvastatin in niche hepatitis C patient population suffering from nonalcoholic fatty liver diseases.
The current study focuses on identification of nonstructural protein 5B inhibitors from existing drugs using cheminformatics and conforming the biological activity of hit drugs through genomics analysis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Accumulating evidence indicates that statins reduce the risk of different cancers and inhibit the proliferation of liver cancer cells. This study aims to explore whether the electrostatic conjugation ...of optimized fluvastatin (FLV) to human immunodeficiency virus type 1 (HIV-1) trans-activator transcription peptide (TAT) would enhance the anti-proliferative activity against HepG2 cells. FLV-TAT conjugation was optimized to achieve the lowest size with highest zeta potential. Nine formulae were constructed, using a factorial design with three factors-FLV concentration, TAT concentration, and pH of the medium-while the responses were zeta potential and size. The optimized formula showed a particle size of 199.24 nm and 29.14 mV zeta potential. Data indicates that conjugation of FLV to TAT (optimized formula) significantly enhances anti-proliferative activity and uptake by HepG2 cells when compared to raw FLV. Flow cytometry showed significant accumulation of cells in the pre-G phase, which highlights higher apoptotic activity. Annexin V staining indicated a significant increase in total cell death in early and late apoptosis. This was confirmed by significantly elevated caspase 3 in cells exposed to FLV-TAT preparation. In conclusion, the FLV-TAT optimized formula exhibited improved anti-proliferative action against HepG2. This is partially attributed to the enhanced apoptotic effects and cellular uptake of FLV.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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