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Aim: A thermosensitive injectable hydrogel composed of nanocomplexes of doxorubicin and hyaluronic acid (HA) for the local treatment of cancer diseases was developed and characterized., Materials & Methods: It was found that the addition of a divalent metal ion of Mg (MgCl2) was required to properly form HA-doxorubicin nanocomplexes, which were mixed with Pluronic® F127 (BASF, Germany) to form thermosensitive injectable hydrogels., Results: The DH700KMF-15 hydrogel resulted in efficient growth inhibition of C26 colon cancer cells and it selectively targeted the lymphatic system by the specific affinity of HA to the lymphatic system in vivo., Conclusion: The optimal formulations of DH700KMF-15 can increase the therapeutic efficacy of the local treatment of cancer with the potential for lymphotropic targeting to inhibit metastasis.

Mucosal surfaces contain specialized dendritic cells (DCs) that are able to recognize foreign pathogens and mount protective immunity. We previously demonstrated that intranasal administration of targeted galactosylated liposomes can elicit mucosal and systemic antibody responses. In the present study, we assessed whether galactosylated liposomes could act as an effective DC-targeted mucosal vaccine that would be capable of inducing systemic anti-tumor immunity as well as antibody responses. We show that targeted galactosylated liposomes effectively facilitated antigen uptake by DCs beyond that mediated by unmodified liposomes both in vitro and in vivo. Targeted galactosylated liposomes induced higher levels of pro-inflammatory cytokines than unmodified liposomes in vitro. C57BL/6 mice thrice immunized intranasally with ovalbumin (OVA)-encapsulated galactosylated liposomes produced high levels of OVA-specific IgG antibodies in their serum. Spleen cells from mice receiving galactosylated liposomes were restimulated with OVA and showed significantly augmented levels of IFN-γ, IL-4, IL-5 and IL-6. In addition, intranasal administration of OVA-encapsulated beta-galactosylated liposomes resulted in complete protection against EG7 tumor challenge in C57BL/6 mice. Taken together, these results indicate that nasal administration of a galactosylated liposome vaccine mediates the development of an effective immunity against tumors and might be useful for further clinical anti-tumoral applications., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Two new pyrrolosesquiterpenes, 1 and 2, were isolated from cultures of the soil actinomycete Streptomyces sp. Hd7-21. The structures of these compounds were established as (2Z,4E,9E)-6,7,11-trihydroxy-3,7,11-trimethyl-1-(1H-pyrrol-2-yl)dodeca-2,4,9-trien-1-one (1) and (2Z,4E)-5-{3-[(2E)-4-hydroxy-4-methylpent-2-en-1-yl]-3-methyloxiran-2-yl}-3-methyl-1-(1H-pyrrol-2-yl)penta-2,4-dien-1-one (2) by extensive spectroscopic analyses including MS, and 1D- and 2D-NMR data. Their cytotoxic activities against a panel of human cancer cell lines were evaluated., (Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.)

Mast cell (MC) degranulation has been implicated in small intestinal ischemia reperfusion (IIR) injury, therein, inhibiting overproduction of histamine released from activated MC may provide promising strategies against IIR-mediated liver injuries. The aim of the present study was to explore whether anti-histamine treatment contribute to attenuating IIR-mediated liver injury. Adult SD rats were randomized into sham-operated group (S group), sole IIR group (IIR group), and IIR treated with Ketotifen, a histamine antagonist (IIR+K group), Cromolyn Sodium, a MC stabilizer (IIR+C group), and Compound 48/80, a MC degranulator (IIR+CP group), respectively. IIR was induced by superior mesenteric artery occlusion for 75 min followed by 4 h of reperfusion. The agents were intravenously administrated 5 min before reperfusion to induce different levels of histamine. Subsequently, serum concentrations of ALT, AST and histamine; levels of LDH,TNF-α, IL-8 and MDA as well as SOD activities in the liver were assessed. Histopathologic changes were also evaluated. IIR resulted in severe liver injury as demonstrated by significant increases in injury scores, with concomitant significant increases in serum ALT, AST and histamine levels, as well as LDH, TNF-α, IL-8, and MDA levels in the liver, accompanied by reduction in SOD activities (all P < 0.05, IIR vs. S). Treatments by Ketotifen and Cromolyn Sodium similarly markedly alleviated IIR-mediated liver injury as confirmed by significant reduction of the above biomedical changes whereas Compound 48/80 further aggravated IIR-mediated liver injury by dramatically enhancing the above biomedical changes. Data of our study suggest that anti-histamine treatments may provide promising benefits in alleviating liver injury triggered by IIR.

The addition of an HDAC inhibitor, suberoylanilide hydroxamic acid (SBHA), to the culture medium of Cladosporium colocasiae, dramatically altered its metabolic profiles. Analysis of the culture broth extract led to the isolation of two new acetylenic sterols (1-2). The isolated compounds were further evaluated for their cytotoxic and antibacterial activities. Compound 1 showed activity against Bacillus subtilis, affording a zone of inhibition of 12mm at 100μg/disk. However, none of them showed noticeable growth inhibitory effects., (Copyright © 2014. Published by Elsevier Inc.)

The experiment aimed to increase the drug-delivery efficiency of poly-lactic-co-glycolic acid (PLGA) nanoparticles. Lipid-polymer hybrid nanoparticles (LPNs-1) were prepared using PLGA as a hydrophobic core and FA-PEG-hyd-DSPE as an amphiphilic shell. Uniform and spherical nanoparticles with an average size of 185 nm were obtained using the emulsification solvent evaporation method. The results indicated that LPNs-1 showed higher drug loading compared with naked PLGA nanoparticles (NNPs). Drug release from LPNs-1 was faster in an acidic environment than in a neutral environment. LPNs-1 showed higher cytotoxicity on KB cells, A549 cells, MDA-MB-231 cells, and MDA-MB-231/ADR cells compared with free doxorubicin (DOX) and NNPs. The results also showed that, compared with free DOX and NNPs, LPNs-1 delivered more DOX to the nuclear of KB cells and MDA-MB-231/ADR cells. LPNs-1 induced apoptosis in KB cells and MDA-MB-231/ADR cells in a dose-dependent manner. The above data indicated that DOX-loaded LPNs-1 could kill not only normal tumor cells but also drug-resistant tumor cells. These results indicated that modification of PLGA nanoparticles with FA-PEG-hyd-DSPE could considerably increase the drug-delivery efficiency and LPNs-1 had potential in the delivery of chemotherapeutic agents in the treatment of cancer.

Traumatic brain injury (TBI) is often associated with intracerebral and intraventricular hemorrhage. Thrombin is a neurotoxin generated at bleeding sites fater TBI and can lead to cell death and subsequent cognitive dysfunction via activation of Src family kinases (SFKs). We hypothesize that inhibiting SFKs can protect hippocampal neurons and improve cognitive memory function after TBI. To test these hypotheses, we show that moderate lateral fluid percussion (LFP) TBI in adult rats produces bleeding into the cerebrospinal fluid (CSF) in both lateral ventricles, which elevates oxyhemoglobin and thrombin levels in the CSF, activates the SFK family member Fyn, and increases Rho-kinase 1(ROCK1) expression. Systemic administration of the SFK inhibitor, PP2, immediately after moderate TBI blocks ROCK1 expression, protects hippocampal CA2/3 neurons, and improves spatial memory function. These data suggest the possibility that inhibiting SFKs after TBI might improve clinical outcomes.

Phytochemical investigation of the ethyl acetate extract of the edible macrofungus, Ramaria madagascariensis, has led to the isolation of two new alkaloids (1 and 2). Their structures were elucidated by HR-ESI-MS, IR, and 1D- and 2D-NMR experiments. The antimicrobial activity of 1 and 2 was also tested and evaluated., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Phytochemical investigation of the AcOEt extract of G. Lucidum has led to the isolation of two new triterpenoids, 1 and 2, together with five known ones, 3-7. The structures of the new compounds were identified as 12β-acetoxy-3β,7β-dihydroxy-11,15,23-trioxolanost-8-en-26-oic acid butyl ester (1) and 12β-acetoxy-3,7,11,15,23-pentaoxolanost-8-en-26-oic acid butyl ester (2) on the basis of detailed spectroscopic analysis (mass spectrometry, and 1D- and 2D-NMR experiments). The antimicrobial activities of 1 and 2 were also evaluated., (Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.)

Doxorubicin (DOX) is a broad-spectrum antitumor drug used in the clinic. However, it can cause serious heart toxicity. To increase the therapeutic index of DOX and to attenuate its toxicity toward normal tissues, we conjugated DOX with either α-linolenic acid (LNA) or palmitic acid (PA) by a hydrazone or an amide bond to produce DOX-hyd-LNA, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HepG2, MCF-7, and MDA-231 cells was higher compared to that of DOX, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HUVECs was lower than that of DOX. DOX-hyd-LNA released significantly more DOX in pH 5.0 medium than it did in pH 7.4 medium. DOX-hyd-LNA induced more apoptosis in MCF-7 and HepG2 cells than DOX or DOX-ami-LNA. Significantly more DOX was released from DOX-hyd-LNA in both MCF-7 and HepG2 cells compared with DOX-ami-LNA. Compared to free DOX, a biodistribution study showed that DOX-hyd-LNA greatly increased the content of DOX in tumor tissue and decreased the content of DOX in heart tissue after it was intravenously administered. DOX-hyd-LNA improved the survival rate, prolonged the life span, and slowed the growth of the tumor in tumor-bearing nude mice. These results indicate that DOX-hyd-LNA improved the therapeutic index of DOX. Therefore, DOX-hyd-LNA is a potential compound for use as a cancer-targeting therapy.

Background: Prosthetic reconstruction using human acellular dermis (ADM) is a common practice in breast reconstruction. AlloDerm and FlexHD are two different forms of ADM, each with unique characteristics. No studies have directly compared the postoperative complications of these 2 products., Methods: The outcomes of 547 consecutive implant-based breast reconstructions were reviewed., Results: Reconstruction was performed in 382 consecutive women (547 total breasts), employing mostly immediate reconstruction (81%). Mean follow-up was 6.4 months. Among immediate reconstructions, 165 used AlloDerm and 97 used FlexHD. Complications were similar by univariate analysis. In multivariate analysis, smoking and higher initial implant fill were risk factors for delayed healing. The use of FlexHD, single-stage reconstruction, and smoking were independent risk factors for implant loss., Conclusions: There is no significant difference in the complication rates between AlloDerm and FlexHD in immediate breast reconstruction. Multivariate analysis suggests that FlexHD may be a risk factor for implant loss.

GRP78 (78 kDa glucose-regulated protein) has ubiquitously existed in nearly all organisms from yeast to humans, reflecting the central roles it plays in cell survival. In this report, we isolated and sequenced the full-length cDNA of GRP78 (designated DjGRP78) from the planarian Dugesia japonica. The cDNA is 2121 bp, including an open reading frame (ORF) of 1983 bp encoding a polypeptide of 660 amino acids with three HSP70 family signatures. DjGRP78 contains signal peptides at the N-terminus and a KTEL peptide motif at the C-terminus, which suggests that it localizes in the endoplasmic reticulum (ER). Fluorescent real time RT-PCR was employed to detect the expression pattern of Djgrp78 in response to different stressors. Our results show that heat shock and heavy metals (Hg(2+) and Pb(2+)) induce Djgrp78 expression, but starvation does not. Interestingly, we found that Djgrp78 was up-regulated in planarians with septic tissues, and also verified that it was up-regulated in response to bacterial challenge. Our data indicate that Djgrp78 may be a multifunctional gene, and play important roles in physiological and pathological stress in planarians., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The supplementation of a DNA methyltransferase inhibitor, 5-azacytidine (5-AZ), to the culture medium of Penicillium funiculosum, dramatically altered its metabolic profiles. Analysis of the culture broth extract led to the isolation of two new prenyleudesmane diterpenoids (1-2). The isolated compounds were further evaluated for their cytotoxic and antibacterial activities. Our findings confirmed that the use of chemical epigenetic modifiers is an effective technique for promoting the expression of silent biosynthetic pathways to produce unique secondary metabolites.

One new pyrrolosesquiterpene 1 was isolated from the cultures of the soil actinomycete Streptomyces sp. Hd7-21. Its structure was elucidated by extensive spectroscopic analyses including MS and one-dimensional and two-dimensional NMR data. Compound 1 showed moderate cytotoxic activity against a panel of human cancer cell lines.

Nanoparticles are finding increasing application because of their unusual optical properties. Processing these materials would be drastically simplified if they could be routinely dispersed into a wide variety of polar and nonpolar solvents. We report the synthesis of a new bidentate thiol ligand, (Z)-octadec-9-en-1-yl-5-(1,2-dithiolan-3-yl)pentanoate, and demonstrate its ability to phase transfer gold nanospheres (5-70 nm), nanorods, and silver nanoparticles efficiently from water into various organic solvents. The protocol obviates the need for solid-phase steps or polymeric ligands. Electronic spectra and electron micrographs demonstrate that the particles are fully dispersed in a variety of organic solvents after transfer.

A new and rare ergostane triterpenoid, 4alpha-methyl-3alpha,4beta-dihydroxy-ergost-8,24(28)-dien-7,11-dion-25-al (1), was isolated from cultures of the basidiomycete Inocybe lilacina, and its structure established on the basis of spectral methods (MS, IR, 1D and 2D NMR).

A new ergostane triterpenoid (4 alpha-methylergost-8,24(28)-dien-3,7,1 1-trione, 1) together with four known compounds (2-5) were isolated from cultures of the spectroscopic and M Sexperiments. basidiomycete Inocybe lilacina. The structure of the new compound was established on the basis of IR, 1D and 2D NMR

The objective of this study was performed to investigate the effects of thapsigargin on apoptosis, actin cytoskeletal dynamics, and actin cytoskeletal proteins in human lung adenocarcinoma cell. Thapsigargin is a specific irreversible inhibitor of ER calcium-ATPase, which may promote ER stress by depletion of lumenal calcium stores and show potential to induce cell death. The effects of thapsigargin on the apoptosis in A549 cells were assayed by Hoechst staining. Moreover, the F-actin staining by Rhodamine-phalloidin and RhoA antibody for cytoskeleton organizations were applied to A549 cells. To confirm the impairment of cytoskeletal dynamics treated with thapsigargin, western blots were applied to analyze the protein levels of p-Cofilin-1 (Ser3), Cofilin-1, and pPaxillin (Tyr118), as well as RhoA and pS6 (S240/244). Results suggest that thapsigargin may induce cell death in A549 cells with a time- and dose-dependent manner. The F-actin fibers and RhoA signals are also reduced with a time- and dose-dependent manner by thapsigargin treatment. The phosphorylation forms of Cofilin-1 and paxillin are attenuated by 1 μM thapsigargin treatment for 24 h. These alternations may be caused by the inhibition of of mTORC1 activities (indicated by pS6 (Ser240/244)) and RhoA pathways after thapsigargin treatment. The present findings highlight important roles of calcium entry in cytoskeleton organization and apoptosis in human lung adenocarcinoma cells and will help to set a stage to the clinical treatment of cancer cell metastasis.

LUFFACHITIN obtained from the residue of the sponge-like dried fruit of Luffa aegyptiaca was developed as a weavable skin substitute in this study. A chemical analysis revealed that LUFFACHITIN was composed of a copolymer containing N-acetyl-glucosamine (~40%) as a major monomer with a filamentary structure as demonstrated by both optical and scanning electron microscopy. The pulp-like white residue of the sponge-like dried fruit of Luffa aegyptiaca after treatment was then woven into a thin, porous membrane by filtration and lyophilization as a skin substitute for conducting wound-healing study on rats. The results indicated that the LUFFACHITIN membrane showed significant wound-healing enhancement (25 days to complete healing) compared to cotton gauze (>30 days), but not inferior to that of SACCHACHITIN. Furthermore, the LUFFACHITIN membrane had advantages of having a high yield, better physical properties for fabrication, and a more attractive appearance.

Ergostane and cucurbitane triterpenoids are relatively rare in mushroom metabolites, and a total of 55 compounds are reported up to May 2013. Many of them exhibited diverse biological properties such as anti-inflammatory, cytotoxic and antioxidative activities. The paper reviewed systematically the isolation, structure elucidation and biological activities of ergostane- and cucurbitane-type triterpenoids from mushroom for the first time.

Milk is a complex colloidal system that responds to changes in temperature imposed during processing. Whilst much has been learned about the effects of temperature on milk, little is known about the dynamic response of casein micelles to changes in temperature. In this study, a comprehensive physico-chemical study of casein micelles in skim milk was performed between 10 and 40 °C. When fully equilibrated, the amount of soluble casein, soluble calcium and the pH of skim milk all decreased as a function of increasing temperature, whilst the hydration and volume fraction of the casein micelles decreased. The effect of temperature on casein micelle size, as determined by dynamic light scattering and differential centrifugation, was less straightforward. Real-time measurements of turbidity and pH were used to investigate the dynamics of the system during warming and cooling of milk in the range 10-40 °C. Changes in pH are indicative of changes to the mineral system and the turbidity is a measure of alterations to the casein micelles. The pH and turbidity showed that alterations to both the casein micelles and the mineral system occurred very rapidly on warming. However, whilst mineral re-equilibration occurred very rapidly on cooling, changes to the casein micelle structure continued after 40 min of measurement, returning to equilibrium after 16 h equilibration. Casein micelle structure and the mineral system of milk were both dependent on temperature in the range 10-40 °C. The dynamic response of the mineral system to changes in temperature appeared almost instantaneous whereas equilibration of casein was considerably slower, particularly upon cooling., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Heat shock proteins (Hsps) are induced by heat shock via heat shock factor proteins binding to heat shock elements in their promoters. Hsp70 is massively induced in response to misfolded proteins following cerebral ischemia in all cell types but is induced mainly in neurons in the ischemic penumbra. Overexpression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia in most reported studies. Hsp27 can exist as unphosphorylated large oligomers that prevent misfolded protein aggregates and improve cell survival. P-Hsp27 small oligomers bind specific protein targets to improve survival. In the brain, protein kinase D phosphorylates Hsp27 following ischemia which then binds apoptosis signal-regulating kinase 1 to prevent MKK4/7, c-Jun NH(2)-terminal kinase, and Jun-induced apoptosis, and decrease infarct volumes following focal cerebral ischemia. Heme oxygenase-1 (HO-1) metabolizes heme to carbon monoxide, ferrous ion, and biliverdin. CO activates cGMP to promote vasodilation, and biliverdin is converted to bilirubin which can serve as an anti-oxidant, both of which may contribute to the reported protective role of HO-1 in cerebral ischemia and subarachnoid hemorrhage. However, ferrous ion can react with hydrogen peroxide to produce pro-oxidant hydroxyl radicals which may explain the harmful role of HO-1 in intracerebral hemorrhage. Heat shock proteins as a class have great potential as treatments for cerebrovascular disease and have yet to be tested in the clinic.

Melatonin, an endogenous ligand for melatonin receptor, plays an important role in modulating various physiological activities through acting on different subtypes MT1, MT2 or the binding site MT3. The distinct roles of the receptor subtypes provide great potential for receptor-specific pharmacological agents. Melatonin has no subtypeselectivity, so it is very important to develop different subtype-selective ligand for receptor subtype research and drug development. In order to provide guidance for developing high selective ligand, this paper focused on the MT2-selective ligands, which developed well in the past years. The MT2-selective ligands, mainly focusing on binding data on MT1 and MT2 receptor, are reviewed in detail according to their structural classes, and the relative pharmacophore, receptor binding models and the relationship between the structure of ligand and the affinity along with selectivity for receptor subtype were discussed, which may facilitate the exploration of more potent and effective MT2-selective ligands.

Naturally occurring spirostanol saponins bear a chacotriose, α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D-glucopyranose residue as the oligosaccharide moiety which is believed to be important for biological activity. Herein the development of a concise, combinatorial method for the synthesis of two series of glycan variants at the 2' and/or 4' positions of chacotriose is described and the structure-activity relationships of the glycone part at 3-OH of chlorogenin investigated. These compounds were found to be weakly-cytotoxic toward leukemia cell lines CCRF and HL-20, indicating that the chacotriose moiety is important for anticancer activity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To explore the effects of metabolic syndrome (MS) on multi-vessel lesions of symptomatic intracranial atherosclerosis., Methods: During April 2009 and October 2010, a total of 139 consecutive hospitalized patients with symptomatic intracranial atherosclerosis were recruited to undergo magnetic resonance angiography (MRA) or/and CT angiography (CTA) or/and digital subtraction angiography (DSA) to measure the stenotic degree and numbers of intracranial atherosclerosis. They were divided into 2 groups according to lesion numbers: single and multi-vessel lesions. MS was defined by the criteria of the Adult Treatment Panel III to examine the incidences of MS. The risk factors were analyzed for multi-vessel lesions of symptomatic intracranial atherosclerosis to explore the relationship between MS and multi-vessel lesions., Results: Among them, 210 intracranial atherosclerotic lesions were documented. Fifty-nine (42.4%) patients had two or more lesions (group with multi-vessel lesions). The incidence of MS was 70.5%. The rates of MS in groups of single and multi-vessel lesions were 56.3% and 89.8% respectively. And statistical significance existed between two groups (P < 0.001). Moreover, the number of MS components increased gradually with the number of lesions (P < 0.001). For the analysis of individual criteria for MS, only abnormal glycemia was found to be associated with multi-vessel lesions (P = 0.002). And multiple Logistic regression analysis showed that MS was associated with multi-vessel lesions of intracranial atherosclerosis (P = 0.001)., Conclusions: MS is an independent predictor for multi-vessel lesions of intracranial atherosclerosis. And its intervention may be an important preventive strategy for intracranial multi-vessel atherosclerosis.

The mucosal immune system produces secretory IgA (sIgA) as the first line of defense against invasion by foreign pathogens. Our aim was to develop a galactose-modified liposome as a targeted carrier which can be specifically recognized by macrophage, one of the most important antigen presenting cells. First, galactose was covalently conjugated with 1,2-didodecanoyl-sn-glycero-3-phosphoethanolamine (DLPE) to give a targeted ligand, a galactosyl lipid. The galactosyl lipid was then incorporated into a liposomal bilayer to form a galactosylated liposome carrier. Further, the ovalbumin (OVA) was encapsulated into the galactosylated liposome carriers and mice were intranasally immunized. Confocal laser scanning microscopy and flow cytometry analysis showed that the targeted galactosylated liposome carrier had a higher uptake rate than unmodified liposomes. The targeted galactosylated liposome induced higher levels of tumor necrosis factor-α and interleukin-6 production than unmodified liposomes (P<0.05). Furthermore, 6-week-old BALB/c female mice immunized with the OVA-encapsulated targeted galactosylated liposome had significantly higher OVA-specific s-IgA levels in the nasal and lung wash fluid (P<0.05). In addition, the targeted galactosylated liposome simultaneously augmented the serum IgG antibody response. In summary, the OVA-encapsulated targeted galactosylated liposome induced significantly higher mucosal IgA and systemic IgG antibody titers and is a potential antigen delivery carrier for further clinical applications., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Folate-aminocaproic acid-doxorubicin (FA-AMA-DOX) was synthesized and characterized by H NMR spectroscopy and mass spectrometry. Cytotoxicity and cellular uptake experiments were performed in KB and HepG2 cells, which express folic acid receptor, and the cell line A549, which does not express folic acid receptor. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cellular uptake was monitored using fluorescence microscopy. The amount of DOX released from FA-AMA-DOX was much greater at pH 5.0 than that at pH 6.5 or 7.4. The cytotoxicity of FA-AMA-DOX toward KB and HepG2 cells was greater than that of DOX or AMA-DOX at the same concentrations, and cytotoxicity could be attenuated by FA in a dose-dependent manner. On the contrary, the cytotoxicity of FA-AMA-DOX and AMA-DOX toward A549 cells was lower than that of DOX at the same concentration, and cytotoxicity could not be reduced by FA. Compared with FA-AMA, FA-AMA-DOX increased the intracellular accumulation of DOX in KB cells. These results suggested that FA-AMA-DOX have suitable attributes for the active targeting of folate-receptor-positive tumor cells and for releasing the chemotherapeutic agent, DOX, in situ; it therefore has potential as a novel cancer therapeutic., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: To explore the effects of cromolyn sodium (CS) on intestinal ischemia-reperfusion (IIR) and its relationship with mast cell activation and protease-activated receptor 2 (PAR-2) expression., Methods: A total of 32 SD rats were randomly divided into 4 groups: sham-operated (S), intestinal ischemia reperfusion (IIR), CS (a mast cell stabilizer, CS, 25 mg/kg) and compound 48/80 (a mast cell degranulation, CP, 0.75 mg/kg) (n = 8 each). IIR was induced by clamping superior mesenteric artery for 75 min followed by reperfusion for 3 hours. The above agents were intravenously administrated at 5 min pre-reperfusion. Rats were then sacrificed and intestinal issues harvested for histological examinations. The tryptase expression and mast cell count were analyzed by immunohistochemistry. PAR-2 was analyzed by Western blot., Results: The Chiu's score (0.75 ± 0.21), mast cell count (10 ± 3), tryptase expression (125 ± 15) and PAR-2 expression (109 ± 10) of group S were the least while those of group CP the most (all P < 0.05). The Chiu's score (2.14 ± 0.64), mast cell count (15 ± 4), tryptase expression (138 ± 17) and PAR-2 expression (124 ± 12) of group CS were less than those of groups IIR and CP (all P < 0.05)., Conclusion: Cromolyn sodium may reduce IIR injury by stabilizing mast cell membrane and inhibiting the expressions of tryptase and PAR-2.

Understanding the effect of evaporative concentration on casein micelle composition is of high importance for milk processing. Alterations to the hydration, composition and size of casein micelles were investigated in skimmed milk evaporated to concentrations of 12-45% total solids content. The size of casein micelles was determined by dynamic light scattering, and the water content and composition determined by analysis of supernatants and pellets obtained by ultracentrifugation. The mass balance and hydration results showed that during the evaporation process, while micelles were dehydrated, water was removed preferentially from the serum. The amount of soluble casein and calcium in the serum decreased as a function of increasing solids content, indicating a shift of these components to the micelles. The formation of a small proportion of micelle aggregates at high concentrations appeared dependent on the time kept at these concentrations. Upon redilution with water, casein micelles were immediately rehydrated and aggregates were broken up in a matter of minutes. Soluble calcium and pH returned to their original state over a number of hours; however, only a small percentage of original soluble casein returned to the serum over the 5h period investigated. These results showed that casein micelles are significantly affected by evaporative concentration and that the alterations are not completely and rapidly reversible., (Copyright © 2012. Published by Elsevier Ltd.)

Background: Survivin is an antiapoptotic molecule that is widely expressed in cancers, including hepatocellular carcinoma (HCC). Survivin has become a general therapeutic target for cancers because of its selective overexpression in a majority of tumors. However, little is known regarding the effect of survivin expression in combination with gemcitabine on HCC., Methods: We generated survivin knockdown cells (survivin-KD) via a short interfering RNA (siRNA) technique. The antiproliferation effects of gemcitabine were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay, and cell cycle evaluation., Results: According to the MTT assay, we found that survivin-KD cells were more sensitive than parental cells and scrambled control cells to gemcitabine treatment. The apoptotic cell population increased in survivin-KD cells that were treated with gemcitabine in comparison to scrambled control cells, as observed by the cell cycle distribution and TUNEL assays. We found that survivin knockdown resulted in a reduction of glucose-regulated protein 78 (GRP78), which may be responsible for the observed increased survivin-KD cell sensitivity to gemcitabine., Conclusions: We conclude that survivin knockdown may contribute to a therapeutic effect of gemcitabine through GRP78 on HCC cells.

Intracerebral hemorrhage (ICH) results in the release of a large number of endogenous molecules, including glutamate, Ca(2+), ROS, thrombin, heme, iron, TNF-α, and others. These molecules participate in excitatory and mitogenic signaling transduction in which N-methyl-D-aspartate (NMDA) receptors and Src family kinases (SFKs) are implicated. Mitogenic signaling initiates the cell cycle for normal cell division of microglia and neural progenitor cells, whereas aberrant mitogenic signaling causes toxicity, killing neurons, astrocytes, and brain microvascular endothelial cells in neurological diseases including ICH. In this review, we summarize (1) how SFKs modulate NMDA receptors to kill neurons following ICH and (2) how SFKs modulate mitogenic signaling transduction to kill neurons and play a role in disrupting the blood-brain barrier (BBB) immediately following ICH and in repairing the BBB during the recovery phases weeks following ICH.

Heat shock protein 90 (HSP90) is an abundant and highly conserved molecular chaperone, playing important roles in multiple cellular stress responses. The full-length cDNA of planarian Dugesia japonica Hsp90 (designated DjHsp90) was firstly cloned using rapid amplification of cDNA ends (RACE) techniques. It is 2,354 bp, including an open reading frame (ORF) of 2,148 bp encoding a polypeptide of 715 amino acids with all five HSP90 family signatures. We sequenced the ORF sequences from genomic DNA, and found only one intron (48 bp) existed in Djhsp90 gene structure. We used western blot and immunohistochemistry to analyze the expression pattern of DjHsp90 in response to heavy metal exposure and thermal stress at the protein level. Our results show that low doses of heavy metals and elevated culture temperature induced, but high doses of heavy metals and severe heat shock inhibited DjHsp90 expression. In response to heavy metals and thermal stress, DjHsp90-positive cells only appeared in the parenchymal tissue under epidermis cells along the bilateral from head to tail. These positive cells are presumably sensor cells that can detect external environment changes. Our work provides basic data for the study of stress responses in planarians.

Cantharidin, an active component in mylabris, is used in traditional Chinese medicine (TCM) to treat scabies and hepatoma, but accompanied by hemorrhagic cystitis. Evidence shows that cantharidin induces human bladder carcinoma cell death through COX-2 overexpression in vitro. In TCM, Scutellaria baicalensis is usually used to cure mylabris-induced hematuria. This work was undertaken to determine the mechanisms of cantharidin-induced rat hemorrhagic cystitis and explore the uroprotective effect of S. baicalensis. In vitro results showed cantharidin could induce cytotoxicity through prostaglandin (PG)E₂ overproduction of T24 cells. Boiling-water extract of S. baicalensis (SB-WE) could significantly inhibit PGE₂ production and COX-2 expression in lipo-polysaccharide-induced RAW 264.7 cells, indicating obvious anti-inflammatory abilities. In vivo results indicated that cantharidin caused rat hemorrhagic cystitis with hematuria via c-Fos and COX-2 overexpression. SB-WE was given orally to cantharidin-treated rats, whereby hematuria level, elevated PGE₂ and COX-2 protein overexpression were significantly and dose-dependently inhibited by SB-WE. The anti-inflammatory components of SB-WE are baicalin and wogonin, whose contents were 200.95 ± 2.00 and 31.93 ± 0.26 μg/mg, respectively. In conclusion, cantharidin induces rat cystitis through c-Fos and COX-2 over-expression and S. baicalensis can prevent the resulting hematuria because of its anti-inflammatory effects.

Aiming at getting the general requirements of the beam combine for ignition scale laser facilities, the analytical expressions including the factors affecting the combine results are derived. The physical meanings of every part are illustrated. Based on these expressions, the effects of the factors, including the beam configuration, piston error, and tip/tilt error, are studied analytically and numerically. The results show that the beam configuration cannot affect the Strehl ratio (SR) of the combined beam, but it influences the FWHM of the main peak and the ratio of the main peak and the side peak. The beam separation should be no more than 1.24 times the individual beam width for the multibeam combine, and be close to the individual beam width for the two-beam combine as much as possible. The piston error can change the characteristics of the combine beam focus, including the peak intensity, the focal spot morphology, the fractional energy contained within a certain area, and the center of mass. For the two-beam combine, a piston error less than 2π/5 rad is suitable, and for the multibeam combine, the standard deviation of the piston error should be no more than 2π/10 rad. The tip/tilt error has a great influence on the combined results. It affects the superposition degree of the focal spots of the combined elements directly. A requirement of 0.5~1 μrad for the standard deviation of the tip/tilt error is adequate.

Mature neurons (MNs), neural progenitor cells (NPCs) and neuroblastoma cells (NBCs) are all neural-derived cells. However, MNs are unable to divide once differentiated; NPCs are able to divide a limited number of times and differentiate to normal brain cell types; whereas NBCs can divide an unlimited number of times but rarely differentiate. Here, we perform whole transcriptome (mRNA, miRNA) profiling of these cell types and compare expression levels of each cell type to the others. Integrated mRNA-miRNA functional analyses reveal that: 1) several very highly expressed genes (e.g., Robo1, Nrp1, Epha3, Unc5c, Dcc, Pak3, Limk4) and a few under-expressed miRNAs (e.g., miR-152, miR-146b, miR-339-5p) in MNs are associated with one important cellular process-axon guidance; 2) some very highly expressed mitogenic pathway genes (e.g., Map2k1, Igf1r, Rara, Runx1) and under-expressed miRNAs (e.g., miR-370, miR-9, miR-672) in NBCs are associated with cancer pathways. These results provide a library of negative mRNAmiRNA networks that are likely involved in the cellular processes of differentiation and division., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Non-classical human leukocyte antigen (HLA)-DM plays an important and unique role in the processing and presentation of exogenous antigens. Polymorphisms of certain genes and frequency of alleles in populations may indicate susceptibility to certain diseases. In this study, the analysis of HLA-DMA and HLA-DMB gene polymorphisms and haplotypes in the Chinese Han population was conducted to obtain population genetic data. HLA-DM typing has been performed previously by other groups by polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR-sequence-specific oligonucleotide probe techniques. In this study, we established a TaqMan PCR typing method as an alternative to these techniques to survey the frequency of DMA and DMB alleles in the population. Genotyping was conducted in 1000 unrelated individuals of Han nationality in South and North China using TaqMan PCR typing. Four different DMA alleles and six different DMB alleles were detected. All loci met the Hardy-Weinberg equilibrium principle that both allele and genotype frequencies in a population remain constant. We found that the DMA*01:01 (69.35%) and DMB*01:01 (52.5%) alleles were more frequent in Chinese Hans. Analysis of the haplotypes for two loci of DMA and DMB showed that a highly significant positive linkage disequilibrium (LD) presented for DMA*01:01-DMB*01:02, DMA*01:01-DMB*01:03, DMA*01:01-DMB*01:04, DMA*01:02-DMB*01:01, DMA*01:02-DMB*01:05, DMA*01:03-DMB*01:07, and DMA*01:04-DMB*01:01 haplotypes. Analysis of haplotypes for four loci associated with antigen processing (DMA-DMB-TAP1-TAP2) showed a highly significant LD in DMA*01:01-DMB*01:04-TAP1*02:01:01-TAP2*01:02, DMA*01: 02-DMB*01:05-TAP1*01:01-TAP2*01:01, and DMA*01:01-DMB*01:03-TAP1* 04:01-TAP2*01:01 haplotypes. The comparison between the Chinese Han population and non-Chinese populations showed that no significant differences were found at the HLA-DMA locus in the Chinese Han population compared with people of German nationality, whereas significant differences presented when compared with Turkish, American Caucasian, Japanese, French, and Italian nationalities. However, at the HLA-DMB locus, highly significant differences presented in the Chinese Han population compared with Germans and Italians. This study lays the foundations for further disease association analyses., (© 2012 John Wiley & Sons A/S.)

Background: Infection rates for breast surgery are 3 to 15 percent, higher than average for a clean surgical procedure. Preoperative and postoperative antibiotics have lowered infection rates in other surgical groups, yet there is no consensus on postoperative prophylactic antibiotic use in microsurgical breast reconstruction., Methods: A retrospective review of consecutive patients who underwent autologous breast reconstruction between 2006 and 2009 was performed. Specific risk factors for autologous reconstruction were reviewed, including medical comorbidities, irradiation, and chemotherapy history. Data were collected on type and duration of prophylactic antibiotics. A prospective cohort of patients who received only 24 hours of postoperative antibiotics was identified. The incidence of surgical-site infections was measured using Centers for Disease Control and Prevention criteria., Results: A total of 256 patients with 360 microvascular breast reconstructions who received both preoperative and postoperative prophylactic antibiotics were analyzed. The overall surgical-site infection rate was 17.2 percent (44 of 256 patients). Surgical-site infection was correlated with increased age, tobacco use, and prior radiation. Duration of postoperative antibiotic use did not differ in those patients who developed surgical-site infections (6.2 versus 7.7 days; p = 0.19). Eighty-two patients (32 percent) received only 24 hours of postoperative antibiotics, while 174 (68 percent) received more than 24 hours of antibiotics for a median duration of 10 days. There was no difference in the overall surgical-site infection rate in those who received more than 24 hours of antibiotics (19.5 versus 15.5 percent; p = 0.47)., Conclusion: There was no reduction in the overall surgical-site infection rate among autologous breast reconstruction patients who received postoperative antibiotic prophylaxis for more than 24 hours., Clinical Question/level of Evidence: Therapeutic, III.

To resolve problems of long treatment durations and frequent administration of the antifungal agent terbinafine (TB), solid lipid nanoparticles (SLNs) with the ability to load lipophilic drugs and nanosize were developed. The SLNs were manufactured by a microemulsion technique in which glyceryl monostearate (GMS), glyceryl behenate (Compritol(®) 888; Gattefossé), and glyceryl palmitostearate (Precirol(®) ATO 5; Gattefossé) were used as the solid lipid phases, Tween(®) and Cremophor(®) series as the surfactants, and propylene glycol as the cosurfactant to construct ternary phase diagrams. The skin of nude mice was used as a barrier membrane, and penetration levels of TB of the designed formulations and a commercial product, Lamisil(®) Once™ (Novartis Pharmaceuticals), in the stratum corneum (SC), viable epidermis, and dermis were measured; particle sizes were determined as an indicator of stability. The optimal SLN system contained a <5% lipid phase and >50% water phase. The addition of ethanol or etchants had no significant effect on enhancing the amount of TB that penetrated the skin layers, but it was enhanced by increasing the percentage of the lipid phase. Furthermore, the combination of GMS and Compritol(®) 888 was able to increase the stable amount of TB that penetrated all skin layers. For the ACP1-GM1 (4% lipid phase; Compritol(®) 888: GMS of 1:1) formulation, the amount of TB that penetrated the SC was similar to that of Lamisil(®) Once™, whereas the amount of TB of the dermis was higher than that of Lamisil(®) Once™ at 12 hours, and it was almost the same as that of Lamisil(®) Once™ at 24 hours. It was concluded that the application of ACP1-GM1 for 12 hours might have an efficacy comparable to that of Lamisil(®) Once™ for 24 hours, which would resolve the practical problem of the longer administration period that is necessary for Lamisil(®) Once™.

Excision of head and neck melanoma is often limited by critical structures, which can lead to incomplete excision with positive pathologic margin and increased local recurrence rate. Complete excision with recommended margins and immediate reconstruction is possible when surgical oncologists and plastic surgeons work collaboratively. Our purpose was to evaluate local recurrence rate after excision and immediate reconstruction. We reviewed 98 consecutive patients treated for primary head and neck cutaneous melanoma at a single institution between 1999 and 2004. We assessed local recurrence rate. A total of 72 patients (73%) were followed for an average of 5.2 ± 1.7 years while 26 patients were excluded due to less than 1 year of follow-up. Adjacent tissue transfer was the most common reconstruction (87%). Local recurrence was reported in 2.8% and distant metastasis in 12.5% of patients. Immediate reconstruction after excision of head and neck melanoma can be safely performed with low local recurrence rate.

Since publishing our earlier report describing a strategy for the treatment of central nervous system (CNS) diseases by inhibiting the cell cycle and without disrupting neurogenesis (Liu et al. 2010), we now update and extend this strategy to applications in the treatment of cancers as well. Here, we put forth the concept of "aberrant cell cycle diseases" to include both cancer and CNS diseases, the two unrelated disease types on the surface, by focusing on a common mechanism in each aberrant cell cycle reentry. In this paper, we also summarize the pharmacological approaches that interfere with classical cell cycle molecules and mitogenic pathways to block the cell cycle of tumor cells (in treatment of cancer) as well as to block the cell cycle of neurons (in treatment of CNS diseases). Since cell cycle inhibition can also block proliferation of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits, we propose that future strategies aimed at cell cycle inhibition in treatment of aberrant cell cycle diseases (i.e., cancers or CNS diseases) should be designed with consideration of the important side effects on normal neurogenesis and cognition.

Background: Survivin has multiple functions during the progression of cancer. However, the role of survivin in the progression and metastasis of hepatocellular carcinoma (HCC) remains unknown., Materials and Methods: Survivin expression in HCC cells (Mahlavu and Hep3B) was assessed using reverse transcription real-time PCR and Western blot analyses. In addition, survivin expression in HCC cells was manipulated using small interfering RNA (siRNA) or overexpression and proliferation and transwell migration assays were performed to monitor the effect of manipulated survivin expression on the growth rate and migratory ability of the transfected cells., Results: Among the HCC cell lines tested, we found high endogenous expression of survivin mRNA and protein in Mahlavu cells. After silencing survivin expression in Mahlavu cells, there was a dramatic decrease in the cell growth rate and an increase in the metastatic potential of the cells. Overexpression of survivin in Hep3B cells suppressed the ability of the cell to migrate. The mechanism of enhanced cell migration caused by decreased survivin expression is mediated through the downregulation of glucose-regulated protein 78 (GRP78) and the upregulation of the epithelial-mesenchymal transition (EMT) marker, vimentin., Conclusions: Survivin may mediate metastasis in HCC. The knockdown of survivin expression may enhance cancer metastasis through the downregulation of GRP78 and upregulation of vimentin expression.

Background: Repair of wide primary cleft palates and secondary cases are challenging. Much literature is dedicated to technique modifications and useful pearls for approaching these patients. Nasal lining is not often highlighted or addressed as a solution to these challenging cleft palate surgeries. The goal of this article was to describe and demonstrate through case examples the simple dissection and significant mobilization of nasal lining as a tool for cleft palate repair., Methods: Retrospective case examples were selected to highlight the technique., Results and Discussion: The surgical technique is standardly used by the senior author and has not been previously published. This technique for tension-free nasal lining closure is detailed, and case examples are provided. This technique for nasal lining mobilization is easily reproducible and is versatile. It can be used as an adjunct to any palatoplasty technique and is particularly useful in the treatment of wide clefts and revision cases.

Taiwanofungus camphoratus, a well-known Chinese medicine used in Taiwan, possesses several pharmacological functions, including anticancer effects. In the present study, we aimed to investigate a novel anticancer effect by pretreating cancer cells with an ethanolic extract of T. camphoratus (TCEE) followed by the administration of an antifungal agent amphotericin B (AmB). Both TCEE and AmB showed significant dose-dependent cytotoxicity in HT29 cells. Pretreatment with a nontoxic dose of TCEE enhanced the cytotoxicity of AmB. Furthermore, significant apoptotic cell death was found in cells treated with TCEE and AmB. A combination treatment with AmB plus TCEE resulted in a significant repression of tumor growth in HT29 xenografts. Collectively, our results indicated that combined treatment with AmB and TCEE effectively induced apoptosis and inhibited tumor growth. In the future, TCEE may serve as a potential complementary and alternative medicine to treat patients suffering from colorectal cancer.

Objectives/aims: We investigated the incidence of immunoglobulin A (IgA) deficiency in Chinese population., Background: The frequency of IgA deficiency, defined as a serum IgA level of <0.05 mg dL(-1) , has been broadly studied in different ethnic groups. Individuals with IgA deficiency may form specific antibodies against IgA, which can cause an anaphylactic response when the patient receives an IgA-containing blood transfusion., Methods: A sandwich enzyme-linked immunosorbent assay was performed to screen for IgA deficiency and particle gel immunoassay used for confirmation. IgA antibodies were further detected by the DiaMed anti-IgA test in IgA-deficient blood donors., Results: Of the total 22,609 healthy blood donors screened, only seven cases were confirmed as having IgA deficiency (<0.05 mg dL(-1) ). Another seven cases displayed relative IgA deficiencies, with mean IgA concentrations ranging from 0.39 to 3.70 mg dL(-1) . Anti-IgA was identified in 2 of the 14 IgA-deficient blood donors whose IgA levels were <5 mg dL(-1) . Estimation of the theoretical risk for IgA anaphylactic transfusion reaction was 0.009%., Conclusion: The prevalence of IgA deficiency in Chinese is low. However, potential risks exist in performing blood transfusion to IgA-deficient persons, and measures should be taken to reduce IgA anaphylaxis., (© 2011 The Authors. Transfusion Medicine © 2011 British Blood Transfusion Society.)

Objective: To investigate the association of plasma homocysteine and OSA (obstructive sleep apnea) syndrome in ischemic stroke (IS)., Methods: A total of 92 male IS patients were classified by apnea hypopnea index (AHI) into 2 groups: non-OSA group (AHI < 5/h) and OSA group (AHI > or = 5). All patients were tested for plasma homocysteine when polysomnography was finished at (14 +/- 2) d after the onset of IS., Results: The mean level of homocysteine was significantly higher in the OSA group than that in the non-OSA group (17 +/- 5 vs 11 +/- 3 micromol/L, P < 0.01). Pearson correlation analysis revealed a positive correlation between the homocysteine level and the severity of AHI (r = 0.482, P < 0.01). Further multiple linear regression analysis showed that AHI and folate were independent predictors of homocysteine level (R2 = 0.553, P < 0.01, beta for AHI = 0.671, beta for folate = -0.256)., Conclusion: The severity of OSA is significantly associated with an elevated level of homocysteine in IS patients. And this association is independent of other causative factors of an elevated level of homocysteine.

In flap reconstruction of complex defects the perfusion of the reconstructive flap is critical to the ultimate success of the reconstruction. This is especially true in perforator-based flaps where it can be difficult to assess the adequacy of perfusion in the operating room. However, the ability to definitively determine the degree of flap perfusion is imperative to clinical decision-making. An emerging technology using near-infrared angiography with indocyanine green (ICG) dye may significantly improve the immediacy and accuracy of the assessment of flap perfusion. This article reviews the current state of ICG angiography and its use in clinical practice in plastic surgery. There are 17 case series, including a total of 386 patients, published in the literature using ICG angiography in various plastic surgical procedures. ICG angiography may aid flap design and assessment in the intraoperative/postoperative settings, reduce complications, and ultimately improve outcomes., (© Thieme Medical Publishers.)