Herb-drug interaction: Effect of sinapic acid on the pharmacokinetics of dasatinib in rats.

Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

Effects of Apigenin on Pharmacokinetics of Dasatinib and Probable Interaction Mechanism.

Dasatinib (DAS), a narrow-therapeutic index drug, Bcr-Abl, and Src family kinases multitarget inhibitor have been approved for chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia (Ph+ ALL). Apigenin (APG) has a long history of human usage in food, herbs, health supplements, and traditional medicine, and it poses low risk of damage. The concomitant use of APG containing herbs/foods and traditional medicine may alter the pharmacokinetics of DAS, that probably lead to possible herb-drug interactions. The pharmacokinetic interaction of APG pretreatment with DAS in rat plasma following single and co-oral dosing was successfully deliberated using the UPLC-MS/MS method. The in vivo pharmacokinetics and protein expression of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 demonstrate that APG pretreatment has potential to drastically changed the DAS pharmacokinetics where escalation in the Cmax, AUC(0-t), AUMC(0-inf_obs), T1/2, Tmax, and MRT and reduction in Kel, Vd, and Cl significantly in rats pretreated with APG 40 mg/kg, thus escalating systemic bioavailability and increasing the rate of absorption via modulation of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 protein expression. Therefore, the concomitant consumption of APG containing food or traditional herb with DAS may cause serious life-threatening drug interactions and more systematic clinical study on herb-drug interactions is required, as well as adequate regulation in herbal safety and efficacy.

Isolation and Identification of Bioactive Compounds from Bidens spp. Using HPLC-DAD and GC-MS Analysis and Their Biological Activity as Anticancer Molecules.

The genus Bidens a member of family Compositae, is widely documented as an ethno-medicinally important genus of plants. In the present study, anticancer potential of three ethno-medicinally important species i.e., B. bipinnata, B. biternata and B. pilosa were tested. For in-vitro evaluation, an MTT (Thiazolyl blue tetrazolium bromide) assay was performed against cervical cancer cells (HeLa), hepatocellular carcinoma (HepG), and adenocarcinoma human alveolar basal epithelial cells (A549). For in vivo evaluation, Artemia salina, Danio rerio, and Caenorhabditis elegans were used. Among all the tested extracts, the ethanol extract of B. biternata appeared to have highest anticancer activity, and the compounds responsible for this activity were identified to be Tris (2,4-di-tert-butylphenyl), 4-hydroxy-2,4'-dimethoxychalcone, and 2,4-di-tert-butylphenol. This is the first report of the isolation of Tris (2,4-di-tert-butylphenyl) phosphate from the genus Bidens and the first report of 4-hydroxy-2,4'-dimethoxychalcone and 2,4-di-tert-butylphenol from B. biternata. Among the isolated compounds, 4-hydroxy-2,4'-dimethoxychalcone showed the highest anticancer activity with an LD50 value of 236.7 µg/mL. Therefore, this compound carries promising potential for being established as a pharmaceutical for chemoprevention and chemotherapy.

Cisplatin bioconjugated enzymatic GNPs amplify the effect of cisplatin with acquiescence.

Enzymatic gold nanoparticles (B-GNPs) have been synthesized using a natural anticancer agent bromelain (a cysteine protease) and these nanoparticles were used to bioconjugate Cisplatin (highly effective against osteosarcoma and lung cancer). Cisplatin bioconjugated bromelain encapsulated gold nanoparticles (B-C-GNPs) were found profoundly potent against same cancers at much lower concentration with minimum side effects due to the synergistic effect of bromelain. The B-C-GNPs have been observed to inhibit the proliferation of osteosarcoma cell lines Saos-2 and MG-63 with IC50 estimation of 4.51 µg/ml and 3.21 µg/ml, respectively, and against small lung cancer cell line A-549 with IC50 2.5 µg/ml which is lower than IC50 of cisplatin against same cell lines. The B-GNPs/B-C-GNPs were characterized by TEM, UV-Visible spectroscopy, Zeta potential and DLS to confirm the production, purity, crystalline nature, stability of nanoemulsion, size and shape distribution. The change in 2D and 3D conformation of bromelain after encapsulation was studied by Circular Dichroism and Fluorometry, respectively. It was found that after encapsulation, a 19.4% loss in secondary structure was observed, but tertiary structure was not altered significantly and this loss improved the anticancer activity. The confirmation of bioconjugation of cisplatin with B-GNPs was done by UV-Visible spectroscopy, TEM, FTIR, 2D 1H NMR DOSY and ICP-MS. Further, it was found that almost ~4 cisplatin molecules bound with each B-GNPs nanoparticle.

Beetroot juice alleviates isoproterenol-induced myocardial damage by reducing oxidative stress, inflammation, and apoptosis in rats.

Beetroot (Beta vulgaris L.) juice (BRJ) is a good source of betalain (betacyanins and betaxanthin) pigments and exhibits antioxidant, anti-inflammatory, and chemo-preventive activities in vitro and in vivo. The current study was performed to determine the cardioprotective effect of BRJ on lipid peroxidation, antioxidant defense, functional impairment, and histopathology in rats with isoproterenol (ISP)-induced myocardial injury. Myocardial ischemia was induced by ISP (85 mg/kg) s.c. injection at 24 h intervals, followed by oral administration of BRJ for 28 days at doses of 150 and 300 mg/kg. ISP-induced myocardial damage was confirmed by an increase in heart weight to body weight ratio, % infarction size, serum cardiac indices (AST, ALT, GGT, ALP, LDH and CK-MB), and histological alterations in the myocardium. Pretreatment with BRJ (150 and 300 mg/kg) followed by ISP induction reduced oxidative/nitrosative stress and restored the cardiac endogenous antioxidants in rats. ISP augmented cardiac inflammatory cytokines (TNF-α, IL-6 and IL-10), myeloperoxidase activity, NF-κB DNA binding and protein expression of NF-κB (p65), and the hyperlipidemia level was significantly reduced by the BRJ pretreatment. Furthermore, the BRJ pretreatment significantly reduced caspase-3, Bax, and MMP-9 protein expression, enhanced the Bcl-2 antiapoptotic protein expression, alleviated the extent of histological damage, myonecrosis, and edema, and maintained the architecture of cardiomyocytes. These findings suggest that BRJ pretreatment mitigates cardiac dysfunction and structural damages by decreasing oxidative stress, inflammation, and apoptosis in cardiac tissues. These results further support the use of BRJ in traditional medicine against cardiovascular diseases.

Effects of sinapic acid on hepatic cytochrome P450 3A2, 2C11, and intestinal P-glycoprotein on the pharmacokinetics of oral carbamazepine in rats: Potential food/herb-drug interaction.

Dietary supplements, herbal medicines, and other foods may affect the pharmacokinetics and/or pharmacodynamics of carbamazepine (CBZ), which may possibly lead to potential drug-drug/herb-drug interactions, as CBZ has a narrow therapeutic window. Sinapic acid (SA) is a bioactive phytoconstituent used as a dietary supplement for the treatment of epilepsy. This study determined the effects of SA on the pharmacokinetics of CBZ and proposed a possible interaction mechanism in twenty-four male wistar rats (180-210 g). A single CBZ dose (80 mg/kg) was administered orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The CBZ concentration in plasma samples was determined by using a sensitive reversed-phase high-performance liquid chromatography assay. The pharmacokinetic parameters were calculated by using non-compartmental analysis. Significance was determined through Dunnett's multiple comparison test or one-way analysis of variance as appropriate; p < 0.05 were considered significant. The change in the pharmacokinetic parameters (Cmax, Tmax, AUC0-t, AUC0-∞, T½, and kel) of CBZ was evaluated after the administration of CBZ alone or after CBZ co-administration with SA pretreatment. The plasma concentration of CBZ was higher after SA pretreatment than that without pretreatment. The pharmacokinetics of orally administered CBZ were found to be significantly altered (p < 0.05) in rats pretreated with SA compared to those in rats administered CBZ alone. The increases in the Cmax, AUC0-t, T1/2, and MRT of CBZ were 29.79%, 57.18%, 77.18%, and 58.31%, respectively, whereas the kel and apparent oral CL/F were significantly reduced (p < 0.05) in rats pretreated with SA compared to those in rats not pretreated with SA (43.87% and 42.50%, respectively). However, no significant change was observed in the Tmax of CBZ in rats pretreated with SA compared to that in rats that did not receive pretreatment. The enhancement in Cmax, AUC0-t, T1/2, and MRT and the reduction in Kel and CL/F values resulted from the significant inhibition of CYP3 A2, the CYP2C11-mediated metabolism of CBZ in the liver, and the inhibition of intestinal P-glycoprotein/MDR1, which enhanced the rate of CBZ absorption. Further studies are required to determine the clinical relevance of these observations.

Magnetic, structural and magnetocaloric properties of Ni-Si and Ni-Al thermoseeds for self-controlled hyperthermia.

Self-controlled hyperthermia is a non-invasive technique used to kill or destroy cancer cells while preserving normal surrounding tissues. We have explored bulk magnetic Ni-Si and Ni-Al alloys as a potential thermoseeds. The structural, magnetic and magnetocaloric properties of the samples were investigated, including saturation magnetisation, Curie temperature (TC), and magnetic and thermal hysteresis, using room temperature X-ray diffraction and magnetometry. The annealing time, temperature and the effects of homogenising the thermoseeds were studied to determine the functional hyperthermia applications. The bulk Ni-Si and Ni-Al binary alloys have Curie temperatures in the desired range, 316 K-319 K (43 °C-46 °C), which is suitable for magnetic hyperthermia applications. We have found that TC strictly follows a linear trend with doping concentration over a wide range of temperature. The magnetic ordering temperature and the magnetic properties can be controlled through substitution in these binary alloys.

In vitro antimicrobial activities of different solvent extracted samples from Iris germinica.

Antibacterial and antifungal activities of different solvents extracted samples of Iris germinica were carried out through disc diffusion assay. For this purpose five different solvent extracts were prepared with two concentrations (1 and 2 mg disc(-1)) and their antimicrobial activity was tested using disc diffusion assay against eight pathogenic bacteria viz. Staphylococcus aureus, B. subtilis, Bacillus atrophaeus, Escherichia coli, Pseudomonas aeruginosa, Erwinia carotovara, Klebsiella pneumoniae, Salmonella typhi and one fungal specie (Candida albicans). Butanol and ethyl acetate fraction were more effective to control the growth of different pathogens followed by chloroform, hexane and aqueous fractions respectively. C. albicans, S. aureus E. carotovara, B. atrophaeus and E. coli were comparatively susceptible inhibited by all extracts of I. germinica compared with the rest of microbes. Maximum activity was shown by ethyl acetate extracted samples against B. atrophaeus followed by the same solvent against E. carotovara. Butanol extracted samples were effective against B. subtilis showing 62% reduction in growth at 1 or 2mg disc(-1) concentration. From these results it can be concluded that different solvent extracted samples from the leaves of I. germinica possess varying degree of antimicrobial against different micro-organisms and can be a good sources of antibiotics for the treatment of certain bacterial and fungal diseases.

Antioxidant Potential and In Situ Analysis of Major and Trace Element Determination of Ood-saleeb, a Known Unani Herbal Medicine by ICP-MS.

The intention of the present research work was to investigate the antioxidant activity and trace element analysis of Ood-saleeb, a known herbal medicine. Preliminary screening of phytochemicals showed that the extract of Ood-saleeb had flavonoids and phenolics. The significant activities in all antioxidant assays were observed in the extract of Ood-saleeb in comparison with the standard antioxidant with respect to dose of Ood-saleeb. Incredible activities to scavenge reactive oxygen species were also observed by the extract of Ood-saleeb. The IC50 values of all factors were determined using ascorbic acid as a standard. The inductive coupled plasma-mass spectroscopy (ICP-MS) was employed for the estimation of trace elements in Ood-saleeb extract. The concentrations of up to 18 elements were detected successfully. Silicon was found in high concentration (85.3 µg/g) while lithium was in low concentration (3 ng/g). The trace elements in the sample were found at different percentage levels which play a key role in the treatment of diseases.

Dietary Pectin Increases Intestinal Crypt Stem Cell Survival following Radiation Injury.

Gastrointestinal (GI) mucosal damage is a devastating adverse effect of radiation therapy. We have recently reported that expression of Dclk1, a Tuft cell and tumor stem cell (TSC) marker, 24h after high dose total-body gamma-IR (TBI) can be used as a surrogate marker for crypt survival. Dietary pectin has been demonstrated to possess chemopreventive properties, whereas its radioprotective property has not been studied. The aim of this study was to determine the effects of dietary pectin on ionizing radiation (IR)-induced intestinal stem cell (ISC) deletion, crypt and overall survival following lethal TBI. C57BL/6 mice received a 6% pectin diet and 0.5% pectin drinking water (pre-IR mice received pectin one week before TBI until death; post-IR mice received pectin after TBI until death). Animals were exposed to TBI (14 Gy) and euthanized at 24 and 84h post-IR to assess ISC deletion and crypt survival respectively. Animals were also subjected to overall survival studies following TBI. In pre-IR treatment group, we observed a three-fold increase in ISC/crypt survival, a two-fold increase in Dclk1+ stem cells, increased overall survival (median 10d vs. 7d), and increased expression of Dclk1, Msi1, Lgr5, Bmi1, and Notch1 (in small intestine) post-TBI in pectin treated mice compared to controls. We also observed increased survival of mice treated with pectin (post-IR) compared to controls. Dietary pectin is a radioprotective agent; prevents IR-induced deletion of potential reserve ISCs; facilitates crypt regeneration; and ultimately promotes overall survival. Given the anti-cancer activity of pectin, our data support a potential role for dietary pectin as an agent that can be administered to patients receiving radiation therapy to protect against radiation-induces mucositis.