Showing papers in "Die Pharmazie in 2013"

Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities.

Abstract: Resveratrol has been shown to possess multiple pharmacological activities including anti-tumor, anti-inflammation and immunomodulation, and participates in the regulation of the NF-kappaB signaling pathway. However, the mechanism of the NF-kappaB signaling pathway inhibited by resveratrol remains obscure. In this study, we first examined the effect of resveratrol on endogenous and TNF-alpha-induced NF-kappaB activation, and found that resveratrol suppressed NF-kappaB activation in a dose dependent manner. Resveratrol reduced the transcriptional activity of p65, but neither affected the DNA-binding activity of NF-kappaB nor blocked the nuclear translocation of p65. Moreover, resveratrol had no effect on the expression level of IkappaBalpha protein and inhibited IkappaBalpha degradation. Further investigation revealed that resveratrol blocked the ubiquitination of NEMO and inhibited IkappaB kinase(beta)-mediated NF-kappaB activation. These results demonstrated that resveratrol effectively suppressed NF-kappaB signaling through inhibiting the activities of NF-kappaB and IkappaB kinase. Therefore, resveratrol may provide a novel approach to treating inflammation-associated diseases and cancer.

Epidermal growth factor receptor localized to exosome membranes as a possible biomarker for lung cancer diagnosis.

Abstract: Detection of drug-target proteins and biomarkers that are expressed in cancer tissue has significant potential for both diagnosis and treatment of cancer. However, current immuno-histochemical and cytogenetic analyses of biopsy specimens for pre-operational diagnosis are highly invasive and often difficult to apply to lung cancer patients. The purpose of this study was to evaluate the possible utility of determining epidermal growth factor receptor (EGFR) expression on exosomal membranes using a targeted ELISA with an anti-CD81 antibody as a capture antibody for lung cancer diagnosis. While soluble EGFR (sEGFR) levels in plasma were not remarkably different between lung cancer patients and normal controls, significantly higher exosomal EGFR expression levels were observed in 5/9 cancer cases compared to normal controls. These results suggest that measurement of exosomal protein levels could be useful for in vitro diagnosis, and that exosomal EGFR is a possible biomarker for characterization of lung cancer.

Fungal endophytes - secret producers of bioactive plant metabolites.

Abstract: The potential of endophytic fungi as promising sources of bioactive natural products continues to attract broad attention Endophytic fungi are defined as fungi that live asymptomatically within the tissues of higher plants This overview will highlight the uniqueness of endophytic fungi as alternative sources of pharmaceutically valuable compounds originally isolated from higher plants, eg paclitaxel, camptothecin and podophyllotoxin In addition, it will shed light on the fungal biosynthesis of plant associated metabolites as well as new approaches developed to improve the production of commercially important plant derived compounds with the involvement of endophytic fungi

A systematic review of the efficacy and pharmacological profile of Herba Epimedii in osteoporosis therapy.

Abstract: The purpose of this systematic review is to assess the efficacy and pharmacological profiles of Herba Epimedii in osteoporosis therapy. Four databases were extensively retrieved that include two Chinese electronic databases (VIP Information and CNKI) and two English electronic databases (CA and MEDLINE). Herba Epimedii has been an important traditional herbal medicine for centuries in China and other Asian countries. Recently, quite a few pharmacological effects of Herba Epimedii, its extracts and active components have been identified that include improving bone health and cardiovascular function, regulating hormone level, modulating immunological function, and inhibiting tumor growth. The anti-osteoporosis activity of Herba Epimedii and its extracts have attracted world-wide attention. The literature search has revealed that a lot of studies have recently been carried out related to the bone-strengthening activity of Herba Epimedii and some of its active compounds, such as total flavonoids and icariin. Pharmacokinetic and toxicity studies have confirmed the efficacy and safety of Herba Epimedii and its most abundant active component icariin, while only a few authors have reviewed the anti-osteoporosis properties of the plants. So we summarize the work of various investigators on the effects of Herba Epimedii, its extracts and active components against osteoporosis. The underlying mechanism of osteoprotective action, derivatives of icariin, animal models and cell lines used in the research were also reviewed in this paper.

Let-7c sensitizes acquired cisplatin-resistant A549 cells by targeting ABCC2 and Bcl-XL.

Abstract: Cancer cells that develop resistance to cisplatin (DDP) are a major clinical obstacle to the successful treatment of cancer, including non-small cell lung cancer (NSCLC). Recent studies have implicated dysregulation of microRNAs (miRNAs) function in chemoresistance. Here, we explored the role of let-7c in the acquisition of DDP-resistant phenotype in A549 cells. Let-7c was downregulated in A549/DDP cell compared with A549 cells. Modulation of let-7c altered the sensitivity of A549/DDP cells to DDP through regulating DDP-induced apopotis. Furthermore, ABCC2 and Bcl-XL were identified as targets of let-7c. ABCC2 and Bcl-XL knockdown increased DDP sensitivity and DDP-induced apoptosis in A549/DDP cells. In conclusion, our findings suggested for the first time that let-7c modulate DDP response in A549/DDP cells, and one of the mechanisms was through targeting ABCC2 and Bcl-XL. Thus, let-7c could be considered for potential therapeutic application for modulating DDP-based therapy.

MicroRNA-98 sensitizes cisplatin-resistant human lung adenocarcinoma cells by up-regulation of HMGA2

Abstract: This study was done to explore the role of microRNA-98 (miR-98) in cisplatin sensitization in human lung adenocarcinoma cell line. Differential expressions of miRNAs were analysed between cisplatin-resistant human lung adenocarcinoma cell line A549/DDP and its parental cell A549 by miRNAs microarray, of which 14 miRNAs were showed to be significantly (>2-fold) up-regulated and 8 miRNAs had marked down-regulation (<0.5-fold) in A549/DDP cells compared with in A549 cells. MiR-98, a member in the let-7 family, acts as a negative regulator in the expression of HMGA2 (high mobility group A2) oncogene, and it has been shown to have a nearly 3-fold decrease in A549/DDP cells. We found that elevated expression of miR-98 led to a higher sensitivity of A549/DDP cells to cisplatin, and the protein level of HMGA2, was clearly up-regulated in both A549/DDP and A549 cells by miR-98. Moreover, both Bcl-XL and Bcl-2, were down-regulated in the Pre-miR-98(TM) transfectants cells. We for the first time demonstrated that the expression of miR-98 increases cells spontaneous apoptosis and sensitizes cells to cisplatin at least in part via HMGA2 up-regulation. Our findings provided insight into some specific miRNAs in lung cancer as potential therapeutic targets.

Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor.

Abstract: Curcumin possesses chemopreventive properties against several types of cancer, but the molecular mechanisms by which it induces apoptosis of cancer cells and inhibits cancer cell proliferation are not clearly understood. To evaluate the antitumor activity of curcumin for prostate cancer, we used an androgen dependent LNCaP prostate cancer cell line and an androgen independent PC-3 prostate cancer cell line as experimental models. We treated these cells with curcumin and then evaluated the effects of curcumin on cell cycle profiling and apoptosis, as well as the activation of NF-kaapaB and c-jun in these cells. The results showed that the ratios of apoptosis in LNCaP and PC-3 cells were significantly elevated in a dose dependent manner after exposure to curcumin. In addition, curcumin induces the G2/M cell cycle arrest of LNCaP and PC-3 cells in a dose dependent manner. Mechanistically, we found that curcumin upregulated the protein level of NF-kappaB inhibitor IkappaBalpha and downregulated protein levels of c-Jun and AR. These data suggest that curcumin is a promising agent for the treatment of both androgen-dependent and androgen-independent prostate cancer.

ABCB1 gene polymorphisms, ABCB1 haplotypes and ABCG2 c.421c > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics.

Abstract: A randomized cross-over pharmacokinetic study of rosuvastatin calcium (single dose: 5 mg, 10 mg and 20 mg; multiple doses: 10mg once daily for 7 days) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of rosuvastatin were determined by an LC-ESI-MS-MS method. Single-nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLCOB1, CYP2C9 and CYP3A5 were determined by TaqMan (MGB) genotyping assay. An impact of the aforementioned SNPs on steady state pharmacokinetic parameters [average steady state concentration (Cav,ss) and area under the plasma concentration versus time curve during the dosing interval at steady state (AUCss)], dose-normalized (based on 5 mg) pharmacokinetic parameters of single-dose rosuvastatin were further analyzed. Rosuvastatin exhibited linear pharmacokinetics and great inter-subject variability. Cav,ss, AUCss and dose-normalized peak plasma concentration (Cmax) and AUC(0-infinity) of single-dose rosuvastatin were significantly related with ABCB1 C1236T, G2677T/A and C3435T polymorphisms and ABCB1 haplotypes. Compared to homozygous wild type and heterozygous mutation gene carriers, subjects carrying the variant ABCB1 1236TT, 2677 non-G or 3435TT genotype had higher Cav,ss, AUCss, Cmax and AUC(0-infinity) (p A had a significant impact on rosuvastatin pharmacokinetics. Homozygotes (AA) carriers had obvious higher Cmax (12.20 +/- 4.09 microg x L(-1) vs 8.70 +/- 3.09 microg x L(-1), p C), CYP3A5*3 g.6986A > G, ABCG2 c.34G > A, SLCO1B1 c.521 T > C, c.388 A > G, g.11187 G > A, c.571 T > C and c.597 C > T. In addition, no difference in rosuvastatin pharmacokinetics was observed among subjects of different genders. We conclude that ABCB1 C1236T, G2677T/A and C3435T polymorphism, ABCB1 haplotypes and ABCG2 c.421C > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics in healthy Chinese volunteers, and potentially affect the efficacy and toxicity of statin therapy.

CYP2C9*3(1075A > C), ABCB1 and SLCO1B1 genetic polymorphisms and gender are determinants of inter-subject variability in pitavastatin pharmacokinetics.

Abstract: A pharmacokinetics study was conducted in 12 Chinese volunteers following a single dose of 1 mg, 2 mg and 4 mg of pitavastatin calcium in an open-label, randomized, three-period crossover design. Plasma concentrations of pitavastatin acid and pitavastatin lactone were determined by a HPLC method. Single-nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLCO1B1, CYP2C9 and CYP3A5 were determined by TaqMan (MGB) genotyping assay. An analysis was performed on the relationship between the aforementioned SNPs and dose-normalized (based on 1 mg) area under the plasma concentration-time curve extrapolated to infinity [AUC(0-infinity)] and peak plasma concentration (Cmax) values of the acid and lactone forms of pitavastatin. Pitavastatin exhibited linear pharmacokinetics and great inter-subject variability. Compared to CYP2C9*1/*1 carriers, CYP2C9*1/*3 carriers had higher AUC(0-infinity) and Cmax of pitavastatin acid and AUC(0-infinity) of pitavastatin lactone (P C and g.11187G > A on pharmacokinetics of the acid and lactone forms were observed. Compared to non-SLCO1B1*17 carriers, SLCO1B1*17 carriers had higher Cmax and AUC(0-infinity) of the acid and lactone forms (P A, c.421C > A, SLCO1B1 c.388A>G, c.571T>C and c.597C>T. We conclude that CYP2C9*3, ABCB1 G2677T/A, SLCO1B1 c.521T>C, SLCO1B1 g.11187G > A, SLCO1B1*17 and gender contribute to inter-subject variability in pitavastatin pharmacokinetics. Personalized medicine should be necessary for hypercholesterolaemic patients receiving pitavastatin.

A new perspective on old drugs: non-mitotic actions of tubulin-binding drugs play a major role in cancer treatment.

Abstract: Microtubule-targeting agents (MTAs) are the most frequently used anti-cancer drugs. They can be divided into tubulin stabilizing and destabilizing agents. Their mode of action has been ascribed to their ability to interfere with the spindle apparatus and, thus, to block mitosis leading to tumor cell death. However, this view has been challenged in the last years and it became increasingly evident that non-mitotic actions of MTAs, i.e. their ability to affect the dynamics of interphase microtubules, are the most relevant mechanism underlying their efficacy. In this review we are presenting a distinct selection of examples of studies describing biological effects of MTAs in three areas: (i) mitosis-independent cell death and metastasis, (ii) tumor angiogenesis, and (iii) vascular-disrupting activity.

Influence of aqueous media properties on aggregation and solubility of four structurally related meso-porphyrin photosensitizers evaluated by spectrophotometric measurements.

Abstract: Porphyrin photosensitizers tend to aggregate in aqueous solutions even in the micromolar concentration range. This is a challenge during formulation of e.g., parenteral preparations for photodynamic cancer therapy, or preparations for local or topical administration in antimicrobial photodynamic therapy. Monomerization is essential to achieve biocompatible drug formulations of high bioavailability and physiological response (i.e., photoreactivity) and low toxicity. The aggregation and solubilization of four structurally related meso-tetraphenyl porphyrin photosensitizers with nonionic (4-hydroxy), anionic (4-sulphonate; 4-carboxy) and cationic (4-trimethylanilinium) substituents were evaluated in various vehicles by use of UV-Vis spectroscopy. Substituents, overall charge and charge distribution influenced the pKa-values and interaction of the porphyrins with different solvents, excipients and impurities. Modification of medium polarity and solubilization by the nonionic surfactant Tween 80 adjusted the acid-base equilibria and increased the solubility by reduction of porphyrin aggregation. The selected porphyrins were sensitive towards ionic strength, temperature and inorganic impurities to various extents. The results will be further used during development of parenteral and topical formulations of porphyrin photosensitizers for use in photodynamic therapy of cancer and bacterial infections.

alpha-Glucosidase and alpha-amylase inhibitory activities of saponins from traditional Chinese medicines in the treatment of diabetes mellitus.

Abstract: Extracts of eleven traditional Chinese medicines (TCM) with a reputation of usefulness in treating diabetes mellitus were examined for alpha-glucosidase and alpha-amylase inhibitory activities in vitro The extract with the highest activity was selected for further characterization The extract of the root bark of Aralia taibaiensis (EAT) outperformed other extracts in the assays with IC50 values of 048 +/- 001 mg/mL (BSG), 041 +/- 002mg/mL (SCG), 061 +/- 03mg/mL (BLA) and 077 +/- 003mg/mL (PPA), respectively To identify which constituents were responsible for the activities, thirteen triterpenoid saponins were isolated from EAT and examined for their inhibitory effects against alpha-glucosidase and alpha-amylase The results revealed that saponins 2, 3, 4 (IC50: 083 +/- 005 microM for BSG and IC50: 072 +/- 003 microM for SCG), 5, 6, 7, 9, 10, 11 and 12 (IC50: 107 +/- 004 microM for BSG and IC50: 093 +/- 005 microM for SCG) showed alpha-glucosidase inhibitory activities, while 2, 3, 4 (IC50: 093 +/- 004 microM for PPA), 5, 6, 7, 9, 10, 11 and 12 (IC50: 102 +/- 003 microM for PPA) possessed significant alpha-amylase inhibitory activities In addition, the structure-activity relationship of the thirteen saponins was discussed based on their structure features and diabetes mellitus related activities It is suggested that the glucuronic acid unit at C-3 of the aglycone is the imperative functional group of the antidiabetic activities, and two characteristic structural features are responsible for the remarkable alpha-glucosidase and alpha-amylase inhibitory activities

Preparation, characterization and antiproliferative activity of thymoquinone-beta-cyclodextrin self assembling nanoparticles.

Abstract: Thymoquinone (TQ) was complexed with beta-cyclodextrin (CD) to form nanosized aggregates. Various TQ:CD ratios were tested and it was found that the ratio of (1:0.25) TQ:CD formed distinguishable nanoparticles with minimum toxicity towards normal cells. These nanoparticles had an average size of 445 +/- 100 nm with a charge 21.8 mV using Zeta-sizer. Particle size measurement using scanning electron microscopy (SEM) showed an average size of 400 nm and it also revealed the presence of smaller structures, with an average size of 50 nm. The in vitro antiproliferative activity on MCF7 cells was determined using MTT assay and an IC50 of 4.70 +/- 0.60 microM for TQ-CD nanoparticles in comparison to 24.09 +/- 2.35 microM of free TQ solution after 72 h of incubation. Simultaneously, TQ-CD nanoparticles showed lesser toxicity than TQ solution using human periodontal fibroblasts as a model for normal cells. It could be concluded from the results that TQ loaded cyclodextrin nanoparticles might serve as a potential nanocarrier to improve TQ solubility as well as its antiproliferative activity with little toxicity to normal tissues.

Magnolol induces apoptosis in MCF-7 human breast cancer cells through G2/M phase arrest and caspase-independent pathway.

Abstract: Magnolol, a small-molecule hydroxylated biphenol, isolated from the root and stem bark of Magnolia officinalis, has been shown to possess antiproliferative effect on various cancer cell lines. In the current study, we found that magnolol potently inhibited proliferation and induced apoptosis in MCF-7 human breast cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with cell cycle arrest at G2/M phase, increased generation of reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP), release of cytochrome c (Cyto c) and apoptosis inducing factor (AIF) from mitochondria to cytosol, upregulation of Bax, p21 and p53, and down-regulation of Bcl-2, cyclin B1 and cyclin-dependent kinase 1 (CDK1). Our findings indicated that magnolol induced apoptosis in MCF-7 cells via the intrinsic pathway with release of AIF from mitochondrial and G2/M phase arrest pathway. Therefore, magnolol might be a potential lead compound in the therapy of breast cancer.

The potential role of IL-37 in atherosclerosis.

Abstract: Atherosclerosis is an inflammatory disease characterized by extensive lipid deposition and atherosclerotic plaque formation in the intima. Interleukin (IL)-37 is anti-inflammatory cytokine in the IL-1 ligand family. Given that IL-37 plays an important function in the development and progression of inflammatory and autoimmune diseases, it may be associated with the development of atherosclerosis. IL-37, which is normally expressed at low levels in peripheral blood mononuclear cells (PBMC), mainly monocytes, and dendritic cells (DC), is rapidly up-regulated in the inflammatory context, and therefore IL-37 conversely inhibits the production of inflammatory cytokines in PBMC and DC. In addition, IL-37 effectively suppresses the activation of macrophage and DC. It is not controversial that the activation of macrophage and DC and the over-expression of inflammatory cytokines are critical component elements in inflammatory process of atherosclerosis. Therefore, IL-37 may play a protective role in atherosclerosis through inhibition of inflammatory cytokines production and suppression of macrophage and DC activation.

Plants containing pyrrolizidine alkaloids used in the traditional Indian medicine--including ayurveda.

Abstract: Pyrrolizidine alkaloids (PAs) show a hazardous potential for humans and animals. They can possess mutagenic, teratogenic, cancerogenic and fetotoxic properties. One pathway of a human intoxication can be the use of medicinal plants which contain toxic PAs. The Traditional Indian medicine--in particular Ayurveda--is a popular and well-known healing system. Within this system several PA-containing plants are used which, on account of their PA level, represent a severe health risk. In general, it is not recommended to use plants containing those toxic compounds.

Preparation, characterization and in vitro release study of gallic acid loaded silica nanoparticles for controlled release.

Abstract: Gallic acid (GA) is an interesting pharmaceutical component of plants. However, the short lifetime and the autoxidation of GA in aqueous solution significantly reduces its bioavailability and the residence time in the body system. In this study, GA was chemically bound to silica nanoparticles to control the release of GA based on the hydrolysis of the chemical bonds, and a silica nanoparticle drug delivery system was established. Gallic acid loaded silica nanoparticles (GA-SiO2) were synthesized by a modified Stober method. The Fourier Transform Infrared Spectroscopy (FTIR) and X-Ray Diffraction (XRD) analysis proved that GA did conjugate to silica nanoparticles. The particle size of the GA-SiO2 nanoparticles observed by Scanning Electron Microscope (SEM) was about 30 nm and the drug loading efficiency determined by Thermo Gravimetric Analysis/Differential Scanning Calorimetry (TGA/DSC) was 89.39%. The in vitro release study demonstrated that GA could be gradually released from the GA-SiO2. In addition, the antioxidant capability increased continuously during the immersion time, so the GA could serve as an excellent antioxidant to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals in a long release period. Therefore, this study provided a novel drug delivery system for GA with controlled release capability and prolonged antioxidant activity.

Incision wound healing activity of pine bark extract containing topical formulations: a study with histopathological and biochemical analyses in albino rats.

Abstract: The present study was designed to identify and compare the in vivo wound healing capacity of a bark extract from Pinus brutia and Pycnogenol in an incision wound model in rats. O/W cream formulations were prepared incorporating 2% Pycnogenol and P. brutia bark extract. The rats were divided into three groups (n = 8). Subsequently placebo and test formulations were applied to animals once a day from day "0" until the 9th day. Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) were studied in addition to histopathological examinations. Treatment with F. brutia extract containing cream inhibited lipid peroxidation by a 35% decrease in MDA and 46.8% increase in SOD activity, whereas 19.3% decrease in MDA and 34.7% increase in SOD activity were attained with Pynogenol compared to control. The histological data revealed a better performance of P. brutia extract enriched formulation in terms of degeneration of hair roots, increased vascularization and a decrease in necrotic area. Consequently, a high wound healing activity was observed in animals treated with P. brutia extract significantly accelerating the wound healing process.

Antimicrobial activity of propolis special extract GH 2002 against multidrug-resistant clinical isolates.

Abstract: The need to discover and develop alternative therapies to treat multidrug-resistant bacterial infections is timely. The aim of this study was to examine the antimicrobial potential of propolis, as a purified and concentrated special extract GH 2002, against clinical isolates of Streptococcus pyogenes, methicillin-resistent Stapylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Candida. Minimal inhibitory concentrations (MICs) and minimal microbicidial concentrations (MMCs) of propolis against microbial pathogens were evaluated using the broth microdilution method. Propolis extract GH 2002 revealed low MICs in the range of 0.03 to 2 mg/ml against S. pyogenes, S. aureus, E. faecium and Candida. A high bactericidal activity of propolis extract in the range of 0.06 to 1.0 mg/ml was determined for S. pyogenes and S. aureus, however propolis was not bactericidal against E. faecium. Propolis concentrations between 0.6 and 2.4 mg/ml displayed fungicidal activity against different Candida species. Whereas all tested MRSA strains were highly susceptible against propolis, only minor activity was found against VRE strains. Time-kill curves demonstrated a high antimicrobial activity at low MICs already after few hours of incubation against reference strains, clinical antibiotic-susceptible strains, clinical antifungal susceptible strains as well as all tested clinical MRSA strains, but not against VRE strains. In conclusion, clinical drug-sensitive as well as some clinical multidrug-resistant microbial isolates, i.e. MRSA, were susceptible to propolis with different degrees of susceptibility. These results suggest that the special propolis extract GH2002 might be used in the development of alternative products for therapy of microbial infections.

Plasma pharmacy - physical plasma in pharmaceutical applications.

Abstract: During the last years the use of physical plasma for medical applications has grown rapidly. A multitude of findings about plasma-cell and plasma-tissue interactions and its possible use in therapy have been provided. One of the key findings of plasma medical basic research is that several biological effects do not result from direct plasma-cell or plasma-tissue interaction but are mediated by liquids. Above all, it was demonstrated that simple liquids like water or physiological saline, are antimicrobially active after treatment by atmospheric pressure plasma and that these effects are attributable to the generation of different low-molecular reactive species. Besides, it could be shown that plasma treatment leads to the stimulation of specific aspects of cell metabolism and to a transient and reversible increase of diffusion properties of biological barriers. All these results gave rise to think about another new and innovative field of medical plasma application. In contrast to plasma medicine, which means the direct use of plasmas on or in the living organism for direct therapeutic purposes, this field - as a specific field of medical plasma application - is called plasma pharmacy. Based on the present state of knowledge, most promising application fields of plasma pharmacy might be: plasma-based generation of biologically active liquids; plasma-based preparation, optimization, or stabilization of - mainly liquid - pharmaceutical preparations; support of drug transport across biological barriers; plasma-based stimulation of biotechnological processes.

Hepatotoxicity of sub-nanosized platinum particles in mice.

Abstract: Nano-sized materials are widely used in consumer products, medical devices and engineered pharmaceuticals. Advances in nanotechnology have resulted in materials smaller than the nanoscale, but the biologic safety of the sub-nanosized materials has not been fully assessed. In this study, we evaluated the toxic effects of sub-nanosized platinum particles (snPt) in the mouse liver. After intravenous administration of snPt (15 mg/kg body weight) into mice, histological analysis revealed acute hepatic injury, and biochemical analysis showed increased levels of serum markers of liver injury and inflammatory cytokines. In contrast, administration of nano-sized platinum particles did not produce these abnormalities. Furthermore, snPt induced cytotoxicity when directly applied to primary hepatocytes. These data suggest that snPt have the potential to induce hepatotoxicity. These findings provide useful information on the further development of sub-nanosized materials.

Simvastatin pharmacokinetics in healthy Chinese subjects and its relations with CYP2C9, CYP3A5, ABCB1, ABCG2 and SLCO1B1 polymorphisms.

Abstract: A pharmacokinetic study of simvastatin (single oral dose, 40 mg) was conducted in 17 healthy Chinese volunteers. Plasma concentrations of simvastatin were determined by an LC-ESI-MS-MS method. The pharmacokinetic parameters of simvastatin were derived with a non-compartmental method. The polymorphisms of CYP2C9, CYP3A5, ABCB1 (encoding P-gp), ABCG2 (encoding BCRP) and SLCO1B1 (encoding OATP1B1) were determined by TaqMan genotyping assay and the impacts of these SNPs on the pharmacokinetics of simvastatin were analyzed. Major pharmacokinetic parameters were as follows: Tmax 1.44 +/- 0.39 h, Cmax 9.83 +/- 2.41 microg x L(-1), t1/2 4.85 +/- 1.23 h and AUC(0-infinity) 40.32 +/- 6.82 microg x h x L(-1). Effect of ABCB1 G2677T/A SNP on dispostion of simvastatin was observed. Significant differences in t1/2, but not Cmax and AUC(0-infinity), were observed between G/A, G/T or G/G carriers and non-G carriers (5.65 +/- 0.50 h vs 4.41 +/- 1.31 h, P C), CYP3A5*3 g.6986A > G, ABCB1 C3435T, ABCG2 c.34G > A, ABCG2 c.421C>A, SLCO1B1 c.388 A > G, SLCO1B1 c.521 T > C, SLCO1B1 g.11187 G > A, SLCO1B1 c.571 T > C and SLCO1B1 c.597 C > T. We conclude here that there is a small inter-subject variation in simvastatin pharmacokinetics in healthy Chinese volunteers. P-gp, OATP1 B1 and BCRP seem unlikely to play an important role in the pharmacokinetics of simvastatin. The gene-dose effects of ABCG2 c.421 C > A and CYP3A5*3 g.6986A > G on simvastatin pharmacokinetics are not strong enough in Chinese subjects.

Development of nanoparticle-bound arylsulfatase B for enzyme replacement therapy of mucopolysaccharidosis VI.

Abstract: Lysosomal storage disorders like mucopolysaccharidosis (MPS) VI are rare diseases with a lack of well-suited treatments. Even though an enzyme replacement therapy (ERT) of recombinant arylsulfatase B (ASB) is available for MPS VI, the administration cannot positively affect the neurologic manifestations such as spinal cord compression. Since nanoparticles (NP) have shown to be effective drug carriers, the feasibility of arylsulfatase B adsorption onto poly(butyl cyanoacrylate) (PBCA) nanoparticles was investigated in this study. In order to advance the ERT of ASB, the adsorption of the latter on the surface of PBCA NP as well as in vitro release in serum was investigated. With alteration of parameters like temperature, incubation time, pH, and enzyme amount, the adsorption process revealed to be stable with a maximum capacity of 67 microg/mg NP at a pH of 6.3. In vitro release experiments demonstrated that the adsorption is stable for at least 60 minutes in human blood serum, indicating that the ASB-loaded PBCA nanoparticles represent a promising candidate for ERT of MPS VI.

Zerumbone induces apoptosis in human renal cell carcinoma via Gli-1/Bcl-2 pathway.

Abstract: Renal cell carcinoma (RCC) is a malignant disease insensitive to conventional treatments such as radiochemotherapy and immunotherapy. Search for new approaches to induce cancer cell apoptosis will improve the management of RCC. Here, we reported that zerumbone, a monosesquiterpine, shows anticancer effects on human RCC cells via induction of apoptosis in vitro. Human renal clear cell carcinoma 786-0 and 769-P cell lines were used as the model system. Exposure of RCC cells to zerumbone resulted in cell viability inhibition, accompanied by DNA fragmentation and increased apoptotic index. Mechanically, treatment of RCC cells with zerumbone activated caspase-3 and caspase-9, and finally led to cleavage of PARR In addition, downregulation of Gli-1 and Bcl-2, which were closely related to the chemoresistance of RCC, was observed in zerumbone-treated RCC cells. Taken together, our study provided the first evidence that zerumbone imparted strong inhibitory and apoptotic effects on human RCC cells. The zerumbone-induced apoptosis might be related to the activation of the caspase cascade and deregulation of the Gli-1/Bcl-2 pathway. Our results suggest that zerumbone merit further investigation as an apoptosis inducer as well as a novel RCC chemotherapeutic agent in the clinical setting.

Response surface methodology and Taguchi approach to assess the combined effect of formulation factors on minocycline delivery from collagen sponges.

Abstract: An important aspect to be considered in the healing of acute or chronic cutaneous wounds is the associated potential infection management. Collagen, the most abundant protein of the extracellular matrix, with proven properties in wounds healing and tissues regeneration, is one of the most widely used biopolymers as carrier matrix for controlled drug delivery systems. For this reason, the purpose of the current paper is the development of some minocycline-loaded collagen topical sponges uncross-linked and cross-linked with glutaraldehyde, obtained by lyophilization of appropriate hydrogels prepared according to the 3-factor, 3-level face-centered central composite design. The determination of drug delivery from the sponges was performed by assessment of some physicochemical parameters involved in this complex process: sponges surface wettability, swelling ratio and the percentage of minocycline released from the sponges. The application of the response surface methodology allowed the setting of the formulation parameters optimum ranges, which ensure an adequate minocycline release to the application site. The design robustness was checked using the signal-to-noise ratio performance indicator. The optimum collagen-minocycline sponges determined based on the statistical screening technique could be suitable for topical drug delivery in infected wounds healing with moderate to high exudate.

Interspecies difference of luteolin and apigenin after oral administration of Chrysanthemum morifolium extract and prediction of human pharmacokinetics

Abstract: The aims of the present study were to study the interspecies difference in the pharmacokinetics of luteolin and apigenin occurring in Chrysanthemum morifolium extract (CME) among rats, beagle dogs, mini-pigs, and humans, and compared the human pharmacokinetic parameters with the data predicted from the above three animals. The plasma concentrations of luteolin and apigenin were determined with a RP-HPLC method. An interspecies difference of pharmacokinetics was found, especially between rats and other species, the plasma concentration of luteolin was much lower than that of apigenin in rats, although the content of luteolin in CME was higherthan that of apigenin, whereas the plasma concentration of luteolin was much higher than that of apigenin in dogs, mini-pigs and humans. Animal scale-up of some pharmacokinetic parameters of luteolin and apigenin were also performed after rats, beagle dogs, mini-pigs and humans were orally given CME at dosages of 400 mg/kg, 102 mg/kg, 90 mg/kg, and 20 mg/kg, respectively. Linear relationships were obtained between log mean retention time (MRT) and log species body weight (W) (kg), and log elimination half-life (t1/2) (h) and logW. The corresponding allometric equations were MRT=9.382W(0.1711) (R2 = 0.9999) and t1/2 = 4.811W(0.1093) (R2 = 0.9013) for luteolin, MRT = 12.53W(0.0356) (R2 = 0.9980) and t1/2 = 7.940W(0.0294) (R2 = 0.9258) for apigenin, respectively. The predicted human pharmacokinetic parameters (MRT and t1/2) by an allometric approach were 18.6 h and 7.46 h for luteolin, 14.3 h and 8.95 h for apigenin, respectively, which were close to the values obtained from humans (20 mg CME/kg) in the present study. The study has demonstrated the possibility to extrapolate the pharmacokinetic behavior of flavonoids from animals to humans.

Rapid identification of sibutramine in dietary supplements using a stepwise approach

Abstract: Adulteration of botanical food supplements with undeclared synthetic drugs is a common problem. One of the most affected product groups are the slimming agents. There are no analytical protocols for the detection of synthetic adulterants from these products. The present study aimed at the development of a multistep analytical method for the quick and reliable determination of sibutramine, one of the most common adulterants among botanical food supplements. The extract of a sibutramine-containing slimming formula was analysed by colour tests, TLC, HPLC-DAD, MS and NMR. The multistep method proposed by the authors allows the quick identification of sibutramine in counterfeit samples in laboratories with different instrumentation.

IL-35: a potential target for the treatment of atherosclerosis.

Abstract: The imbalance of anti- inflammatory/pro-inflammatory cytokines plays an important role in the process of atherosclerosis. IL-35 is an anti-inflammatory cytokine comprising the p35 subunit of IL-12 and the subunit Epstein-Barr virus (EBV) -induced gene 3(EBI3). Accumulating evidence showed that IL-35 up-regulates the expression of anti-inflammatory cytokines, induces the generation of CD4 + regulatory T cells, inhibits CD4 + effector T cells response and other target cells activity, and reduces the progression of inflammatory and autoimmune diseases. In addition, it has been found that Ebi3 and p35 strongly coexpressed in human advanced lesions. Therefore, we hypothesize that IL-35 may become a novel target for the treatment of atherosclerosis. Further studies are required to investigate the precise effect and the signaling pathway of IL-35 in atherosclerosis process.

A novel flavonoid isolated from Sophora flavescens exhibited anti-angiogenesis activity, decreased VEGF expression and caused G0/G1 cell cycle arrest in vitro.

Abstract: Kushen, the dried root of Sophora flavescens Ait, is a traditional Chinese herbal medicine. Kushen alkaloids have been developed in China as anticancer drugs, and more potent antitumor activities have been identified in kushen flavonoids than in kushen alkaloids. In this study, the anti-angiogenic properties of (2S)-7,2',4'-triihydroxy-5-methoxy-8-dimethylallyl flavanone (Compound 1, a novel flavonoid isolated from Kushen), were examined using the human umbilical vein endothelial cell line (ECV304) in vitro. The results indicated that compound 1 shows anti-angiogenesis activity via inhibitory effects on cell proliferation, cell migration, cell adhesion, and tube formation. Further studies indicated that compound 1 blocks cell cycles in the G0/G1 phase without inducing apoptosis, and down regulates vascular endothelial growth factor (VEGF) expression. The free radical scavenging activity of compound 1 was found through 2',7'-dichlorofluorescin diacetate (DCFH-DA) incubation assay in cells. The anti-angiogenic properties of compound 1 and its antiproliferative effect on endothelial cells without causing apoptosis make it a good candidate for development as a agent against development of tumors.

Evaluation of sunscreen safety by in vitro skin permeation studies: effects of vehicle composition.

Abstract: For sunscreens to be safe and effective, the lowest possible UV-filter percutaneous absorption should be achieved. In this paper, we evaluated in vitro release and permeation through human skin of two UV-filters, octyl methoxycinnammate (OMC) and butyl methoxydibenzoyl methane (BMBM) from six commercial O/W emulsions and we estimated their margin of safety (MoS). OMC and BMBM in vitro release and skin permeation were investigated in Franz-type diffusion cells and permeation data were used to calculate MoS. OMC in vitro skin permeation depended on both its concentration and vehicle composition while BMBM skin permeation depended on its release from the vehicle. MoS values were well beyond the lowest limit accepted for safe products. Although sunscreen skin permeation may depend on many factors, the commercial products investigated are safe under normal "in use" conditions.