The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre, randomized, double-blind, placebo-controlled phase I clinical trial.

CONTEXT: Capsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma. OBJECTIVE: To observe the clinical safety and tolerability of CALAS. MATERIALS AND METHODS: Subjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects. RESULTS: Sixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%). DISCUSSION AND CONCLUSIONS: CALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.

[Liposomal curcumin inhibits tumor growth and angiogenesis in Lewis lung cancer].

OBJECTIVE: To prepare water soluble curcumin liposome and investigate its anti-tumour and antiangiogenic effects. METHODS: Liposomal curcumin was prepared by alcohol injection method. Proliferation inhibition to murin Lewis lung cancer cell line LL/2 of curcumin liposome was evaluated by MTT assay. Apoptosis and cell cycle arrest induced by liposomal curcumin were analysed by flow cytometry. Anti-tumour effects were investigated in a murine lung cancer model, and the anti-angiogenic effect was determined by aginate encapsulation assay. RESULTS: In vitro, liposomal curcumin inhibits the proliferation of LL/2 cells and induces apoptosis and cell cycle arrest. In vivo, the systemic administration of liposomal curcumin resulted in the inhibition of tumour. Aginate encapsulation assay revealed angiogenesis was decreased by curcumin liposome. CONCLUSION: The curcumin liposome treatment can significantly inhibit tumour growth in vivo.

Efficient Photopolymerization of Dental Resin Composites Using the Photoluminescent Long Afterglow of Sr2MgSi2O7:Eu2+,Dy3.

Dental curing light with blue emission acts as the excitation source for the photopolymerization of the dental composite resin to achieve dental repairing. However, the current repair methods still suffer from a low monomer conversion degree and incomplete resin curing. In this study, novel dental resin composites (DRCs) were prepared by combining Sr2MgSi2O7:Eu2+,Dy3+ (SMSED), a photoluminescent material with a blue long afterglow, and dental resin composites. The curing depth, double bond conversion, elastic modulus, compressive strength, water absorption and solubility, and cytotoxicity were investigated systematically. The results suggest that adding 1 wt % SMSED to dental resin composites can maximize the curing depth and double bond conversion rate of DRCs and reduce its water absorption capacity without affecting the mechanical properties and biological toxicity. This work explores the practical applications of SMSED in dental resin composites, which provides an important reference for further improving the effect of dental caries repair.

High response organic deep ultraviolet photodetector with PEDOT:PSS anode.

We have fabricated an organic deep ultraviolet photodetector (PD) using PEDOT:PSS (PH 1000) as a transparent anode. NPB and PBD were employed as electron donor and acceptor, respectively. The PD exhibits a dark current of 0.0829 µA/cm(2) and a photocurrent of 85.3 µA/cm(2) at -12 V under 280 nm light illumination with an intensity of 0.488 mW/cm(2). A high response at 248-370 nm with its peak of 0.18 A/W at 280 nm and a detectivity of 1.1×10(12) cm Hz(1/2) W(-1) were achieved. The more detailed mechanism of harvesting high performance and the dependence of photocurrent density on illumination intensity are also discussed.

Synthesis and infrared property of polyaniline/phase-change nanocapsule composite.

A composite of polyaniline (PANI) and nanoencapsulated phase-change material (PCM) with polystyrene (PS) as the shell and n-octadecane as the core was synthesized using the ultrasonic technique assisted by in situ polymerization. The composite's morphology, structure, and thermal properties were characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The results showed that the surface of the PCM nanocapsules was covered with PANI. The phase-change temperature of the nanocapsules of PCM and the composite was slightly lower than that of n-octadecane. Their latent heat was less than the calculated value based on the mass ratio of n-octadecane measured by TGA. The infrared emission properties of PANI, the phase-change nanocapsule, and the composite were studied using an IR-II infrared emissivity instrument and an infrared camera. It was found that the infrared emissivity of the composite was appreciably higher than that of PANI. However, the composite showed lower temperature than the PANI when observed by infrared camera with the increasing ambient temperature around the n-octadecane phase-change temperature. This occurred because the phase-change material in the composite absorbs so much heat that infrared emissions were obviously decreased when the ambient temperature rose.

Synthesis and conductive properties of polypyrrole nanocomposites.

This paper studies the impact on the different surfactants and capacity of the oxidant for the synthesis of polypyrrole (PPy). The soluble PPy has also been studied. PPy was characterized mainly from the surface morphology, Fourier transform infrared spectroscopy, and conductivity sigma. First, using cetyltrimethylammonium bromide (CTAB) as the surfactant doped in an acid doping environment and without using ammonium persulfate (APS) as an oxidant, we determined the different capacities of the oxidant to synthesize the PPy. Scanning electron microscopy, Fourier transform infrared spectroscopy, and a four-probe conductivity meter were used to characterize the PPy. The acid doping conductivity was found to be 25 S/cm higher. Then, the solubility of polypyrrole was studied by doping with sodium dodecyl benzene sulfonate (SDBS), polyethylene glycol (PEG), and poly(styrene sulfonate) (PSS), proceeding the above-mentioned characterization.

Preclinical Safety Evaluation of a Recombinant Plasmid Vector Encoding Mature Human Neutrophil Peptide-1 by Repeated Local Administrations in Nonhuman Primates.

In our previous studies, a novel gene therapy approach was developed based on a plasmid vector pSecTag2B in which recombinant HNP1 gene was regulated under a cytomegalovirus promoter to encode a mature human neutrophil peptide-1 (HNP1) form. We showed for the first time in various tumor models, including human cancer xenografts, that overexpression of HNP1 in the tumor milieu by intratumoral pSecTag-HNP1 (pHNP1) administration efficiently attenuated in vivo tumor progression, mediated host immune responses to tumors, and produced a synergistic effect when combined with chemotherapeutics. In this study, a preclinical safety investigation of HNP1 gene therapy was conducted in nonhuman primates. Eleven cynomolgus monkeys were divided into three groups of three to four animals each and received either repeated s.c. injections of pHNP1/cationic liposome complexes at a low (0.625 mg/kg) or a high (2.5 mg/kg) dose or glucose as control. Significant HNP1 in vivo accumulation was detected after consecutive administrations. All primates reached the end of the study with good body conditions. Injection site inflammation was the only obvious toxic reaction during observation period. In addition, elevation of monocyte/macrophage and neutrophil as well as decline of lymphocyte were detected in the peripheral blood of pHNP1-treated primates. These alterations were partially alleviated at the end of observation period. Besides, dose-related histopathological changes of the immune organs were observed at necropsy, including a minimal thymic lymphocyte decrease and a minimal-to-mild lymph node erythrocyte increase, but which cannot be excluded from HNP1-induced immune reactions. Together, these data support future clinical studies of pHNP1-based local gene delivery in tumor patients.

5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice.

BACKGROUND: Colorectal peritoneal carcinomatosis (CRPC) is a common form of systemic metastasis of intra-abdominal cancers. Intraperitoneal chemotherapy is a preferable option for colorectal cancer. Here we reported that a new system, 5-FU-loaded hydrogel system, can improve the therapeutic effects of intraperitoneal chemotherapy. METHODS: A biodegradable PEG-PCL-PEG (PECE) triblock copolymer was successfully synthesized. The biodegradable and temperature sensitive hydrogel was developed to load 5-FU. Methylene blue-loaded hydrogel were also developed for visible observation of the drug release. The effects and toxicity of the 5-FU-hydrogel system were evaluated in a murine CRPC model. RESULTS: The hydrogel system is an injectable flowing solution at ambient temperature and forms a non-flowing gel depot at physiological temperature. 5-FU-hydrogel was subsequently injected into abdominal cavity in mice with CT26 cancer cells peritoneal dissemination. The results showed that the hydrogel delivery system prolonged the release of methylene blue; the 5-FU-hydrogel significantly inhibited the peritoneal dissemination and growth of CT26 cells. Furthermore, intraperitoneal administration of the 5-FU-hydrogel was well tolerated and showed less hematologic toxicity. CONCLUSIONS: Our data indicate that the 5-FU-hydrogel system can be considered as a new strategy for peritoneal carcinomatosis, and the hydrogel may provide a potential delivery system to load different chemotherapeutic drugs for peritoneal carcinomatosis of cancers.

Liposomal honokiol inhibits VEGF-D-induced lymphangiogenesis and metastasis in xenograft tumor model.

Lymph nodes metastasis of tumor could be a crucial early step in the metastatic process. Induction of tumor lymphangiogenesis by vascular endothelial growth factor-D may play an important role in promoting tumor metastasis to regional lymph nodes and these processes can be inhibited by inactivation of the VEGFR-3 signaling pathway. Honokiol has been reported to possess potent antiangiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we established lymph node metastasis models by injecting overexpressing VEGF-D Lewis lung carcinoma cells into C57BL/6 mice to explore the effect of honokiol on tumor-associated lymphangiogenesis and related lymph node metastasis. The underlying mechanisms were systematically investigated in vitro and in vivo. In in vivo study, liposomal honokiol significantly inhibited the tumor-associated lymphangiogenesis and metastasis in Lewis lung carcinoma model. A remarkable delay of tumor growth and prolonged life span were also observed. In in vitro study, honokiol inhibited VEGF-D-induced survival, proliferation and tube-formation of both human umbilical vein endothelial cells (HUVECs) and lymphatic vascular endothelial cells (HLECs). Western blotting analysis showed that liposomal honokiol-inhibited Akt and MAPK phosphorylation in 2 endothelial cells, and downregulated expressions of VEGFR-2 of human vascular endothelial cells and VEGFR-3 of lymphatic endothelial cells. Thus, we identified for the first time that honokiol provided therapeutic benefit not only by direct effects on tumor cells and antiangiogenesis but also by inhibiting lymphangiogenesis and metastasis via the VEGFR-3 pathway. The present findings may be of importance to investigate the molecular mechanisms underlying the spread of cancer via the lymphatics and explore the therapeutical strategy of honokiol on antilymphangiogenesis and antimetastasis.

Improved therapeutic efficacy against murine carcinoma by combining honokiol with gene therapy of PNAS-4, a novel pro-apoptotic gene.

PNAS-4, a novel pro-apoptotic gene activated during the early response to DNA damage, can inhibit proliferation via apoptosis when overexpressed in some tumor cells. Recent studies have indicated that honokiol can induce apoptosis, inhibit angiogenesis, and suppress tumor growth. In the present study, we investigated whether mouse PNAS-4 (mPNAS-4) could augment the apoptosis of tumor cells induced by honokiol in vitro, and whether the antiangiogenic activity of honokiol and induction of apoptosis by mPNAS-4 could work cooperatively to improve the antitumor efficacy in vivo. In vitro, mPNAS-4 inhibited proliferation of murine colorectal carcinoma CT26 and Lewis lung carcinoma LL2 cells through induction of apoptosis, and significantly augmented the apoptosis of CT26 and LL2 cells induced by honokiol. Compared with treatment with mPNAS-4 or honokiol alone, in vivo systemic administration of an expression plasmid encoding mPNAS-4 and low-dose honokiol significantly suppressed tumor growth through the enhanced induction of apoptosis and the augmented inhibition of angiogenesis. Our data suggest that the combined treatment with mPNAS-4 plus honokiol augments antitumor effects in vitro and in vivo, and that the improved antitumor activity in vivo may be associated with enhanced induction of apoptosis and augmented inhibition of angiogenesis. The present study may provide a novel and effective method for the treatment of cancer.

Grayscale photomask fabricated by laser direct writing in metallic nano-films.

The grayscale photomask plays a key role in grayscale lithography for creating 3D microstructures like micro-optical elements and MEMS structures, but how to fabricate grayscale masks in a cost-effective way is still a big challenge. Here we present novel low cost grayscale masks created in a two-step method by laser direct writing on Sn nano-films, which demonstrate continuous-tone gray levels depended on writing powers. The mechanism of the gray levels is due to the coexistence of the metal and the oxides formed in a laser-induced thermal process. The photomasks reveal good technical properties in fabricating 3D microstructures for practical applications.

A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus.

The matrix (M) protein of vesicular stomatitis virus (VSV) plays a key role in inducing cell apoptosis during infection. To investigate whether M protein-mediated apoptosis could be used in cancer therapy, its cDNA was amplified and cloned into eukaryotic expression vector pcDNA3.1(+). The recombinant plasmid or the control empty plasmid pcDNA3.1(+) was mixed with cationic liposome and introduced into various tumor cell lines in vitro, including lung cancer cell LLC, A549, colon cancer cell CT26 and fibrosarcoma cell MethA. Our data showed that the M protein induced remarkable apoptosis of cancer cells in vitro compared with controls. Fifty micrograms of plasmid in a complex with 250 microg cationic liposome was injected intratumorally into mice bearing LLC or MethA tumor model every 3 days for 6 times. It was found that the tumors treated with M protein plasmid grew much more slowly, and the survival of the mice was significantly prolonged compared with the mice treated with the control plasmid. In MethA fibrosarcoma, the tumors treated with M protein plasmid were even completely regressed, and the mice acquired longtime protection against the same tumor cell in rechallenge experiments. Both apoptotic cells and CD8(+) T cells were widely distributed in M protein plasmid-treated tumor tissue. Activated cytotoxic T lymphocytes (CTLs) were further detected by means of (51)Cr release assay in the spleen of the treated mice. These results showed that M protein of VSV can act as both apoptosis inducer and immune response initiator, which may account for its extraordinary antitumor effect and warrant its further development in cancer gene therapy.

Effects of Acute Fluorene-9-Bisphenol Exposure on Mouse Oocyte in vitro Maturation and Its Possible Mechanisms.

Fluorene-9-bisphenol (BHPF), a substitute of bisphenol A (BPA) used in the production of the so-called "BPA-free" plastics, has now been shown to be released from commercial plastic bottles into drinking water and has strong anti-estrogenic activity in mice, which suggests that BHPF is also an environmental toxin. However, whether BHPF exposure has effects on mouse oocyte development is unknown. In this study, the influence of acute exposure to BHPF (50-150 µM, 12 hr) on mouse oocyte maturation and its possible mechanisms were investigated. Of note, 50-µM BHPF had no effects on the maturation of mouse oocytes, whereas 100- and 150-µM BHPF significantly blocked germinal vesicle breakdown and led to the failure of first polar body extrusion. Particularly, 100-µM BHPF exposure severely decreased the cellular adenosine triphosphate in a time-dependent manner, which finally brought out the loss of spindles. In addition, the actin cytoskeleton was also impaired. The defective mitochondrial dynamics and decreased mitochondrial DNA implied the damage of mitochondria in BHPF-treated oocytes. Increased PINK1, Beclin1, and LC3B protein level and decreased TOMM20 and TOMM17A protein level illustrated that mitophagy was induced, which also confirmed that BHPF exposure impaired the cellular mitochondria. Moreover, BHPF induced reactive oxygen species accumulation and early apoptosis. Oocyte quality was also impaired by BHPF exposure through altering histone modifications evidenced by increased H3K9me3 and H3K27me3 levels. Collectively, our results indicated that BHPF exposure disrupted mouse oocyte maturation and reduced oocyte quality through affecting cytoskeleton architecture, mitochondrial function, oxidative stress, apoptosis, and histone modifications. Environ. Mol. Mutagen. 60:243-253, 2019. © 2018 Wiley Periodicals, Inc.

Vesicular stomatitis virus matrix protein gene enhances the antitumor effects of radiation via induction of apoptosis.

Vesicular stomatitis virus (VSV) matrix (M) protein can directly induce apoptosis by inhibiting host gene expression when it is expressed in the absence of other viral components. Previously, we found that the M protein gene complexed to DOTAP-cholesterol liposome (Lip-MP) can suppress malignant tumor growth in vitro and in vivo; however, little is known regarding the biological effect of Lip-MP combined with radiation. The present study was designed to determine whether Lip-MP could enhance the antitumor activity of radiation. LLC cells treated with a combination of Lip-MP and radiation displayed apparently increased apoptosis compared with those treated with Lip-MP or radiation alone. Mice bearing LLC or Meth A tumors were treated with intratumoral or intravenous injections of Lip-MP and radiation. The combined treatment significantly reduced mean tumor volumes compared with either treatment alone in both tumor models and prolonged the survival time in Meth A tumor models and the intravenous injection group of LLC tumor models. Moreover, the antitumor effects of Lip-MP combined with radiation were greater than their additive effects when compared with the expected effects of the combined treatment in vivo. This study suggests that Lip-MP enhanced the antitumor activity of radiation by increasing the induction of apoptosis.

Osteoblastic cell response on fluoridated hydroxyapatite coatings.

Fluoridated hydroxyapatite (FHA) coatings were deposited onto Ti6Al4V substrates by sol-gel dip-coating method. X-ray photoelectron spectroscopy results showed that fluoride ions were successfully incorporated into the hydroxyapatite (HA) lattice structure. The dissolution behavior in Tris-buffered physiological saline indicated that all fluoridated HA coatings had lower solubility than that of the pure HA coating. The lowest solubility was obtained at fluoride ion concentrations of 0.8-1.1M. In vitro cell responses were evaluated with human osteosarcoma MG63 cells in terms of cell morphology, proliferation and differentiation (alkaline phosphatase activity and osteocalcin level). For all coatings tested, similar cell morphologies and good cell viability were observed. Coatings fluoridated to 0.8-1.1 had a stronger stimulating effect on cell proliferation and differentiation activities. The influences on cell phenotypes were attributed mainly to a combined ion effect of Ca, P and F released from the coating during dissolution. For the best dissolution resistance and cell activities, it is recommended that the molar level of fluoride ion be from 0.8 to 1.1, such that the coating takes the form of Ca(10)(PO(4))(6)(OH)(1.2-0.9)F(0.8-1.1).

Preparation of an enteric-soluble solid-state emulsion using oily drugs.

To improve the patient's compliance and enhance the stability of oily drugs in the gastric fluid, an enteric-soluble solid-state emulsion (ESE), was developed. The ESE was prepared by spreading liquid o/w-emulsions on a flat glass and drying at the oven maintained at 40 degrees C. Aerosil 200 was applied as solid carrier and emulsifier. And Eudragit L30D-55 was used as enteric coating material. The influence of various preparation parameters on the residual volatile oil and the release behavior was investigated. Droplet size distribution of the primary emulsions and the emulsion after reconstitution of zedoary turmeric oil (ZTO) ESE in the phosphate buffer were also measured. When ZTO ESE was immersed into phosphate buffer (pH 6.8), the stable emulsion was formed in 20min, but the release was obviously suppressed when it was exposed to the gastric fluid. It was concluded that preparation of enteric-soluble solid-state emulsion by the present method for oral oily drug was feasible.

Preparation of roxithromycin-polymeric microspheres by the emulsion solvent diffusion method for taste masking.

Microspheres of roxithromycin with Eudragit S100 and silica were prepared by the emulsion solvent diffusion method to mask the bitter taste of the antibiotic. The effect of different polymers and drug-polymer ratios on the taste masking and the characteristics of the microspheres were investigated. It was found that Eudragit S100 was the best for masking the unpleasant taste of roxithromycin among the six kinds of polymers investigated. The results of DSC, X-ray diffraction and IR showed that there were several combinations of roxithromycin and Eudragit S100. The influence of other formulation factors, i.e. dichloromethane-acetone ratios and silica-polymer ratios on the properties of the microspheres were also examined. In conclusion, the results of the present study will be helpful for the preparation of oral forms of roxithromycin with an acceptable taste.

Study of the preparation of sustained-release microspheres containing zedoary turmeric oil by the emulsion-solvent-diffusion method and evaluation of the self-emulsification and bioavailability of the oil.

The purpose of this study was to design a sustained-release formulation of an oily drug. The sustained-release microspheres with self-emulsifying capability containing zedoary turmeric oil (ZTO) were prepared by the quasi-emulsion-solvent-diffusion method. The micromeritic properties, the efficiency of emulsification and the drug-release behavior of the resultant microspheres were investigated. The bioavailability of the microspheres was compared with conventional ZTO self-emulsifying formulations for oral administration using 12 healthy rabbits. An HPLC method was employed to determine the concentration of germacrone in plasma, which was used as an index of ZTO. Spherical and compacted microspheres with average diameters of 100-600 microm have been prepared, and their release behavior in distilled water containing 1.2% (w/v) of polysorbate-80 can be controlled by the ratio of polymer/Areosil200 in the microspheres. The resultant emulsions with mean droplet sizes of 200-500 nm are produced when the microspheres are immersed in phosphate buffer (pH 6.8) under gentle agitation. The stability and the droplet size of the resultant emulsions are also affected by the polymer/Areosil200 ratio in the formulation, while the amount of talc has a marked effect on the self-emulsifying rate. The plasma concentration-time profiles with improved sustained-release characteristics were achieved after oral administration of the microspheres with a bioavailability of 135.6% with respect to the conventional self-emulsifying formulation (a good strategy for improving the bioavailability of an oily drug). In conclusion, the sustained-release microspheres with self-emulsifying capability containing ZTO have an improved oral bioavailability. Our study offers an alternative method for designing sustained-release preparations of oily drugs.

[The study of electroplex emission based on PVK/BCP].

Electroplex emission based on poly(N-vinylcarbazole) (PVK) and 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (BCP) has been studied. A emission peak at 595 nm was observed in EL spectrum but not in PL spectra in the devices. The emission originates from the transition between the excited state of BCP and the ground state of PVK. Because of the increase of emission zone, the device of PVK: BCP blend exhibited stronger electroplex emission. The emission of electronplex was enhanced for both of PVK/BCP double layer device and PVK:BCP blend device, and it is stronger for blend devices. At higher drive voltage, only electroplex emission was observed in the blend device.

Enhanced antitumor effect of curcumin liposomes with local hyperthermia in the LL/2 model.

Curcumin previously was proven to inhibit angiogenesis and display potent antitumor activity in vivo and in vitro. In the present study, we investigated whether a combination curcumin with hyperthermia would have a synergistic antitumor effect in the LL/2 model. The results indicated that combination therapy significantly inhibited cell proliferation of MS-1 and LL/2 in vitro. LL/2 experiment model also demonstrated that the combination therapy inhibited tumor growth and prolonged the life span in vivo. Furthermore, combination therapy reduced angiogenesis and increased tumor apoptosis. Our findings suggest that the combination therapy exerted synergistic antitumor effects, providing a new perspective fpr clinical tumor therapy.