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Abstract

Two-step targeted 2D planar chromatographic method (2DTLC) was used in the determination of ginkgolic acids in pharmaceuticals and dietary supplements. The choice of the extraction method and the separation technique was guided by the formulation type (capsule, tablet, tincture) with expected low amounts of ginkgolic acids in the analyzed herbal samples. Separation of ginkgolic acids C15:1 and C17:1 on HPTLC RP18 WF254s was preceded by its separation from the sample matrix on TLC Si60 F254s. Mobile phases consisted of acetonitrile/water/formic acid (80:20:1, V/V/V) and n-heptane/ethyl acetate/formic acid (20:30:1, V/V/V), resp. Identification of separated compounds was based on 2D-TLC co-chromatography with reference substances and off-line 2D-TLC x HPLC-DAD-ESI-MS analysis. Quantification of ginkgolic acids C15:1 and C17:1 was conducted densitometrically. Among the analyzed products, the presence of ginkgolic acids was confirmed only in herbal drugs containing 60 % ethanolic tinctures of Ginkgo biloba leaves. The use of TLC in the quantification of ginkgolic acids C15:1 and C17:1 in ginkgo extracts was described for the first time.

Abstract

The biopharmaceutical classification of drugs was designed as a basis for bio-waivers – a mechanism with the double ethical benefit of delivering new drug formulations to the market with less human testing and lower cost. However, many drugs defy simple classification because in vitro permeability and stability assessment can be challenging as shown in this study for desloratadine. Literature shows that desloratadine is highly soluble, while data on luminal stability and permeability are circumstantial. Combined with borderline bioavailability and not really known fraction of absorbed dose, desloratadine was found to be a good example for showing the innovative in vitro approaches necessary to unambiguously classify desloratadine according to Biopharmaceutical Classification System (BCS) guideline. Presented study undoubtedly confirmed that desloratadine solubility is high and dissolution is very rapid for immediate release reference tablets. We have demonstrated deslorata-dine stability under legally required conditions and also in more physiologically relevant media. High in vitro desloratadine permeability was confirmed using Caco-2 and Parallel Artificial Membrane Permeability Assay (PAMPA). Well-established in vitro model with rat intestinal tissue could not be used due to reasons elaborated in this paper.

Abstract

Curcumin is a lipophilic anti-cancer compound extracted from turmeric. Our previous study demonstrated that the curcumin-loaded nanostructured lipid carrier (Cur-NLC) exhibits superior anti-cancer activity in inhibiting proliferation as well as inducing apoptosis of human HepG2 cells compared to native curcumin. This study aims to unveil the mechanisms underlying the pro-apoptotic effect of Cur-NLC on HepG2 cells. Evidence indicates that low expression of death receptors (DRs) on cancer cell membranes leads to attenuated apoptosis signaling. This study showed that Cur-NLC significantly increased total expression of DR5 protein while simultaneously upregulated cell membrane expression of DR5. Cur-NLC significantly increased caspase-8 and caspase-3 activities, accompanied by increased apoptosis. Furthermore, enhanced apoptosis was inhibited in the presence of a pan-caspase inhibitor, Z-VAD-FMK. Therefore, Cur-NLC induced activation of the extrinsic apoptosis pathway via modulating the DR5/caspase-8/-3 mediated apoptosis pathway in HepG2 cells, suggesting that Cur-NLC is a promising therapeutic agent or supplement for the treatment of hepatocellular carcinoma.

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) had emerged and spread because of the worldwide travel and inefficient healthcare provided for the infected patients in several countries. Herein we investigated the anti-MERS-CoV activity of newly synthesized sixteen halogenated triazole compounds through the inhibition of helicase activity using the FRET assay. All new compounds underwent justification for their target structures via microanalytical and spectral data. SAR studies were performed. Biological results revealed that the most potent compounds were 4-(cyclopent-1-en-3-ylamino)-5-(2-(4-iodophenyl)hydrazinyl)-4H-1,2,4-triazole-3-thiol (16) and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol (12). In silico molecular docking of the most potent compounds was performed to the active binding site of MERS-CoV helicase nsp13. Molecular docking results are in agreement with experimental findings.

Abstract

The introduction of the second generation triptans in clinical and experimental practice was a major progress in the pharmacotherapy of migraine. Frovatriptan is a second generation triptan with strong 5-HT1B/1D serotonergic agonism and low 5-HT1A/7 receptor affinity, while almotriptan possesses not only the typical 5-HT1B/1D receptor agonist activity, but shows an affinity to the 5-HT1F receptor. The aim of our study was to assess the impact of frovatriptan and almotriptan on hemodynamics in male and female rats. We used a non-invasive “tail-cuff” method to measure the arterial blood pressure. Female and male Wistar rats were treated separately with high and low dosages of frovatriptan and almotriptan. Male and female rats showed reduction in all hemodynamic parameters, but only male rats showed an increase in the heart rate. In general, we could say that both almotriptan and frovatriptan potentiate cardiovascular safety.

Abstract

Self-medication of children by their parents (SMCP) is an important public health issue as the effects and potential risks may be unpredictable. The objective of this first national Montenegrin study was to assess the prevalence of and factors influencing SMCP among schoolchildren. Data were obtained from a national representative sample of 4496 schoolchildren aged 7–13 years (50.4 % boys). Parents/caregivers completed a questionnaire concerning their demographic characteristics, socio-economic and cultural status, as well as the self-medication (SM) of their children. The association between SMCP and parents’ socio-economic, demographic or cultural status was assessed by logistic regression analyses. The prevalence rate of SMCP was 24.6 %. Univariate logistic regression showed that maternal socio-demographic characteristics (educational level, employment status, health care profession and smoking habits) were relevant for SMCP. In a multiple logistic regression the independent effect /adjusted odds ratio (AOR) (95 % CI)/of maternal factors on SMCP remained for: education /2.23 (1.18–4.24)/, university-level vs. no education; profession /1.50 (1.07–3.00)/, health profession vs. non-health profession; and smoking habit /1.22 (1.04–1.42)/smokers vs. non-smokers. SMCP may be expected for every fourth child in Montenegro. Specific maternal factors that independently raise the probability of SMCP are higher education, health profession and smoking.

Abstract

Heliangolide is a naturally occurring sesquiterpene lactone and its derivatives are biologically active compounds present in most medicinal plants. This study evaluated the antioxidant and antidiabetic properties of a heliangolide sesquiterpene lactone isolated from Helianthus annuus L. leaves. The heliangolide sesquiterpene lactone was isolated through a combination of solvent-solvent partitioning, column chromatography, thin layer chromatography and high-performance liquid chromatography techniques. The antioxidant activity of the compound was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide radical scavenging assays while the antidiabetic effects were investigated in alloxan-induced diabetic rats. The heliangolide derivative at the concentration of 954.2 µmol L−1 showed 23.7 % DPPH and 26 % nitric oxide radical inhibitions compared with 96.6 and 50.9 %, resp., displayed by the controls (2,271.2 µmol L−1). It also reduced the fasting blood glucose (FBG) levels in a time-dependent manner. The highest activity was recorded within 6 h post-treatment at 0.2 mmol kg−1 bm. The heliangolide derivative exhibited significant (p < 0.05) antioxidant and antidiabetic properties and provides a basis for further development of constituents of Helianthus annuus leaves for the management of such diseases.

Abstract

Breast cancer is the most common cancer and is the leading cause of cancer deaths among women worldwide. Despite the availability of numerous therapeutics for breast cancer management, cytotoxicity and emergence of drug resistance are major challenges that limit their benefits. The acidic microenvironment surrounding tumor cells is a common feature inducing cancer cell invasiveness and chemoresistance. Proton pump inhibitors (PPIs) are one of the most commonly prescribed drugs for the treatment of acid-related conditions. PPIs have been reported to exhibit antitumorigenic effects in many cancer types. In this study, the anti-proliferative and anti-migratory effects of PPIs in three breast cancer cell lines; MCF-7, T47D, and MDA-MB-231 cells, have been investigated. In addition, the combined effects of PPIs with anticancer drugs, as well as the mechanism of PPI-mediated anti-proliferative activity were evaluated. The anti-proliferative and combined effects of PPIs were evaluated by MTT assay. Cell migration was assessed using the wound-healing assay. The mechanism of cell death was assessed using annexin V-FITC/propidium iodide staining flow cytometry method. Our results indicated that PPIs treatment significantly inhibited the growth of breast cancer cells in a dose-dependent manner. The antiproliferative activity of PPIs was significantly induced by apoptosis in all tested cell lines. The combined treatment of PPIs with doxorubicin resulted in a synergistic effect in all cell lines, whereas the combined treatment with raloxifene exhibited synergistic effect in T47D cells only and additive effects in MDA-MB-231 and MCF-7 cells. In addition, PPIs treatment significantly reduced cell migration in MDA-MB-231 cells. In conclusion, the addition of PPIs to the treatment regimen of breast cancer appears to be a promising strategy to potentiate the efficacy of chemotherapy and may suppress cancer metastasis.

Abstract

The incidence of mortality of prostate cancer (PCa) has been an uptrend in recent years. Our previous study showed that the sex-determining region Y-box 7 (SOX7) was low-expressed and served as a tumor suppressor in PCa cells. Here, we describe the effects of polyphyllin D (PD) on proliferation and cell cycle modifications of PCa cells, and whether SOX7 participates in this process. PC-3 cells were cultured in complete medium containing PD for 12, 24, and 48 h. MTT assay was used to investigate the cytotoxic effects of PD. Cell cycle progression was analyzed using propidium iodide (PI) staining, and protein levels were assayed by Western blot analysis. Our results showed low expression of SOX7 in PCa tissues/cells compared to their non-tumorous counterparts/RWPE-1 cells. Moreover, PD inhibited the proliferation of PC-3 cells in a dose- and time-dependent manner. PD induced G0/G1 cell cycle arrest, while co-treatment with short interfering RNA targeting SOX7 (siSOX7) had reversed this effect. PD downregulated SOX7, cyclin D1, cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) expressions in a dose-dependent manner, whereas co-treatment of siSOX7 and PD rescued the PD-inhibited cyclin D1 expression. However, no obvious changes were observed in CDK4 or CDK6 expression. These results indicate that SOX7 is involved in PD-induced PC-3 cell cycle arrest through down-regulation of cyclin D1.

Abstract

A series of nine new 2,3-disubstituted 4(3H)-quinazolin-4-one derivatives was furnished starting from the 2-propyl-4(3H)-quinazo-line-4-one (2). The reinvestigation of the key starting quinazolinone 2 was performed under microwave irradiation (MW) and solvent-free conditions. Combination of MW and phase-transfer catalysis using tetrabutylammonium benzoate (TBAB) as a novel neutral ionic catalyst was used for carrying out N-alkylation and condensation reactions of compound 2 as a simple, efficient and eco-friendly technique. The structure of the synthesized compounds was elucidated using different spectral and chemical analyses. In vitro antimicrobial activity of the compounds was investigated against four bacterial and two fungal strains; very modest activity was achieved. Some of the synthesized compounds were screened for their antitumor activity against different human tumor cell lines. The screened compounds exhibited a significant antitumor activity on some of the cancer cell lines, melanoma (SK-MEL-2), ovarian cancer (IGROV1), renal cancer (TK-10), prostate cancer (PC-3), breast cancer (MCF7) and colon cancer (HT29). The most active, even more active than the reference 5-fluorouracil, were found to be ethyl 4-[(4-oxo-2-propylquinazolin-3(4H)-yl)methyl]benzoate (3c), 3-{2-[6-(pyrrolidin-1-yl-sulfonyl)-1,2,3,4-tetrahydroquinoline]-2-oxoethyl}-2-propylquinazolin--4(3H)-one (3e), N’-[(E)-(2H-1,3-benzodioxo-5-yl)methylidene]-2-(4-oxo-2-propylquinazolin-3(4H)-yl)acetohydrazide (10a), N’-[(E)-(4-hydroxyphenyl)methylidene]-2-(4-oxo-2-propylquinazo-lin-3(4H) -yl)acetohydrazide (10b) and N’-[(E)-(4-nitrophenyl)methyl idene]-2-(4-oxo-2-propylquinazolin-3(4H)-yl)acetohydrazide (10c).