Modular Approach to Highly Substituted 3-Methylpyridones.

A method has been developed for the rapid synthesis of highly substituted 3-methylpyridones via the condensation of Baylis-Hillman amines and ketones under benzoic acid catalysis. The process features readily available starting materials, broad substrate scope, high functional group tolerance, excellent regioselectivity, and gram-scale synthesis. We envision that this on-demand construction of 3-methylpyridones will provide exciting opportunities in biological research, therapeutics, and material sciences.

Quercetin nanocrystals prepared using a microfluidic chip with improved in vitro dissolution.

OBJECTIVE: In order to improve the dissolution property of quercetin (QCT), the quercetin nanocrystals (QNCs) were prepared in this study. METHODS: QNCs were prepared by a 100 µm diameter Y-shape microfluidic channel. Some impact factors affecting the generation of QNCs such as concentration and flow rate were investigated. Furthermore, the fluid mixing in the microfluidic channel was simulated by fluid software. RESULTS: XRPD and DSC analyses indicated that the prepared QNCs were amorphous. Stable QNCs with a particle size of 77.9 ± 3.63 nm and polydispersity index of 0.26 ± 0.02 were obtained. TEM showed that the as-prepared QNCs had a uniform spherical shape with an average particle size of about 100-300 nm. In the dissolution medium without cosolvent Tween -80, the dissolution of QCT was poor, its final accumulated dissolution was only 3.95%, while that of QNCs was 66%. CONCLUSION: When QCT was changed to QNCs by microfluidic technology, its dissolution property could be obviously improved. Therefore, microfluidic technology as a new method to prepare nanocrystals has a good applying prospect in improving dissolution property for poorly water-soluble drugs.

Bilayer nanofibrous wound dressing prepared by electrospinning containing gallic acid and quercetin with improved biocompatibility, antibacterial, and antioxidant effects.

OBJECTEIVES: The purpose of this study was to prepare an antibacterial, antioxidant, and biocompatible bilayer nanofibrous wound dressing by using electrospinning. METHODS: The micromorphology and bilayer structure characteristics of the GA-Qe-PVP-PCL nanofibers were analyzed by SEM. The physicochemical characteristics were analyzed by XRD and FTIR. The uptake, mechanical properties, water contact angle, water vapor transmission and in vitro drug release were evaluated. In addition, the effect of antibacterial, antioxidant and biocompatability of the nanofibers were evaluated, respectively. RESULTS: The SEM results showed that the GA-Qe-PVP-PCL nanofibers had a smooth surface, no beading phenomenon, and a prominent bilayer structure. The diameter and porosity of the drug-loading layer and waterproof support layer of the nanofibers were 842 ± 302 nm, 242 ± 50 nm, and 88.56 ± 1.67%, 94.49 ± 1.57%, respectively. Moreover, the water uptake, mechanical properties, water contact angle, and water vapor transmission showed ideal performance. The results of in vitro drug release indicated that GA and Qe were both released rapidly, which was conducive to accelerating wound healing. The GA-Qe-PVP-PCL nanofibers exhibited antibacterial effects against both bacteria as well as high antioxidant activity. Additionally, the GA-Qe-PVP-PCL nanofibers possessed good compatibility, could promote the proliferation, adhesion, and migration of L929 fibroblast cells. CONCLUSION: The nanofibers we developed met the requirements of ideal materials for wound dressing, which makes the nanofibers the potential to be a wound dressing for wound care.

Chitosan/Polylactic Acid Nanofibers Containing Astragaloside IV as a New Biodegradable Wound Dressing for Wound Healing.

The ideal wound dressing should adequately protect the wound from bacterial infection and provide a suitable healing environment for the wound. Thus, we prepared a biodegradable functional nanofiber dressing with good antibacterial and biocompatibility by electrospinning technology. The average diameter of the dressing was 354 ± 185 nm, and the porosity was 93.27%. Scanning electron microscopy (SEM) showed that the dressing was smooth without beading. It was also characterized by Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The wettability and water vapor permeability of the dressing were tested; the results showed that the dressing had good wettability and permeability. The ability of drug release indicates that continuous release over a period of time is beneficial to wound healing. Finally, the antibacterial effect and in vivo pharmacodynamic evaluation of AS/CS/PLA nanofiber dressing were studied; the result showed that it had significant antibacterial activity and the ability to promote wound healing.

Choroidal and retinal thickness in patients with vitamin C deficiency using swept-source optical coherence tomography.

BACKGROUND: To investigate the effects of vitamin C on central retinal thickness and choroidal thickness. METHODS: A total of 69 patients diagnosed with vitamin C deficiency and 1:1 age- and gender-matched 69 healthy individuals with normal serum vitamin C were included in this study. Demographic characteristics of the individuals were collected. All patients underwent a comprehensive ophthalmic examination. Subfoveal choroidal thickness and retinal thickness were measured using a swept-source optical coherence tomography (SS-OCT). RESULTS: The average retinal thickness was 269.07 ± 13.51 µm in the vitamin C deficiency group and 276.92 ± 13.51 µm in the control group. The average choroidal thickness was 195.62 ± 66.40 µm in the in the vitamin C deficiency group and 238.86 ± 55.08 µm in the control group. There was a significant decrease in both average choroidal thickness and retinal thickness in vitamin C deficiency group compared with normal individuals (p < 0.001, and = 0.001 respectively). CONCLUSION: The central retinal and choroidal thickness were thinner in vitamin C deficiency group compared with normal individuals. These findings suggested that vitamin C deficiency might play an important role in retinal and choroidal diseases.

Endophthalmitis caused by Mycobacterium houstonense: case report.

BACKGROUND: Mycobacterium houstonense is rapidly growing mycobacteria (RGM) that belongs to M. fortuitum group. So far, there have been few associated reports of human diseases induced by M. houstonense worldwide. CASE PRESENTATION: We present a delayed-onset postoperative endophthalmitis caused by M. houstonense after glaucoma drainage implant (GDI) surgery. The ocular infection lasted for 2 months without appropriate treatment that developed into endophthalmitis and the patient underwent an emergency enucleation. CONCLUSION: Implant erosion and a delay in diagnosis of ocular infection could lead to irreversible damage as observed in our case. Ophthalmologists should be alert for ocular RGM infection, and prompt laboratory diagnosis with initiation of effective multidrug therapy might prevent loss of vision.

Case report-immune recovery posterior scleritis in a HIV positive patient.

BACKGROUND: Posterior scleritis is an uncommon vision-threatening disorder that is often recurrent and difficult to cure due to its complex etiology. In HIV patients, posterior scleritis may develop several months after significant rise in CD4+ T-lymphocyte, even after several years, which may be diagnosed as late-onset immune recovery scleritis. CASE PRESENTATION: Here we report a case of posterior scleritis in a HIV positive patient who presented with severe periocular pain and decreased vision in the left eye, with exudative retinal detachment and optic nerve involvement. CONCLUSIONS: Early differential diagnosis of immune recovery posterior scleritis and intensive corticosteroids treatment, can prevent vision loss effectively in HIV patients.

Terminal Sliding Mode Control with a Novel Reaching Law and Sliding Mode Disturbance Observer for Inertial Stabilization Imaging Sensor.

High-performance control of inertial stabilization imaging sensors (ISISs) is always challenging because of the complex nonlinearities induced by friction, mass imbalance, and external disturbances. To overcome this problem, a terminal sliding mode controller (TSMC) based on a novel exponential reaching law (NERL) method with a high-order terminal sliding mode observer (HOTSMO) is suggested. First, the TSMC based on NERL is adopted to improve system performance. The NERL incorporates the power term and switching gain term of the system state variables into the conventional exponential reaching law, and the convergent speed of the TSMC is accelerated. Then, an HOTSMO is designed, which considers the speed and lumped disturbances of the system as the observation object. The estimated disturbance is then provided as a compensation for the controller, which enhances the disturbance rejection ability of the system. Comparative simulation and experimental results show that the proposed method achieves the best tracking performance and the strongest robustness than PID and the traditional TSMC methods.

One-step preparation of ibuprofen fast- and sustained-release formulation by electrospinning with improved efficacy and reduced side effect.

In this study, we developed a one-step method to prepare ibuprofen fast- and sustained-release complex preparation. It was based on a double jets electrospinning process. Ibuprofen, a poorly water-soluble drug, was electrospun into fibers with polyvinyl pyrrolidone and hydroxypropyl methyl cellulose by two jets, respectively. The complex preparation had an enough initial dose come from fast-release part and a maintenance dose come from sustained-release part. Through the study of X-ray diffraction, differential scanning colorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM), it was confirmed that ibuprofen was highly dispersed in nanofibers (NFs) in amorphous state. Because one line of NFs was very thin and could only extend along two directions, it was difficult for ibuprofen to transform from amorphous to crystal in this kind of approximate one-dimensional structure. Additionally, it was confirmed by animal experiment that the complex preparation also had a benefit to reduce gastric irritation that usually caused by traditional oral ibuprofen preparation. Therefore, the method developed in this study was a convenient and good-quality approach for ibuprofen pain-alleviating preparation.

Neuroprotective effects of Danshensu in Parkinson's disease mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Parkinson's disease (PD) causes major changes in dopaminergic neurons of the brain, resulting in motor symptoms in older adults. A previous study showed that Danshensu alleviates the cognitive decline by attenuating neuroinflammation. In the present study, we investigated the neuroprotective effect of Danshensu in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. C57BL/6 mice were randomly divided into the following four groups: control, MPTP, Danshensu at 15 mg/kg, and Danshensu at 60 mg/kg. The mice were administered Danshensu intragastrically for 14 days. In the behavioral tests, Danshensu treatment alleviated motor dysfunction induced by MPTP. The number of tyrosine hydroxylase-positive neurons in the substantia nigra was significantly reduced in the MPTP group, relative to the control group; Danshensu partially blocked this reduction in tyrosine hydroxylase-positive neurons. In addition, Danshensu attenuated the reductions in striatal dopamine and 5-HT levels induced by MPTP. Danshensu also diminished the increase in Iba1-positive cells in the substantia nigra and reduced the levels of interleukin-1ß and tumor necrosis factor-α in the striatum. These findings suggest that Danshensu exerts neuroprotective effects and improves motor function in PD mice, at least in part, by reducing neuroinflammation.

Atorvastatin ameliorates LPS-induced inflammatory response by autophagy via AKT/mTOR signaling pathway.

Macrophages play crucial roles in immune response and atherosclerosis-related cardiovascular disease. Recent evidence of macrophage autophagy has demonstrated a novel pathway through which contributes to vascular inflammation. The aim of this study was to elucidate the role of autophagy in the inhibition of inflammatory response in macrophages by atorvastatin. We found that atorvastatin promoted autophagy flow determined by up-regulating the expression of autophagy-related protein microtubule-associated protein light chain (LC3B), inducing the formation of autophagosomes and down-regulating the expression of SQSTM1/P62, which is consumed during autophagy. Atorvastatin also inhibited the expression of inflammatory factors IL-1ß and TNFα induced by LPS in RAW264.7 cells. Furthermore, pretreatment with an autophagy inhibitor 3MA or LY294002 attenuated the suppressive effect of atorvastatin on LPS-induced IL-1ß and TNFα expression. Additionally, knockdown autophagy-related gene 5(Atg5) with a special siRNA also prevented the role of atorvastatin in decreasing IL-1ß and TNFα release induced by LPS. Finally, we detected that AKT/mTOR/P70S6K signaling pathway was involved in atorvastatin-induced autophagy in macrophages. These data suggest that atorvastatin attenuates LPS-induced inflammatory factors secretion, at least in part, through enhancing autophagy by AKT/mTOR signaling pathway. Our findings provide a novel evidence that statins exert anti-inflammatory effect in atherosclerosis by autophagy activation.

Unpacking Care Coordination Through a Multiteam System Lens: A Conceptual Framework and Systematic Review.

BACKGROUND: The 2016 President's Cancer Panel Connected Health report calls for thoroughly characterizing the team structures and processes involved in coordinating care for people with chronic conditions. We developed a multilevel care coordination framework by integrating existing frameworks from the teams and care coordination literatures, and used it to review evidence examining care coordination processes for patients with cancer, diabetes, cardiovascular disease, and combinations of these conditions. METHODS: We searched Pubmed/MedLINE, CINAHL Plus, Cochrane, PsycINFO (December 2009-June 2016), and references from previous reviews. Studies describing behavioral markers of coordination between ≥2 US health care providers caring for adults with cancer, chronic heart disease, diabetes, or populations with a combination of these conditions were included. Two investigators screened 4876 records and 180 full-text articles yielding 33 studies. One investigator abstracted data, a second checked abstractions for accuracy. RESULTS: Most studies identified information sharing or monitoring as key coordination processes. To execute these processes, most studies used a designated role (eg, coordinator), objects and representations (eg, survivorship plans), plans and rules (eg, protocols), or routines (eg, meetings). Few examined the integrating conditions. None statistically examined coordination processes or integrating conditions as mediators of relationships between specific coordination mechanisms and patient outcomes. LIMITATIONS: Restricted to United States, English-language studies; heterogeneity in methods and outcomes. CONCLUSIONS: Limited research unpacks relationships between care coordination mechanisms, coordination processes, integrating conditions, and patient outcomes suggested by existing theory. The proposed framework offers an organizer for examining behaviors and conditions underlying effective care coordination.

High-sensitivity photonic crystal fiber long-period grating methane sensor with cryptophane-A-6Me absorbed on a PAA-CNTs/PAH nanofilm.

A high-sensitivity photonic crystal fiber long-period grating (PCF-LPG) methane sensor with cryptophane-A-6Me absorbed on a poly(acrylic acid)-carbon nanotubes/ polypropylene amine hydrochloride (PAA-CNTs/PAH) nanofilm was investigated. The sensing film was coated onto the internal surface of a photonic crystal fiber cladding air holes by an electrostatic self-assembly technique. Based on a finite element method and the coupled local-mode theory, the effects of the sensing film's refractive index (RI) and thickness on the resonant wavelength were theoretically and numerically analyzed. When the sensing film RI decreases from 1.55 to 1.53, and the thickness increases from 100 nm to 200 nm, the resonant wavelength has a blue shift. A higher RI sensitivity with 1.075 × 103 nm RIU-1 is observed for the film thickness of 200 nm. The PCF-LPG methane sensor was fabricated by a pressurized injection method. The sensing experimental result shows that the resonant wavelength of the transmission spectra has a blue shift when the methane concentration increases from 0.0% to 3.5% by volume. The sensor has a good sensitivity of 1.078 nm%-1 and a low detection limit of 0.18% for a film thickness of 210 nm.

Long-term floating control-released intravesical preparation of 5-fluorouracil for the local treatment of bladder cancer.

In order to overcome the low compliance due to the frequent bladder perfusion of anti-cancer drugs in the treatment of bladder cancer, a long-term control-release of the anticancer drug in the bladder, the floating intravesical preparation was developed. 5-fluorouracil was used as model drug. The floating preparations were prepared by tableting (mini-tablets) and melting (mini-pellets) method. The proportion of 5-fluorouracil and glyceryl tristearate (GTS) was altered among formulations. Dissolution test, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) were used to investigate the in vitro properties of the formulations. The in vivo evaluation was carried out in beagle dogs. The control-release property of the preparation was not only related to the content of 5-fluorouracil but also related to the preparing method. The releasing time of the mini-tablets was nearly several days, whereas that of the mini-pellets was almost several weeks. DSC and XRPD showed that GTS had polymorphic conversion in the preparing process, therefore, the stabilization procedure was necessary at the end of preparing. In vivo evaluation showed that the prepared long-term floating preparations could maintain an effective 5-fluorouracil concentration in the bladder for about one month, furthermore, in this period the 5-fluorouracil concentration in blood was always far less than that in urine.

Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds.

Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first reported small molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the conformational flexibility of the key amine moiety of UNC669 would result in a unique set of ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic amine were designed and synthesized. To gauge the potential of these amine-containing compounds to interact with Kme regulatory proteins, the compounds were screened against a panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors.

Evaluation of the Antidepressant Activity, Hepatotoxicity and Blood Brain Barrier Permeability of Methyl Genipin.

Geniposide (GE) is the main bioactive component of Gardeniae Fructus. The hepatotoxicity of geniposide limited clinical application. In order to get a new geniposide derivative that has less hepatotoxicity and still possesses the antidepressant activity, a new C-1 hydroxyl methylation derivative named methyl genipin (MG) was synthesized from geniposide. In the present study, we demonstrated that MG did not increase the liver index, alanine aminotransferase (ALT) and aspirate aminotransferase (AST). Histopathological examination suggested that no toxic damages were observed in rats treated orally with MG (0.72 mmol/kg). More importantly, a 7-day treatment with MG at 0.13, 0.26, and 0.52 mmol/kg/day could reduce the duration of immobility. It showed that the antidepressant-like effects of MG were similar to GE in the tail suspension test and the forced swim test. Furthermore, we found MG could be detected in the brain homogenate of mice treated orally with MG 0.52 mmol/kg/day for 1 day by HPLC. The area under the curve (AUC) of MG in the brain homogenate was enhanced to 21.7 times that of GE. The brain amount and distribution speed of MG were improved significantly after oral administration. This study demonstrated that MG possessed the antidepressant effects and could cross the blood-brain barrier, but had less hepatotoxicity.

Stereoselective oxidation metabolism of 20(S)-protopanaxatriol in human liver microsomes and in rats.

1. In this study, the oxidative metabolites of 20(S)-protopanaxatriol (PPT) were identified in human liver microsomes (HLMs) and in rats using liquid chromatography-electrospray ionization tandem mass spectrometry. 2. Twelve oxidative metabolites were found in HLM, eight of which have not been previously reported. Twenty-four oxidative metabolites were found in rat feces after oral administration and 20 of these, including six found in HLM, were first reported. The results indicated PPT was more extensively metabolized in rats than in HLM. C20-24 epoxides, a pair of epimers (namely, M1-1 and M1-2) were the major metabolites, and other metabolites were derived from their further metabolism. 3. Enzyme kinetics experiments showed that the apparent formation Vmax of M1-1 was 10.4 folds and 2.4 folds higher than that of M1-2 in HLM and in rat liver microsomes (RLMs), respectively. The depletion rate of M1-2 was 11.0 folds faster than M1-1 in HLM, and was similar in RLM. Hence, the remarkable species differences of PPT metabolism mainly resulted from the stereoselective formation and further metabolic elimination of M1-1 and M1-2. 4. Chemical inhibition study and recombinant human P450 isoforms analysis showed that CYP3A4 was the predominant isoform involved in the oxidative metabolism of M1-1 and M1-2.

Development of cyclosporine A microemulsion for parenteral delivery.

The goal of this study was to develop a parenteral microemulsion formulation of cyclosporine A (CyA). The CyA solubility in caprylic capric triglyceride (GTCC), ethyl oleate and soybean oil were determined. The pseudo-ternary diagrams of oil (GTCC), surfactant (Solutol® HS-15), cosurfactants (ethanol/polyethylene glycol 400 [PEG 400] mixture) and water were constructed to identify boundaries for microemulsion existence. The CyA was added at 3, 6 and 9% w/w to the optimal microemulsion composition. Microemulsion particle size, solution viscosity and conductivity were examined. The microemulsion stability and haemolytic potential were examined after dilution in 5% dextrose solution for injection to 1 mg/mL CyA. Microemulsion stability was examined after a three-month storage at 4 and 25 °C. The GTCC was selected as an oil phase for CyA microemulsion based on solubility results. The optimum CyA microemulsion formulation consisted of 2.5% CyA, 9% GTCC, 24% Solutol® HS 15, 8% PEG 400, 4% ethanol and 52.5% water based on weight percent. The average particle sizes of the optimized blank and drug-loaded microemulsions were 68.7 nm and 71.6 nm, respectively and remained unchanged upon 25-fold dextrose dilution. The results of microemulsion physical and CyA chemical were confirmed by a three-month stability study at 4 and 25 °C. In vitro haemolysis studies indicated that CyA microemulsions were well tolerated by erythrocytes. The novel microemulsion formulation of CyA was developed that is suitable for parenteral administration. This new formulation could potentially have less vehicle-associated side effects that current commercial formulation of CyA based on Cremophor® EL and ethanol solution.

Metabolism of salvianolic acid A and antioxidant activities of its methylated metabolites.

This study investigated the metabolism of salvianolic acid A (SAA) both in vivo and in vitro. Liquid chromatography-mass spectrometry analysis of drug-containing rat bile samples and bile samples hydrolyzed by glucuronidase revealed a series of methylated conjugates of SAA and its glucuronides, as well as the predominance of the methylation pathway of SAA in rats. For the first time, four major methylated metabolites present in vivo were prepared for structure characterization and bioactivity evaluation using in vitro coincubation systems with rat hepatic cytosol protein as the enzyme donor. By using nuclear magnetic resonance imaging and other spectroscopic methods, these metabolites were unambiguously elucidated as 3-O-methyl-SAA (M1), 3'-O-methyl-SAA (M2), 3,3″-O-dimethyl-SAA (M3), and 3',3″-O-dimethyl-SAA (M4), respectively. Along with results from the enzyme inhibition study, selective formation of these meta-O-methylated derivatives indicated that catechol O-methyltransferase (COMT) is responsible for methylated transformation of SAA. All of these metabolites displayed fairly high antioxidant potency against in vitro rat liver lipid peroxidation with half-maximal inhibitory concentrations that were much lower than those of the positive controls and even SAA. Overall, the results from this study demonstrate that SAA is a metabolically unstable compound that undergoes rapid methylation metabolism catalyzed by COMT, and these generated O-methylated metabolites may be largely responsible for its in vivo pharmacological effects.

Discovery of ß-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.

Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D(2) receptor (D(2)R) signaling via ß-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D(2)R agonists that display signaling bias via ß-arrestin-ergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented ß-arrestin-biased D(2)R ligands. These compounds also represent unprecedented ß-arrestin-biased ligands for a G(i)-coupled G protein-coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G(i)-regulated cAMP production and partial agonists for D(2)R/ß-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of ß-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely ß-arrestin-biased D(2)R agonist, in wild-type mice was completely abolished in ß-arrestin-2 knockout mice. Taken together, our results suggest that ß-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, ß-arrestin-biased D(2)R ligands represent valuable chemical probes for further investigations of D(2)R signaling in health and disease.