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Coptidis rhizoma (C. rhizoma) had been demonstrated as an antioxidant and anticancer agent, however, its antioral cancer mechanism still remains unclear. Using water extracts of C. rhizoma, growth and apoptosis-related experiments for the treatment of multi-stage of oral cancer were carried out on immortalized human oral keratinocytes (IHOK), primary oral cancer cells (HN4), metastatic oral cancer cells (HN12) and human skin keratinocytes (HaCaT) by MTT assay, three-dimensional (3-D) raft cultures, western blotting, cell cycle analysis, nuclear staining and cytochrome c expression related to the apoptosis signaling pathway. C. rhizoma inhibited the proliferation of immortalized and malignant oral keratinocytes in a dose- and time-dependent manner. In 3-D organotypic culture, C. rhizoma-treated cells showed less maturation than the control cells, displaying low surface keratinization and decreased epithelial thickness. The major mechanism of growth inhibition by C. rhizoma appears to be the induction of apoptosis, which is supported by the results of the cell cycle analysis, FITC-annexin V staining, DNA fragmentation assay and DAPI staining. The induction of apoptosis by C. rhizoma was more prominent in immortalized keratinocytes than in malignant oral keratinocytes. Cytochrome-c release from mitochondria, accompanied by the activation of caspase-3, was observed in C. rhizoma-treated IHOK and oral cancer cells. These results suggest that C. rhizoma has apoptotic effects in immortalized and malignant oral keratinocytes via the mitochondrial signaling pathway.

The roles of IL-1alpha and TNF-alpha in early pulp inflammation were investigated by determining the alkaline phosphatase (ALP) activity, the osteonectin (ON), osteocalcin (OC), bone sialoprotein (BSP), and heme oxygenase-1 (HO-1) expression using an immunoblot method. Primary cultured dental pulp cells were treated with IL-1alpha, TNF-alpha, or both for 3, 7, and 14 days. The pulp cells treated with IL-1alpha for 3 days showed elevated ALP activity and increased ON, OC, and HO-1 expression, whereas TNF-alpha treatment did not increase the ALP activity and no BSP was expressed until day 14. The pulp cells treated with both IL-1alpha and TNF-alpha for 3 days showed increased HO-1 expression compared with that of the control. These data suggest that IL-1alpha and TNF-alpha produced in the early inflammatory reaction have different functions in human pulp cells. IL-1alpha induces ALP, ON, and OC in tooth mineralization and it may play a role in the cytoprotection of pulp cells via HO-1 expression, while long-term treatment of TNF-alpha may inhibit the tooth mineralization.

Lomonaco and Kauffman developed a knot mosaic system to introduce a precise and workable definition of a quantum knot system. This definition is intended to represent an actual physical quantum system. A knot $$(m,n)$$(m,n)-mosaic is an $$m \times n$$m×n matrix of mosaic tiles ($$T_0$$T0 through $$T_{10}$$T10 depicted in the introduction) representing a knot or a link by adjoining properly that is called suitably connected. $$D^{(m,n)}$$D(m,n) is the total number of all knot $$(m,n)$$(m,n)-mosaics. This value indicates the dimension of the Hilbert space of these quantum knot system. $$D^{(m,n)}$$D(m,n) is already found for $$m,n \le 6$$m,n≤6 by the authors. In this paper, we construct an algorithm producing the precise value of $$D^{(m,n)}$$D(m,n) for $$m,n \ge 2$$m,n?2 that uses recurrence relations of state matrices that turn out to be remarkably efficient to count knot mosaics. $$\begin{aligned} D^{(m,n)} = 2 \, \Vert (X_{m-2}+O_{m-2})^{n-2} \Vert \end{aligned}$$D(m,n)=2?(Xm-2+Om-2)n-2?where $$2^{m-2} \times 2^{m-2}$$2m-2×2m-2 matrices $$X_{m-2}$$Xm-2 and $$O_{m-2}$$Om-2 are defined by $$\begin{aligned} X_{k+1} = \begin{bmatrix} X_k&O_k \\ O_k&X_k \end{bmatrix} \ \hbox {and } \ O_{k+1} = \begin{bmatrix} O_k&X_k \\ X_k&4 \, O_k \end{bmatrix} \end{aligned}$$Xk+1=XkOkOkXkandOk+1=OkXkXk4Okfor $$k=0,1, \cdots , m-3$$k=0,1,?,m-3, with $$1 \times 1$$1×1 matrices $$X_0 = \begin{bmatrix} 1 \end{bmatrix}$$X0=1 and $$O_0 = \begin{bmatrix} 1 \end{bmatrix}$$O0=1. Here $$\Vert N\Vert $$?N? denotes the sum of all entries of a matrix $$N$$N. For $$n=2$$n=2, $$(X_{m-2}+O_{m-2})^0$$(Xm-2+Om-2)0 means the identity matrix of size $$2^{m-2} \times 2^{m-2}$$2m-2×2m-2.

The purpose of the study was to prepare the pegylated liposome carrying plasmid DNA with optimal encapsulation efficiency. Plasmid DNA (pCEP4 clone 790, 10.6 kb) was entrapped in the pegylated liposome composed of neutral lipid, POPC (l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), cationic lipid, DDAB (dimethyl dioctadecyl ammonium bromide) and anionic lipids, DSPE-PEG 2000 (distearoyl phosphatidyl ethanolamine polyethylene glycol 2000) and DSPE-PEG 2000-maleimide by freezing/thawing method. Free plasmid DNA was separated from the encapsulated one by Sepharose CL-4B column chromatography. The DNA amount encapsulated into the pegylated liposome was increased as cationic lipid concentration, initial amount of plasmid DNA and total lipid amount were increased.

The objective of this study was to investigate the stability of tetracycline HCl on encapsulation into and inside reverse micelles. To do so, tetracycline HCl was first mixed with cetyltrimethylammonium bromide, water and ethyl formate to make reverse micelles. The degradation kinetics of tetracycline HCl inside the reverse micelles was then assessed by scrutinizing its stability data. Under our experimental conditions, the reverse micelles formed spontaneously in absence of any mixing devices. During the preparation of the reverse micelles, however, considerable portions of tetracycline HCl underwent a chemical reaction (e.g., epimerization). For instance, of an initial concentration of tetracycline HCl was transformed into a degradation product. Once dissolved inside the reverse micelles, the degradation of tetracycline HCl followed an exponential decay pattern. The plot of log{the degradation rate of tetracycline HCl} versus log{tetracycline HCl concentration} made it possible to determine the order of degradation reaction and rate constant. It was proven that the degradation of tetracycline HCl inside the reverse micelles followed a first order kinetics with a rate constant of 0.0027 . Meriting further investigation might be formulation studies to stabilize tetracycline HCl on encapsulation into and inside the reverse micelles.

Multiwalled carbon nanotubes (MWNTs) (diameter range, 10−20 nm) were functionalized with 4-methoxybenzoic acid and 4-ethoxybenzoic acid via a Friedel−Crafts reaction in polyphosphoric acid to afford methoxybenzoyl- and ethoxybenzoyl-functionalized MWNTs. As-received MWNT, methoxybenzoyl-functionalized (MeO-MWNT), and ethoxybenzoyl-functionalized (EtO-MWNT) nanotubes were dispersed in ethylene glycol (EG). Because of the structural similarity, the mixture of EtO-MWNT (0.4 wt %) and EG was a homogeneous dispersion, whereas MeO-MWNT and pristine MWNT were dispersed in EG rather heterogeneously at the same loading. In situ polycondensation of EG and terephthalic acid in the presence of pristine MWNT, MeO-MWNT, or EtO-MWNT was carried out to generate the corresponding MWNT/PET, MeO-MWNT/PET, and EtO-MWNT/PET nanocomposites. High molecular weight poly(ethylene terephthalates) (PETs), with intrinsic viscosity range 0.6−0.7 dL/g (o-chlorophenol at 30 ± 0.1 °C), were obtained in all cases. In comparing the images ...

Multidrug resistance (MDR) of cancer cells is, at least in part, associated with the overexpression of P-glycoprotein (P-gp). Many studies have demonstrated that natural compounds obtained from fruits, vegetables, teas and medicinal plants may modulate P-gp activity. The objective of the present investigation was to examine the effect of seven natural compounds on the P-gp activity in human uterine sarcoma cell line, MES-SA/DX5. Daunomycin uptake was significantly increased by biochanin A and silymarin (p value of daunomycin (p

Background Numerous epidemiological studies have reported that tobacco smoking is a major risk factor for oral cancer, but relatively little is known about the effect of nicotine, a major product of cigarette smoking, on immortalized oral keratinocytes and cancer cells. Methods We investigated the effects of nicotine on the growth and differentiation of immortalized human oral keratinocytes (IHOK), primary oral cancer cells (HN4), metastatic oral cancer cells (HN12), and human skin keratinocytes (HaCaT), in the monolayer and in the three-dimensional (3D) raft cultures using the MTT assay, Western blotting, and cell cycle analysis. Results Nicotine inhibited the proliferation of immortalized and malignant keratinocytes in dose- and time-dependent manners as determined by MTT assay. The 3D organotypic culture showed that nicotine at high concentration (300 microM) inhibits epithelial maturation, surface keratinization, and decreased epithelial thickness. Flow cytometry showed that nicotine inhibited cell cycle progression by inducing G(0)/G(1) arrest of HaCaT, IHOK, HN4, and HN12 cells without causing apoptosis. Nicotine treatment increased p21 expression in immortalized cells (HaCaT, IHOK) and oral cancer cells (HN4, HN12), but decreased pRb and p53 expression in oral cancer cells. Moreover, after high-dose nicotine treatment, the involucrin expression increased markedly in immortalized cells, but not in oral cancer cells. Conclusions We demonstrated that nicotine inhibits growth through cell cycle arrest at G(0)/G(1) phase probably by increasing the expression of p21(WAF1/CIP1). Nicotine also affects epithelial differentiation in immortalized and malignant oral keratinocytes. Malignant oral keratinocytes appear to be more resistant to the effects of nicotine on epithelial growth and differentiation as compared to the immortalized cells.

A rapid, selective and sensitive reversed-phase HPLC method for the determination of glipizide in human serum was validated and applied to the pharmacokinetic study of glipizide. Glipizide and internal standard, tolbutamide, were extracted from human serum by liquid-liquid extraction with benzene and analyzed on a Nova Pak column with the mobile phase of acetonitrile-potassium dihydrogen phosphate (10 mM, pH 3.5) (4:6, v/v). Detection wavelength of 275 nm and flow rate of 0.7 ml/min were fixed for the study. The assay robustness for the changes of mobile phase pH, organic solvent content, and flow rate was confirmed by factorial design using a fixed glipizide concentration (500 ng/ ml) with respect to its peak area and retention time. And also, the ruggedness of this method was investigated at three different laboratories using same quality control (QC) samples. This method showed linear response over the concentration range of 10-1000 ng/ml with correlation coefficient greater than 0.999. The lower limit of quantitation using 0.5 ml of serum was 10.0 ng/ml, which was sensitive enough for pharmacokinetic studies. The overall accuracy of the quality control samples ranged from 82.6 to 105.0% for glipizide with overall precision (% C.V.) being 1.13-13.20%. The percent recovery for human serum was in the range of 85.2 93.5%. Stability studies showed that glipizide was stable during storage, or during the assay procedure in human serum. The peak area and retention time of glipizide were not significantly affected by the changes of mobile phase pH, organic solvent content, and flow rate under the conditions studied. This method showed good ruggedness (within 15% C.V.) and was successfully used for the analysis of glipizide in human serum samples for the pharmacokinetic studies at three different laboratories, demonstrating the suitability of the method.

An HPLC method was employed for the determination of ethambutol in human plasma. After addition of internal standard (IS, octylamine, ) and alkalinization of the plasma with 5 M sodium hydroxide, the drug and IS were extracted into the mixture of chloroform and diethyl ether (40:60, v/v). Following a 15-min vortex-mixing and a 10min centrifugation, the organic phase was spiked with of phenylethylisocyanate for chemical derivatization, mixed for 5 min and evaporated to dryness under a stream of nitrogen. The residue was reconstituted with of mobile phase and was injected into C18 column with a mobile phase consisting of methanol:water (70:30, v/v). The samples were detected utilizing an ultraviolet detector at 200 nm. The method was specific and validated with a limit of . Intra- and inter-day precision and accuracy were acceptable for all quality control samples including the lower limit of quantification. The applicability of this method was demonstrated by analysis of human plasma after oral administration of a single 1200-mg dose to 20 healthy subjects. From the plasma ethambutol concentration vs. time curves, the mean AUC was and Cmax of reached 2.73 hr after administration. The mean biological half-life of ethambutol was hr. Based on the results, this simple and validated assay could readily be used in any pharmacokinetic studies using humans.

Caesalpinia sappan L. (C. sappan) has been used in Oriental medicine as an antitumor agent. The present study shows the effects of the chloroform extract of C. sappan on cell death in head and neck cancer cell lines. The viability of HNSCC4 and HNSCC31 cells (head and neck cancer cell lines) was noticeably decreased compared to that of HaCaT cells (control group) in the presence of chloroform extract. No significant difference was observed in the viability of HNSCC4 and HNSCC31 cells when compared with HaCaT cells in the presence of n-butanol, methanol, and water extracts. Exposure to the chloroform extract of C. sappan resulted in an increase in the Sub-G1 phase of the cell cycle and condensation and shrinkage of nuclei in the HNSCC4 and HNSCC31 cells. The levels of p53 and p21WAF1/CIP1 were also increased in the HNSCC4 and HNSCC31 cells. The results suggest that the chloroform extract of C. sappan may increase cell death in the HNSCC4 and HNSCC31 cells, which is linked to increased cellular levels of p53 and p21WAF1/CIP1 .

Department of Life Sciences, College of Natural Sciences, Ewha Womans University, Seoul 120-750, KoreaReceived December 3, 2012, Accepted March 26, 2013Key Words : Vitis vinifera cv. Muscat of Alexandria, Respiratory syncytial virus (RSV), VitaceaeRespiratory syncytial virus (RSV) is the most commonworldwide cause of lower respiratory tract infections (LRI)in infants, elderly people, and immune-compromised indivi-duals.

One mechanism which plays a prominent role in development of multi-drug resistance seen in cancer cells is the over-expression of P-glycoprotein (P-gp). It is known that compounds found in vegetables and fruits not only have anticarcinogenic properties but may also modulate P-gp activity. The effect of some dietary components on efflux of daunomycin (DNM), a P-gp substrate, was examined in P-gp over-expressed human uterine sarcoma cell line, MES-SA/DX5. The efflux of DNM from the cells was significantly inhibited by quercetin and verapamil, but not by 1-naphtyl-isothiocyanate (NITC). The values for DNM in MES-SA/DX5 cells were increased by flavonoids (quercetin and fisetin), but not by NITC after 72 hour incubation with dietary constituents. In conclusion, flavonoids may play a role in the modulation of P­-gp activity in human uterine sarcoma cells.

One of the possible mechanisms of multi-drug resistance found in cancer cells is the over-expression of P­glycoprotein (P-gp). Studies have shown that compounds in plants including vegetables and fruits not only have anticancer activities but may also modulate P-gp activity. The effect of flavonoids and organic isothiocyanate on P-gp activity was studied in human uterine sarcoma cell lines, MES-SA (sensitive) and MES-SA/DX5 (resistant) cells. The accumulation of daunomycin (DNM), a P-gp substrate, was approximately 10 times greater in the sensitive cell as compared to the resistant cells over the entire time course (up to 2 hours). The positive control, verapamil increased the two hour accumulation of DNM while quercetin decreased that of DNM in the resistant cells. 1-Naphtyl-isothiocyanate (NITC) showed no effect on the two hour accumulation of DNM. The values for DNM in the resistant cells was about 20 times higher than that observed in the sensitive cells . Verapamil reduced the value for DNM whereas flavonoids (quercetin and fisetin) increased those for DNM in the resistant cells.

The objective of this study was to construct the pegylated liposomes containing plasmid DNA with optimal encapsulation efficiency. Plasmid DNA was encapsulated by the freeze/thawing method into liposomes composed of 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphocholine (POPC), didodecyl dimethyl ammonium bromide (DDAB), distearoylphosphatidyl ethanolamine polyethylene glycol 2000 (DSPE-PEG 2000) and DSPE-PEG 2000-male-imide. The liposomes containing plasmid DNA were then extruded through two stacked polycarbonate filters with series of different pore sizes to control the liposome size. The plasmid DNA entrapped in the liposomes was separated from free plasmid DNA by Sephadex CL-4B column chromatography. The decreased pore size of polycarbonate filters resulted in the decreased size of liposomes. The encapsulation efficiency was markedly affected by the cationic lipid (DDAB) concentration, but to a low degree by the size of liposomes and by the amount of plasmid DNA.

Gender differences have been well described in pharmacokinetics and contribute to the interindividual variation in drug disposition, therapeutic response, and drug toxicity. Sex-related differences in the membrane transport of endogenous substrates and xenobiotics have been reported in various organs of the body including kidney, liver, intestine, and brain. These gender-related differences in transport systems could also contribute to interindividual variability in pharmacokinetics and pharmacodynamics. This review will focus on current knowledge of gender-associated differences in the transport of endogenous and exogenous compounds in a variety of body organs and will discuss the implications and the clinical significance of these observations.

The 528 murine monoclonal antibody (MAb) to the human epidermal growth factor receptor (EGFR) was sequentially cationized with hexamethylenediamine and conjugated with diethylenetriaminepentaacetic acid (DTPA) as a potential antibody radiopharmaceutical for imaging EGFR-expressing cancer. The cationized 528 MAb was characterized with isoelectric focusing and electrophoresis, and an immunoradiometric assay, which showed the affinity of the 528 MAb for the human EGFR was retained following cationization. The native or cationized 528 MAb, labeled with (111)In, was injected intravenously in scid mice bearing human U87 flank tumors, which express the EGFR, and tumor imaging was performed with both external detection in live animals and with whole body autoradiography. However, the tumor signal was not increased with the cationized MAb, relative to the native MAb, and this was due to a serum inhibition phenomenon that was confirmed by a pharmacokinetics analysis in control mice. In an attempt to block the serum inhibition, the cationized 528 MAb was pegylated with 2000 Da poly(ethylene glycol), and the cationized/pegylated MAb was conjugated with DTPA and labeled with (111)In. However, a pharmacokinetics analysis showed the pegylation did not reverse the serum inhibition of the cationic charge on the MAb. These studies describe methods for reformulating monoclonal antibodies to develop improved radiopharmaceuticals, but show that radiolabeling a cationized MAb with DTPA produces a serum neutralization of the initial cationization modification.

Aβ1–40is a potential peptide radiopharmaceutical that could be used to image the brain Aβ amyloid of Alzheimer disease in vivo, should this peptide be made transportable through the blood–brain barrier in vivo. The blood–brain barrier transport of [125I]-Aβ1–40in a transgenic mouse model was enabled by conjugation to the rat 8D3 monoclonal antibody to the mouse transferrin receptor. The Aβ1–40–8D3 conjugate is a bifunctional molecule that binds the blood–brain barrier TfR and undergoes transport into brain and binds the Aβ amyloid plaques of Alzheimer disease. AppSW/ Psen1 double-transgenic and littermate control mice were administered either unconjugated Aβ1–40or the Aβ1–40–8D3 conjugate intravenously, and brain scans were obtained 6 hours later. Immunocytochemical analysis showed abundant Aβ immunoreactive plaques in the brains of the AppSW/ Psen1 transgenic mice and there was a selective retention of radioactivity in the brains of these mice at 6 hours after intravenous administration of the conjugate. In contrast, there was no selective sequestration either of the conjugate in control littermate mouse brain or of unconjugated Aβ1–40in transgenic mouse brain. In conclusion, the results show that it is possible to image the Aβ amyloid burden in the brain in vivo with an amyloid imaging agent, provided the molecule is conjugated to a blood–brain barrier drug-targeting system.

Non ionic, amphipathic molecules form vesicles and this property correlates with the disruption of membranes. In the present studies, high mM concentrations of aliphatic alcohols, 1-O-hexyldiglycerol (HDG) and 1-O-heptyltriglycerol (HTG), are shown to cause enhanced drug transport into brain via disruption of the blood-brain barrier (BBB) in vivo, as determined with an internal carotid artery perfusion method. The intravenous administration of comparable concentrations of HDG or HTG caused no increase in BBB transport of drug. The enhanced transport of drug showed a dependency on molecular weight as 45 mM HTG increased the transport of sucrose, 360 Da, but did not increase the transport of arginine vasopressin (AVP), 1084 Da, although AVP transport across the BBB was increased by 80 mM HDG or HTG. Quasielastic light scattering measurements provided evidence for the formation of vesicular structures in aqueous solutions containing high mM concentrations of the HDG or HTG. In summary, these studies demonstrate BBB disruption following the internal carotid arterial infusion of high mM concentrations of membrane active alkyl glycerols.

Purpose. This work describes the synthesis of pegylated immunonanoparticles by conjugation of an anti-transferrin receptor monoclonal antibody (MAb) to maleimide-grafted pegylated nanoparticles prepared from poly(lactic acid) (PLA) and a bi-functional polyethyleneglycol (PEG). Methods. Maleimide-PEG3500-PLA40000 and methoxyPEG2600-PLA40000 copolymers were synthesized by ring opening polymerization of L-lactide using stannous octoate as catalyst. Pegylated nanoparticles were prepared from these copolymers by a multiple emulsion/solvent evaporation method and thiolated OX26 MAb was conjugated through the maleimide function located at the distal end of the PEG spacer. The pegylated immunonanoparticles were characterized by quasi-elastic light scattering, gel permeation chromatography, turbidimetry assays, and transmission electron microscopy. Results. NMR spectroscopy confirmed the synthesis of both copolymers and the preservation of the maleimide function. The pegylated immunonanoparticles had an average diameter of 121 ± 5 nm and appeared spherical by transmission electron microscopy. The number of OX26 MAb molecules conjugated per individual pegylated nanoparticle was 67 ± 4. The MAb conjugated to the surface of the pegylated immunonanoparticle was visualized directly by electron microscopy using a conjugate of 10 nm gold and an anti-mouse immunoglobulin secondary antibody. Conclusion. Pegylated immunonanoparticles can be synthesized with bifunctional PEG derivatives that bridge the nanoparticle and the targeting MAb. This novel formulation may enable the targeted delivery of small molecules, protein drugs, and gene medicines.

In this paper, we calculate the Kauffman polynomials [Formula: see text] of Kanenobu knots [Formula: see text] with [Formula: see text] half twists and determine their spans on the variable [Formula: see text] completely. As an application, we determine the arc index of infinitely many Kanenobu knots. In particular, we give sharper lower bounds of the arc index of [Formula: see text] by using canonical cabling algorithm and the 2-cable [Formula: see text]-polynomials. Moreover, we give sharper upper bounds of the arc index of some Kanenobu knots by using their braid presentations.

MicroRNAs (miRNA) are short oligonucleotides of endogenous origin involved in post-transcriptional regulation and are altered in disease, making them potential therapeutic targets. miRNA replacement is necessary in cells with downregulated miRNAs levels in response to disease. miRNA 145 is a novel tumor suppressor gene involved in cell suppression, invasion and migration of cancer cells; it is downregulated in most cancers. Delivery of therapeutic miRNA using nanoparticles enhances the chances of successful delivery and expression of genes at the target site. We evaluated polysorbitol-mediated transporter (PSMT) in the cellular delivery of miRNA 145. The polysorbitol backbone possesses osmotic properties and leads to enhanced cellular uptake. PSMT delivers genes into cells by a caveolae-mediated endocytic pathway. Caveolae expression is usually altered in transformed cancer cells. Physicochemical characterization, and the transfection efficiency and transgene expression capability of PSMT/reporter plasmid DNA nanoparticles, were determined. GFP-tagged miRNA 145 delivery with PSMT was confirmed by confocal microscopy and Western blotting. The functional effects of miRNA 145 delivered with PSMT were analyzed by confocal microscopy, as well as in apoptosis, proliferation and wound healing assays. Finally, the expression of an miRNA 145 target protein, c-myc, was determined by Western blotting after intracellular delivery of PSMT/miRNA 145 nanoparticle (NP).

Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark ofCudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-αin HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α(HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1αactivator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1αinhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.

Intestinal P-glycoprotein (P-gp) is a limiting step for oral absorption of drugs. Therefore, P-gp inhibitors have been studied as enhancers of oral absorption of drugs that are P-gp substrates. We investigated the in vitro and in vivo P-gp inhibitory activity of synthesized xanthone analogues. With 3-(3-chloro-2-hydroxypropoxy)-1-hydroxy-9H-thioxanthen-9-one, compound 13, accumulation of daunomycin (DNM) increased 707% and efflux of DNM decreased 66% compared to DNM alone. Relative bioavailability (RB) of paclitaxel (PTX, 25 mg/kg) increased 2.5-fold after oral administration with 13 (5 mg/kg). In a xenograft animal model, oral administration of PTX (40 mg/kg) with 13 (10 mg/kg) significantly inhibited tumour growth and was more effective than intravenously administered PTX (10 mg/kg) alone. Therefore, the synthesized xanthone analogue 13 might have therapeutic benefits for oral absorption of P-gp substrate anticancer drugs.

Aiming at tumor targeting delivery of oxaliplatin using polymer therapy, a new monomeric platinum(II) complex (dach)Pt[HEDM] (dach: trans-(±)-1,2-diaminocyclohexane; HEDM: 2-hydroxyethoxydiethylmalate) was designed to include the antitumor moiety (dach)Pt and HEDM as a linker to the polyphosphazene backbone. This monomeric Pt-complex could easily be grafted to the PEGylated polyphosphazene backbone to prepare a novel polyphosphazene-Pt conjugate, [NP(MPEG550)(dach)Pt(EM)]n [MPEG550: methoxy poly(ethylene glycol) with an average molecular weight of 550; EM: ethoxymalate]. This amphiphilic polyphosphazene-Pt conjugate was found to self-assemble into stable polymeric micelles of a mean diameter of 130nm, which is suitable for passive tumor targeting by enhanced permeability and retention (EPR) effect. Pharmacokinetic study of this polymer conjugate exhibited long blood circulation as expected and longer half-life (t1/2β=9.52h) compared with oxaliplatin (3.47h), and much larger AUC (area under the curve) value (25,831ng·h/mL) compared with oxaliplatin (1194ng·h/mL). Biodistribution study of the polymer conjugate has shown excellent tumor selectivity with the tumor to tissue ratio of 3.84 at 2h post injection and 11.7 at 24h post injection probably due to the EPR effect of the polymer conjugate while no tumor selectivity was observed for monomeric oxaliplatin. Furthermore, accumulation of this polymer conjugate in kidney was much lower compared with oxaliplatin. Also the nude mouse xenograft trial of the polymer conjugate has shown higher antitumor efficacy compared with oxaliplatin.

A beta1-40 peptide radiopharmaceuticals could be used to image A beta brain amyloid in transgenic mouse models of Alzheimer's disease should the A beta peptide radiopharmaceutical be made transportable through the blood-brain barrier (BBB) in vivo. The present studies used the RI7-217 rat monoclonal antibody to the mouse transferrin receptor as a BBB drug targeting vector for the delivery to brain of A beta1-40 radiolabeled with either 125-Iodine or 111-Indium. The A beta peptide radiopharmaceutical is conjugated to the RI7 MAb using avidin biotin technology, wherein the A beta1-40 peptide radiopharmaceutical is monobiotinylated (bio) and bound to a conjugate of the RI7 MAb and streptavidin (SA). The [125 I]-bio-A beta1-40 or the [111 In]-bio-A beta1-40 either free or bound to the RI7/SA conjugate was injected intravenously into anesthetized adult mice and plasma pharmacokinetics and organ uptake were measured over the next 60 minutes. The A beta1-40 peptide radiopharmaceutical radiolabeled with 111-Indium was the preferred formulation, compared to peptide labeled with 125-Iodine, because there was a greater metabolic stability and reduced artifactual organ uptake of metabolites associated with the use of the 111-Indium nuclide. However, biotinylated A beta1-40 peptide radiopharmaceuticals conjugated to the RI7/SA brain drug targeting system were metabolically unstable in mice in vivo owing to active biotinidase activity. Future work involving brain drug targeting in mice that utilizes avidin biotin technology will need to incorporate biotin analogues that are resistant to biotinidase.

Purpose. Brain drug targeting may be achieved by conjugating drugs,that normally do not cross the blood-brain barrier (BBB), to brain drugdelivery vectors. The murine 83-14 MAb to the human insulin receptor(HIR) is a potential brain drug targeting vector that could be used inhumans, if this MAb was genetically engineered to form a chimericantibody, where most of the immunogenic murine sequences arereplaced by human antibody sequence.

Changes in membrane fluidity have been shown to alter the sodium-dependent renal transport of glucose and phosphate; however, this has not been examined for sodium/sulfate cotransport in the renal proximal tubule. Sodium/sulfate cotransport regulates the homeostasis of sulfate in mammals. The objective of this study was to investigate the influence of alterations of membrane fluidity on sodium-coupled sulfate transport in the Madin-Darby canine kidney cells, which have been stably transfected with sodium/sulfate cotransporter (NaSi-1) cDNA (MDCK-Si). Preincubation of cells with 0. 2 mM cholesterol significantly decreased the V(max) for sodium/sulfate cotransport (13.69 +/- 1.11 vs 10.15 +/- 1.17 nmol/mg protein/5 min, mean +/- SD, n = 4, p0.01) with no significant alteration in K(m). The addition of benzyl alcohol (20 mM) to cells increased the V(max) of sulfate uptake by 20% (11.97 +/- 0.91 vs 14. 35 +/- 0.56 nmol/mg protein/5 min, mean +/- SD, n = 3, p0.05) with no significant change in K(m). Membrane fluidity, as measured by the fluorescence polarization of 1,6-diphenyl 1,3,5-hexatriene (DPH), was significantly increased in MDCK-Si cells treated with 20 mM benzyl alcohol and decreased in the cells preincubated with 0.2 mM cholesterol, compared with control cells. Our results suggest that alterations in membrane fluidity that may occur as a result of disease states, aging, and pregnancy may play an important role in the modulation of renal sodium/sulfate cotransport.

We recently reported that overexpression of thymosin beta-4 (Tβ4) in transgenic mice promotes abnormal hair growth and tooth development, but the role of Tβ4 in dental pulp regeneration was not completely understood. The aim of this study was to investigate the role of Tβ4 on odontoblastic differentiation and the underlying mechanism regulating pulp regeneration in human dental pulp cells (HDPCs). Our results demonstrate that mRNA and protein expression of Tβ4 is upregulated during odontogenic differentiation in HDPCs. Transfection with Tβ4 siRNA decreases OM-induced odontoblastic differentiation by decreasing alkaline phosphatase (ALP) activity, mRNA expression of differentiation markers, and calcium nodule formation. In contrast, Tβ4 activation with a Tβ4 peptide promotes these processes by enhancing the phosphorylation of p38, JNK, and ERK mitogen-activated protein kinases (MAPKs), bone morphogenetic protein (BMP) 2, BMP4, phosphorylation of Smad1/5/8 and Smad2/3, and expression of transcriptional factors such as Runx2 and Osterix, which were blocked by the BMP inhibitor noggin. The expression of integrin receptors α1, α2, α3, and β1 and downstream signaling molecules including phosphorylated focal adhesion kinase (p-FAK), p-paxillin, and integrin-linked kinase (ILK) were increased by Tβ4 peptide in HDPCs. ILK siRNA blocked Tβ4-induced odontoblastic differentiation and activation of the BMP and MAPK transcription factor pathways in HDPCs. In conclusion, this study demonstrates for the first time that Tβ4 plays a key role in odontoblastic differentiation of HDPCs and activation of Tβ4 could provide a novel mechanism for regenerative endodontics.

Lomonaco and Kauffman developed knot mosaics to give a definition of a quantum knot system. This definition is intended to represent an actual physical quantum system. A knot $n$-mosaic is an $n \times n$ matrix of 11 kinds of specific mosaic tiles representing a knot or a link. The mosaic number $m(K)$ of a knot $K$ is the smallest integer $n$ for which $K$ is representable as a knot $n$-mosaic. In this paper we establish an upper bound on the mosaic number of a knot or a link $K$ in terms of the crossing number $c(K)$. Let $K$ be a nontrivial knot or a non-split link except the Hopf link. Then $m(K) \leq c(K) + 1$. Moreover if $K$ is prime and non-alternating except $6^3_3$ link, then $m(K) \leq c(K) - 1$., Comment: 7 pages, 8 figures

Lomonaco and Kauffman introduced knot mosaic system to give a definition of quantum knot system. This definition is intended to represent an actual physical quantum system. A knot $(m,n)$-mosaic is an $m \times n$ matrix of mosaic tiles which are $T_0$ through $T_{10}$ depicted as below, representing a knot or a link by adjoining properly that is called suitably connected. An interesting question in studying mosaic theory is how many knot $(m,n)$-mosaics are there. $D_{m,n}$ denotes the total number of all knot $(m,n)$-mosaics. This counting is very important because the total number of knot mosaics is indeed the dimension of the Hilbert space of these quantum knot mosaics. In this paper, we find a table of the precise values of $D_{m,n}$ for $4 \leq m \leq n \leq 6$ as below. Mainly we use a partition matrix argument which turns out to be remarkably efficient to count small knot mosaics. \begin{center} \begin{tabular}{|c|r|r|r|} \hline $D_{m,n}$ & $n=4$ & $n=5$ & $n=6$ \\ \hline $m=4$ & $2594$ & $54,226$ & $1,144,526$ \\ \hline $m=5$ & & $4,183,954$ & $331,745,962$ \\ \hline $m=6$ & & & $101,393,411,126$ \\ \hline \end{tabular} \end{center}, 13 pages, 9 figures, 1 table

1. The interactions between herbal dietary supplements and therapeutic drugs have emerged as an important issue and P-glycoprotein (P-gp) has been reported as one of the significant factors of these interactions. 2. The objective of this article is to examine the effects of single and repeated administrations of silymarin on pharmacokinetics of a P-gp substrate, risperidone, and its major metabolite, 9-hydroxyrisperidone, in rats. 3. To determine the plasma levels of risperidone and 9-hydroxyrisperidone in rats, a HPLC method was developed using a liquid-liquid acid back extraction. When risperidone (6 mg/kg) was co-administered with silymarin (40 mg/kg) to rats orally, the C(max) of 9-hydroxyrisperidone was significantly increased to1.3-fold (p0.05), while the other pharmacokinetic parameters did not show any significant differences. Expanding the experiment where rats were repeatedly administered with silymarin for 5 days prior to giving risperidone, the C(max) of risperidone and 9-hydroxyrisperidone were significantly increased to 2.4-fold (p0.001) and 1.7-fold (p0.001), respectively, and the AUC(0-t), as well to 1.7-fold (p0.05) and 2.1-fold (p0.01), respectively. 4. The repeated exposures of silymarin, compared to single administration of silymarin, increased oral bioavailability and affected the pharmacokinetics of risperidone and 9-hydroxyrisperidone, by inhibiting P-gp.

In this paper, we construct an algorithm to produce canonical grid diagrams of cable links and Whitehead doubles, which give sharper upper bounds of the arc index of them. Moreover, we determine the arc index of [Formula: see text]-cable links and Whitehead doubles of all prime knots with up to eight crossings.

Poor aqueous solubility and the unpleasant taste of aripiprazole (APZ) have been recurring problems, owing to its low bioavailability and low patient tolerance, respectively. Herein, we prepared a nanohybrid system that was based on a bentonite clay material, montmorillonite (MMT), which could both mask the taste and enhance the solubility of APZ (i.e., APZ-MMT). To further improve the efficacy of this taste masking and drug solubility, APZ-MMT was also coated with a cationic polymer, polyvinylacetal diethylamino acetate (AEA). In vitro dissolution tests at neutral pH showed that the amount of drug that was released from the AEA-coated APZ-MMT was greatly suppressed (

Ji-Hee Lee1,*, Goeun Choi1,*, Yeon-Ji Oh1, Je Won Park1, Young Bin Choy3, Mung Chul Park1, Yeo Joon Yoon1, Hwa Jeong Lee2, Hee Chul Chang4, Jin-Ho Choy1 1Center for Intelligent Nano-Bio Materials (CINBM), Department of Bioinspired Science and Department of Chemistry and Nano Science, 2Division of Life and Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul, Korea; 3Department of Biomedical Engineering, College of Medicine and Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University, Seoul, Korea; 4Global Strategy Center and Pharmaceutical Research Institute, Daewoong Pharmaceutical Co., Ltd., Seoul, Korea*These authors contributed equally to this workAbstract: A nanohybrid was prepared with an inorganic clay material, montmorillonite (MMT), for taste masking of sildenafil (SDN). To further improve the taste-masking efficiency and enhance the drug-release rate, we coated the nanohybrid of SDN–MMT with a basic polymer, polyvinylacetal diethylaminoacetate (AEA). Powder X-ray diffraction and Fourier transform infrared experiments showed that SDN was successfully intercalated into the interlayer space of MMT. The AEA-coated SDN–MMT nanohybrid showed drug release was much suppressed at neutral pH (release rate, 4.70 ± 0.53%), suggesting a potential for drug taste masking at the buccal cavity. We also performed in vitro drug release experiments in a simulated gastric fluid (pH = 1.2) and compared the drug-release profiles of AEA-coated SDN–MMT and Viagra®, an approved dosage form of SDN. As a result, about 90% of SDN was released from the AEA-coated SDN–MMT during the first 2 hours while almost 100% of drug was released from Viagra®. However, an in vivo experiment showed that the AEA-coated SDN–MMT exhibited higher drug exposure than Viagra®. For the AEA-coated SDN–MMT, the area under the plasma concentration–time curve from 0 hours to infinity (AUC0-∞) and maximum concentration (Cmax) were 78.8 ± 2.32 µg • hour/mL and 12.4 ± 0.673 µg/mL, respectively, both of which were larger than those obtained with Viagra® (AUC0-∞ = 69.2 ± 3.19 µg • hour/mL; Cmax = 10.5 ± 0.641 µg/mL). Therefore, we concluded that the MMT-based nanohybrid is a promising delivery system for taste masking of SDN with possibly improved drug exposure.Keywords: montmorillonite, nanohybrids, polyvinylacetal diethylaminoacetate, sildenafil citrate, taste masking

To evaluate the metabolic interaction between host and gut microflora on drug metabolism, pseudo germ-free rats were prepared with an antibiotics cocktail to change their gut conditions. The usefulness of the pseudo germ-free model was evaluated for observing the DMPK of acetaminophen (APAP). Pseudo germ-free rats were prepared by orally administering antibiotic cocktails consisting of bacitracin, streptomycin and neomycin, and then APAP was orally administered to control and pseudo germ-free rats. The plasma concentration of APAP and its six metabolites were quantified using a validated LC-MS/MS method. A non-compartment model estimated the pharmacokinetic parameters of APAP and its metabolites, and the ratios of the area under curve (AUC; AUC(metabolite) /AUC(APAP) ) were also observed to evaluate the change of APAP metabolism. The AUCs of APAP and APAP-Glth (glutathione) were higher and the AUC(APAP-Sul) /AUC(APAP) (metabolic efficiency of sulfate conjugation) was lower in pseudo germ-free rats than those in the control rats. The decrease in metabolic efficiency of sulphate conjugation could result from the reduction of the sulphate supply, causing an increase of the AUC of APAP and APAP-Glth. The activities of gut microflora can affect the state of hepatic sulphate for drug conjugation, indirectly leading to characteristic APAP metabolism. These results indicate that gut microflora may play an important role in the pharmacokinetics and metabolism of APAP. Thus, the metabolic interaction between host and gut microflora should be considered upon drug administration and pseudo germ-free rats prepared in the present study can be competent for investigating the metabolic interaction between host and gut microflora on drug metabolism.

Superparamagnetic iron oxide nanoparticle (SPION)-based diagnostic properties with accompanying therapeutics such as drugs or genes have been explored for improvement of their therapeutic efficacy. Positively charged SPION-loaded polymersomes was prepared to deliver genes to the target sites; this process was concomitantly monitored by magnetic resonance imaging (MRI). The surface characteristics and morphology were respectively measured by dynamic light scattering and transmission electron microscopy. The complex between the polymer and the pDNA was confirmed by a gel retardation assay. The transfection efficiency and cytotoxicity in vitro were tested by treating of the CT-26 colon cancer cell line with luciferase-expressing plasmids/SPION complex. MRI was also used to check the detectability of SPION in vitro and in vivo. A SPION-loaded polymersome carrying genetic materials was delivered and then accumulated in the tumor site of the murine colon cancer xenograft model after intravenous injection, possibly through a passive targeting mechanism. The accumulation was monitored using clinical MRI. This result indicates that the SPION-loaded polymersome can be applied to MR imageguided gene therapy.

Glucans are reported to elicit immune responses through activation of macrophages by a specific interaction of beta-glucan with an immune cell-specific (1,3)-beta-D-glucan receptor or Dectin-1 receptor. In this study, superparamagnetic iron oxide nanoparticles (SPIONs) were coated with beta-glucan in order to target the immune cells residing in the metastatic liver as an aid for discriminating metastasized tumor regions from normal hepatic parenchymal tissue. The morphology of prepared beta-glucan-coated SPIONs (Glu-SPIONs) was characterized with dynamic light scattering (DLS) and transmission electron microscopy (TEM). The cytotoxicity of Glu-SPIONs was analyzed and compared to that of dextran- and PVA-coated SPIONs. The uptake of Glu-SPIONs by peritoneal macrophages was also confirmed with Prussian blue staining and MRI phantom tube imaging. The in vivo uptake of Glu-SPIONs in liver and lymph nodes in a metastatic mouse liver model was tracked by MR imaging after the systemic injection. The Glu-SPIONs predominantly accumulated in the macrophages surrounding the metastatic regions of the liver thereby indicating the distribution of tumor cells in the liver. MR imaging of the Glu-SPIONs clearly revealed macro- or micro-metastasized tumor regions throughout the liver, due to the preferential uptake of Glu-SPIONs into macrophages, not tumor cells. The Glu-SPION-accumulating regions were further confirmed with H&E and Prussian blue stainings after tissue sectioning. Based on our study, we propose that Glu-SPIONs can be successfully applied for diagnosing hepatic metastasis. (C) 2011 Elsevier Ltd. All rights reserved.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. It is mainly metabolized by phase 1 and 2 reactions in the liver, and thus it could be involved in many drug-drug interactions. Therefore, the study of APAP metabolism is important in toxicological and pharmacokinetic studies. The objective of this study was to develop a rapid and sensitive method for the determination of APAP and its six metabolites in rat plasma for the pharmacokinetic studies. APAP and its metabolites were separated through a Capcell Pak MGII C(18) column and quantitated with a 16 min run in a triple-quadruple mass spectrometer. The mobile phases were composed of 0.1% formic acid in either 95% water or 95% acetonitrile and analysis was performed twice in positive and negative modes. Validations such as accuracy, precision, recovery, matrix effect and stability were found to be within acceptance criteria of validation guidelines, indicating that the assay was applicable to the determination of the plasma concentrations of drug and its six metabolites. In conclusion, we developed an LC-MS/MS method for the quantitative analysis of APAP and its six metabolites in rat plasma, and this method appears to be useful for pharmacokinetic/toxicokinetic studies of APAP and its metabolites in rats.

Inflammatory bowel disease is associated with increased risk of cholelithiasis. However, the histologic patterns in gallbladders have not been extensively studied. This study is designed to characterize the histopathologic features of cholecystectomy specimens in inflammatory bowel disease patients, compared to a control group.Cholecystectomy specimens in 78 Crohn's disease patients and 50 ulcerative colitis patients were reviewed. These were compared with 93 cholecystomies from noninflammatory bowel disease patients of approximate age and sex. The pattern and extent of inflammation was noted.Marked chronic cholecystitis was present in 12% of ulcerative colitis patients (P0.05) and 10.3% of Crohn's disease patients (P0.05), compared to 4.3% of the noninflammatory bowel disease control group. Eight percent of ulcerative colitis patients (P0.05) and 2.6% of Crohn's disease patients (P0.05) had acute serositis, compared to 0% of the noninflammatory bowel disease control. The third inflammatory pattern, nodular lymphoid aggregates, was significantly increased in Crohn's disease patients after adjusting for the effect of cholelithiasis. Nodular lymphoid aggregates were found in 21.2% of Crohn's disease patients and 9.7% of ulcerative colitis patients without cholelithiasis, compared to 5% of noninflammatory bowel disease controls without cholelithiasis, a statistically significant difference between the Crohn's disease and control groups (P0.05).Inflammatory bowel disease patients show similar inflammatory patterns in cholecystectomy specimens compared to the general population. However, two inflammatory patterns that occur more often in ulcerative colitis patients are marked chronic cholecystitis and acute serositis, while nodular lymphoid aggregates are more common in Crohn's disease patients.

Positively charged superparamagnetic iron oxide nanoparticle (SPION)-loaded polymersome was prepared in order to deliver genes to the target sites, which was monitored by magnetic resonance imaging (MRI), concomitantly. The transfection efficiency in vitro was tested by treating CT-26 colon cancer cell line with luciferase-expressing plasmids/SPION complex. MRI was also used to check the detectability of SPION in vitro and in vivo. SPION-loaded polymersome, carrying genetic materials, was delivered and then accumulated at the tumor site of the murine colon cancer xenograft model after intravenous injection, possibly through a passive targeting mechanism. Clinical MRI monitored this accumulation. This result indicates that the SPION-loaded polymersomecan be applied to MR image-guided gene therapy.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and most common cause of dementia. However, there is no known way to halt or cure the neurodegenerative disease. Oxidative stress is a cardinal hallmark of the disease and has been considered as therapeutic target for AD treatment. Several factors may contribute to oxidative stress in AD brains. First, mitochondrion is a key player that produces reactive oxygen species (ROS). Mitochondrial dysfunction found in AD patients may exaggerate generation of ROS and oxidative stress. Second, amyloid-beta peptide generates ROS in the presence of metal ions such as Fe(2+) and Cu(2+). Third, activated glial cells in AD brains may produce excessive amount of superoxide and nitric oxide through NADPH oxidase and inducible nitric oxide synthase, respectively. Increased ROS can cause damage to protein, lipid and nucleic acids. Numerous studies demonstrated that natural polyphenolic compounds protect against various neurotoxic insults in vitro and in vivo AD models. In these studies, dietary polyphenolic compounds exhibit neuroprotective effects through scavenging free radicals and increasing antioxidant capacity. Furthermore, they could facilitate the endogenous antioxidant system by stimulating transcription. Some epidemiological and clinical studies highlighted their therapeutic potential for AD treatment. In this review, we will briefly discuss causes of oxidative stress in AD brains, and describe antioxidant neuroprotective effects and therapeutic potential for AD of selected natural polyphenolic compounds.

Docetaxel micelle-encapsulated by a tripodal cyclotriphosphazene amphiphilile [NP(PEG750)(GlyPheLeu)2Et]3 (CP750) exhibited outstanding drug-loaded micelle stability in aqueous solution compared with the polymeric micelles assembled from linear block copolymers. Furthermore, docetaxel micelle-encapsulated by CP750 is obtainable in solvent free powder form, which is immediately soluble in any aqueous media including saline and PBS and very stable to photo-degradation even in the room light at room temperature. Although docetaxel micelle-encapsulated by CP750 did not display highly improved pharmacokinetic profile compared with Taxotere® currently in clinical use, its in vivo xenograft trials exhibited excellent antitumor efficacy by showing complete tumor regression against the breast cancer cells (MDA-MB-231) at a lower dose of 5 mg/kg and better efficacy against gastric cancer cells (MKN-28) compared with Taxotere®. Furthermore, according to the comparative acute toxicity study, toxicities associated with Taxotere® may be remarkably reduced by micelle-encapsulation of docetaxel using CP750, which afforded a much higher LD50 value of 75 mg/kg compared with 28 mg/kg of docetaxel in Taxotere®. Thus docetaxel micelle-encapsulated by CP750 has entered the stage of preclinical studies.

Metastatic lymph nodes (LN) originate from primary cancer cells that metastasize to the lymphatic system. It is difficult to non-invasively discriminate between metastatic LN and normal LN because of their similarities in size and shape. Magnetic resonance (MR) contrast agents are widely utilized to enhance the image contrast among different tissues. Currently available dextran-based contrast agents are non-specifically internalized by macrophages. Therefore, the aim of this study was to develop mannan-coated superparamagnetic iron oxide nanoparticles (mannan-SPION) for specific delivery to immune cells in LN by receptor-mediated endocytosis for facilitated uptake in the target cells and faster acquisition of MR images. Mannan is a water soluble polysaccharide with a high content of D-mannose residues that can be recognized by mannose receptors on activated macrophages and dendritic cells. Mannan-SPION are proven to be suitable for MRI due to their small size, excellent aqueous stability, and lower cytotoxicity. Mannan-SPION are taken up by antigen-presenting cells such as macrophages and dendritic cells, which could be confirmed by Prussian blue and fluorescent staining. In addition, mannan-SPION exhibit enhanced delivery efficiency in targeting macrophages in LN in vivo compared with polyvinyl alcohol (PVA)-SPION. More specifically, the enhancement of MRI of LN by mannan-SPION increased dramatically during the earlier stages after intravenous injection, compared with PVA-SPION as a control, which indicates the potential for successful and early detection of metastastatic LN.

It is known that the arc index of alternating knots is the minimal crossing number plus two and the arc index of prime nonalternating knots is less than or equal to the minimal crossing number. We study some cases when the arc index is strictly less than the minimal crossing number. We also give minimal grid diagrams of some prime nonalternating knots with 13 crossings and 14 crossings whose arc index is the minimal crossing number minus one., Comment: 30 pages, 31 figures, 1 table and 379 minimal grid diagrams

Background: A specific and effective strategy is in demand to treat ovarian cancer successfully. Epidermal growth factor receptor (EGFR) is highly expressed in ovarian cancer, and thus EGFR antisense gene therapy can be a potential therapeutic strategy. Method: L-Arginine-grafted-polyamidoamine dendrimer (PAMAMArg) has been reported to be a novel nonviral gene delivery carrier. Therefore, the ability of PAMAM-Arg in transferring a luciferase gene to ovarian carcinoma SK-OV3 cells has been examined, and the cytotoxicity of the cationic polymer has been investigated. In addition, the suppression of cell proliferation has been evaluated by transferring an EGFR antisense gene to SK-OV3 cells using PAMAM-Arg. Polyethyleneimine (PEI) 25K was used as a positive control. Results: As a result, in vitro gene transfection efficiency of PAMAMArg was enhanced with increasing transfection time and N/P ratios. PAMAM-Arg transferred the luciferase gene into cells more efficiently than PEI. In addition, PAMAM-Arg was minimally toxic to the cells whereas PEI 25K was highly toxic. The polyplexes formed by the EGFR antisense gene and PAMAM-Arg significantly reduced thymidine incorporation into the cells suggesting the suppression of cancer cell proliferation. Conclusion: These results suggest that a PAMAM-Arg/EGFR antisense gene complex can be used as a safe and efficient therapeutic agent for cancer gene therapy.

A novel T-type calcium channel blocker, 4-amino-1-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-butan-1-one (HYP-10) has been synthesized, and the compound has shown promise as both a nociceptive and inflammatory pain reliever as well as an analgesic in a rat neuropathic pain model. A quantification method was developed for the determination of HYP-10 in rat plasma. After simple protein precipitation with methanol, HYP-10 and the internal standard, methaqualone were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma HYP-10 concentration after a single intravenous administration of the compound in rats.

A hydrophobic and water-insoluble platinum(II) compound, cis -(cha) 2 Pt(NO 3 ) 2 was encapsulated by macromolecular micelles self-assembled from an amphiphilic cyclotriphosphazene [NP(MPEG750)(GlyPheLeu) 2 Et] 3 (CP750). The micelle-encapsulated platinum(II) compound exhibited outstanding pharmacokinetics in rats by showing long blood circulation and much larger systemic exposure (AUC = 43.5 μg h/ml) compared with the free carboplatin (AUC = 4.32 μg h/ml). Biodistribution study of the micellar platinum(II) compound using male Sprague–Dawley rats has shown excellent tumor to tissue ratios of 4.03 at 2 h post injection and 4.67 at 24 h post injection. Furthermore, the micellar platinum(II) compound exhibited more than 6 times higher cellular uptake in human cervical (HeLa) and lung (A549) tumor cells compared with the free platinum compound. Also it is surprising that the micellar platinum(II) compound displayed specifically high cytotoxicity against the stomach tumor cells (SNU638), which are one of the least responsive to chemotherapeutic agents currently in clinical use. The acute toxicity study has shown that the LD 50 values of free and the micellar cis -(cha) 2 Pt(NO 3 ) 2 are approximately 70 mg/kg and 90 mg/kg, respectively. Thus the platinum compound encapsulated by cyclotriphosphazene micelles is a promising candidate for preclinical studies.

Introduction It was recently reported that heme oxygenase-1 (HO-1) activity is related to stem cell differentiation; however, the involvement of HO-1 in pulp cell growth and differentiation has not been well explored. The purpose of this study was to investigate the role of HO-1 in the growth and differentiation of human dental pulp cells (HDPCs). Methods We evaluated cell growth by MTT assay, mineralization by alizarin red staining, and differentiation marker mRNA expression by reverse transcriptase polymerase chain reaction. Results HO-1 induction by cobaltic protoporphyrin IX (CoPP) in HDPCs increased cell growth and mineralization and up-regulated the messenger RNA expression of such odontoblastic markers as alkaline phosphatase, osteopontin, bone sialoprotein, dentin matrix protein-1, and dentin sialophosphoprotein. Carbon monoxide scavenger, iron chelator, HO-1 inhibitor, and HO-1 small interfering RNA (siRNA) attenuated HDPC growth and differentiation. Conclusions CoPP treatment results in dental pulp cell proliferation and odontoblast differentiation that appears partly mediated by HO-1. Our results suggest that odontoblastic differentiation and growth are positively regulated by HO-1 induction and negatively regulated by HO-1 inhibition. Thus, pharmacologic HO-1 induction might represent a potent therapeutic approach for pulp capping and the regeneration of HDPCs.