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1.
Inflamm Res ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31797003

RESUMO

OBJECTIVE: This study sought to evaluate short-term treatment with COX-2 inhibitors and acute changes in colonic PGE2 levels as predictors of long-term efficacy in a genetic model of colorectal cancer. METHODS: Celecoxib oral suspension (40 mg/kg BID) was dosed to Apc-mutant Pirc (F344/NTac-Apcam1137) rats for 4 days (short-term group), or the equivalent dose of 1500 ppm celecoxib was administered in the diet for 4 months (long-term group). Percent inhibition of colonic PGE2 was calculated, and the reduction in colonic PGE2 was assessed in relation to suppression of adenomatous colon polyps. RESULTS: Colonic mucosa PGE2 was fourfold higher in Pirc than in F344 wild-type rats (21 vs. 5.6 pg/mg epithelial tissue), due at least in part to higher COX-2 expression, and this was confirmed by elevated PGE2-d11 levels in Pirc colonic S9 incubations. In the 4-day study, dose-dependent reductions in PGE2 were observed in colonic epithelium (-33% (P>0.05) and -57% (P=0.0012)), after low- and high-dose celecoxib treatments of 4 mg/kg and 40 mg/kg (bid), respectively. In the 4-month study, 1500 ppm celecoxib suppressed colonic epithelium PGE2 by 43.5%, and tumor multiplicity by 80% (P<0.0015). Suppression of plasma 6-keto PGF1α also was corroborated following long-term treatment with 1500 ppm celecoxib (P<0.05). CONCLUSIONS: Acute changes in colonic mucosa PGE2 provided a rapid means of predicting long-term chemopreventive effects from celecoxib, and might be useful for screening of new COX-2 inhibitor compounds.

2.
Transbound Emerg Dis ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31793242

RESUMO

From 2010, porcine epidemic diarrhea virus (PEDV) variants caused sequential outbreaks of disease in Asia and the United States. In this retrospective study, 49 complete spike (S) gene sequences were obtained from PEDV strains collected in China from 2014-2016. We observed that variant PEDV strains with novel insertions, deletions, and multiple S gene recombination types were present in China. In addition, mixed infections involving different variant strains were observed in some areas. Based on phylogenetic and recombination analyses, we determined that the newly emerged PEDV variants potentially originated via recombination between the earliest Chinese G1 genogroup strain, JS-2004-2, and earlier Korean pandemic strains. These findings provide important information for understanding ongoing PEDV outbreaks, and suggest that novel variants make it more difficult to prevent PEDV infection.

3.
Res Vet Sci ; 128: 16-23, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31707096

RESUMO

Pseudorabies has caused huge economic losses in China's pig industry and recurred on many large pig farms since late 2011. The disease is caused by highly pathogenic, antigenic variant pseudorabies virus (vPRV) strains. Therefore, the prevention and control of this recurrence of pseudorabies in China has been given priority. In a previous study, we showed that a suitable dose [1 × 106.3 50% tissue culture infectious dose (TCID50) per animal] of commercial Bartha-K61 vaccine protects growing pigs against lethal challenge by the emerging vPRV strain XJ5. In this study, different doses of the Bartha-K61 vaccine and our newly developed rPRV-gI-/gE-/TK- prototype vaccine derived from the vPRV strain XJ5 were used to evaluate immune protection against sublethal challenge by the vPRV strain XJ5. Pigs vaccinated with high doses of the Bartha-K61 vaccine or rPRV-gI-/gE-/TK- prototype vaccine showed no differences in their humoral immune responses, clinical symptoms, body weight gains, viral shedding, or gross and histological lesions after sublethal challenge by the vPRV strain XJ5. Therefore, we concluded that the Bartha-K61 vaccine at a dose of 1 × 105 TCID50 per animal protects pigs against sublethal challenge by the vPRV strain XJ5 and performs equally well as the same dose of the rPRV-gI-/gE-/TK- vaccine, whereas lower doses of the Bartha-K61 vaccine alone do not protect pigs from this challenge. These findings provide useful information for vaccination interventions and the ultimate eradication of pseudorabies caused by vPRV strains emerging in China.

4.
Microb Biotechnol ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758659

RESUMO

Ethyl-N-dodecanoyl-l-arginate hydrochloride (LAE, ethyl lauroyl arginate HCl) is a cationic surfactant used as a food preservative with broad-spectrum antibacterial activities. However, its resistance development, influences on gut microbiome and molecular target are unclear. In this study, bacteria were stimulated by LAE for 30 days to test the bacterial resistance. Several infected animal models were used to evaluate the antibacterial effect of LAE in vivo. Mice were orally treated with LAE to test its effect on animal growth. The influence of LAE on mice gut microbiome was analysed by 16S rDNA sequencing. The results indicated that Escherichia coli did not develop resistance to LAE. LAE significantly combats bacterial infection in mice, ducklings and piglets. Moreover, LAE promotes mouse weight gain without changing body composition or reducing animal vitality, and induces lower hepatotoxicity than ampicillin. In the mouse gut microbiome assessment and characterization, LAE modifies host gut microbiota structure. Mechanistically, LAE specifically binds to acidic phospholipids including phosphatidylserine, depolarizes the membrane and disrupts the bacterial membrane followed by bacterial growth inhibition. This study investigates the molecular mechanism of LAE as well as its antibacterial functions in poultry and livestock. Our data suggest LAE is a potential antibacterial agent in animal health.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31731743

RESUMO

The spatiotemporal variability in air pollutant concentrations raises challenges in linking air pollution exposure to individual health outcomes. Thus, understanding the spatiotemporal patterns of human mobility plays an important role in air pollution epidemiology and health studies. With the advantages of massive users, wide spatial coverage and passive acquisition capability, mobile phone data have become an emerging data source for compiling exposure estimates. However, compared with air pollution monitoring data, the temporal granularity of mobile phone data is not high enough, which limits the performance of individual exposure estimation. To mitigate this problem, we present a novel method of estimating dynamic individual air pollution exposure levels using trajectories reconstructed from mobile phone data. Using the city of Shanghai as a case study, we compared three different types of exposure estimates using (1) reconstructed mobile phone trajectories, (2) recorded mobile phone trajectories, and (3) residential locations. The results demonstrate the necessity of trajectory reconstruction in exposure and health risk assessment. Additionally, we measure the potential health effects of air pollution from both individual and geographical perspectives. This helped reveal the temporal variations in individual exposures and the spatial distribution of residential areas with high exposure levels. The proposed method allows us to perform large-area and long-term exposure estimations for a large number of residents at a high spatiotemporal resolution, which helps support policy-driven environmental actions and reduce potential health risks.

6.
Oncologist ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748336

RESUMO

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti-HER2 therapies in these patients prompt us to examine impact of HER2 variants and co-mutations on responses to anti-HER2 treatments in lung cancer. PATIENTS AND METHODS: Patients with stage IV/recurrent HER2-mutant lung cancers identified through next-generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co-mutations in lung cancer and a cohort B to assess associations between HER2 variants, co-mutations, and clinical outcomes. RESULTS: The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty-one HER2 variants and 35 co-mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co-mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%-26.8%), 40% (4/10, 14.7%-72.6%), and 13% (1/8, 0.7%-53.3%) in group 1 (A775_G776insYVMA, n = 14), group 2 (G778_P780dup, G776delinsVC, n = 10), and group 3 (missense mutation, n = 8), respectively (p = .018). Median progression-free survival in group 1 (1.2 months; 95% CI, 0-2.4) was shorter than those in group 2 (7.6 months, 4.9-10.4; hazard ratio [HR], 0.009; 95% CI, 0.001-0.079; p < .001) and group 3 (3.6 months, 2.6-4.5; HR, 0.184; 95% CI, 0.062-0.552; p = .003). TP53 co-mutations (6.317; 95% CI, 2.180-18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098-92.039; p < .001) conferred additional resistance to afatinib. CONCLUSION: G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co-mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co-mutations may help improve the efficacy of anti-HER2 treatment in lung cancer. IMPLICATIONS FOR PRACTICE: Human epidermal growth factor receptor 2 (HER2)-mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti-HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti-HER2 treatments. TP53 is the most common co-mutation in HER2-mutant lung cancers. Co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti-HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.

7.
J Agric Food Chem ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31690080

RESUMO

(2S)-Naringenin, a (2S)-flavanone, is widely used in the food, chemical, and pharmaceutical industries because of its diverse physiological activities. The production of (2S)-naringenin in microorganisms provides an ideal source that reduces the cost of the flavonoid. To achieve efficient production of (2S)-naringenin in Saccharomyces cerevisiae, we constructed a biosynthetic pathway from p-coumaric acid, a cost-effective and more efficient precursor. The (2S)-naringenin synthesis pathway genes were integrated into the yeast genome to obtain a (2S)-naringenin production strain. After gene dosage experiments, the genes negatively regulating the shikimate pathway and inefficient chalcone synthase activity were verified as factors limiting (2S)-naringenin biosynthesis. With fed-batch process optimization of the engineered strain, the titer of (2S)-naringenin reached 648.63 mg/L from 2.5 g/L p-coumaric acid. Our results indicate that the constitutive production of (2S)-naringenin from p-coumaric acid in S. cerevisiae is highly promising.

8.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(10): 1219-1223, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31771718

RESUMO

OBJECTIVE: To observe the effects of abnormal body temperature and the area under temperature curve on the prognosis of patients with septic shock. METHODS: A retrospective cohort study was conducted. Patients with septic shock admitted to intensive care unit (ICU) of Wuxi People's Hospital Affiliated to Nanjing Medical University from September 2013 to June 2019 were enrolled. Data were obtained from the hospital case database, including the gender, age, infection source, the length of ICU stay, sequential organ failure assessment (SOFA) score, 21-day prognosis; within the first 24 hours and throughout the period in ICU, the maximum temperature (24 h Tmax, Tmax), lowest temperature (24 h Tmin, Tmin), and the temperature range (24 h Tmax-min, Tmax-min) were aggregated. The area under temperature curve when body temperature was higher than T (A> T), or lower than T (A< T), and area section between T1 and T2 (AT1-T2) was calculated respectively. Patients were divided into survival group and death group according to 21-day prognosis. Binary Logistic regression was used to analyze the effect of the above temperature indices on the prognosis. RESULTS: 635 septic shock patients were enrolled in the study. 476 patients were survived and 159 died within 21 days. Compared with the survival group, the age, SOFA score were higher in the death group, while the length of ICU stay was shorter. There was no significant difference in gender or infection source between two groups. After adjusting for gender, age, the length of ICU stay and SOFA score, binary Logistic regression analysis showed that the increase of Tmax, decrease of Tmin, and increase of Tmax-min were risk factors for 21-day mortality [Tmax: odds ratio (OR) = 2.959, 95% confidence interval (95%CI) was 1.620-5.398, P > 0.001; Tmin: OR = 0.329, 95%CI was 0.140-0.790, P = 0.012; Tmax-min: OR = 3.258, 95%CI was 1.840-5.471, P > 0.001], while 24 h Tmax, 24 h Tmin and 24 h Tmax-min were not related to prognosis. A< 36.0 centigrade (OR = 1.335, 95%CI was 1.102-1.745, P = 0.014), and A> 38.0 centigrade (OR = 1.041, 95%CI was 1.019-1.077, P = 0.001) showed positive correlation with 21-day mortality. When the T level was set at 38.0-40.0 centigrade, for every 1 centigrade×hour increase in A> T, the 21-day relative risk of death increased by 4.1%-83.2%. CONCLUSIONS: When the body temperature of patients with septic shock is lower than 36.0 centigrade, or higher than 38.0 centigrade, the 21-day relative risk of death rose with the increase of the magnitude and duration of abnormal body temperature.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31769646

RESUMO

Flexible pressure sensors have garnered enormous attention in recent years as they hold great promise in wearable electronic devices. However, the realization of a high-performance flexible pressure sensor via a facile and cost-effective approach still remains a challenge. In this work, a capacitive pressure sensor based on a poly(vinylidenefluoride-co-trifluoroethylene) [P(VDF-TrFE)] dielectric film that incorporates nanopillars on both sides, is demonstrated. Unlike the previous complicated and expensive methods, large-scale regular and uniform nanopillars are easily and economically achieved by the pattern transfer of anodized aluminum oxide templates. The double-sided nanopillars constituting the P(VDF-TrFE) dielectric layer enable the pressure sensor with high sensitivity (~0.35 kPa-1), wide working range (4 Pa~25 kPa), short response time (~48 ms) and excellent durability. In addition to these salient features, our sensor also exhibits superior performances under bending states, ensuring that it can be used for detecting diverse practical stimuli as experimentally validated by perceiving real-time and in-site human physiological signals and body motions that respectively corresponds to the low- and high-pressure range. A sensor array is finally constructed and is shown to be capable of perceiving the spatial pressure distribution of either a contact- or non-contact object. These demonstrations show a promising future of our sensor in healthcare monitoring, smart robot skin and human-machine interfaces.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31650631

RESUMO

BACKGROUND: Hypertrophic scars are complications of severe wound healing characterized by excessive fibrosis associated with aberrant function of fibroblasts. However, no available drugs can be utilized to effectively treat these scars. The transforming growth factor ß (TGFß) signaling pathway regulates collagen synthesis and plays an important role in scar formation. OBJECTIVES: To evaluate the anti-scar effects of TGFß inhibitors in vitro and in vivo. METHODS: Col1α2-luciferase reporter assay was used to screen the compounds suppress type I collagen gene transcription. Sulforhodamine B colorimetric assay and colony formation assay were used to test the compound's effect on cell proliferation. Wound healing and trans-well assay were performed to test the cell migration and invasion. Western blotting, immunofluorescence, immunohistochemistry and Q-PCR assay were used to determine the protein and mRNA levels. 3D cell contraction assay was used to examine the cell contraction. Flow cytometry was performed to analyze cell apoptosis. Masson stain, H&E stain and immunochemistry were used to analyze the scar formation in vivo. RESULTS: WG449E, as one of the most potent inhibitors, was identified to significantly downregulate the mRNA and protein levels of collagen in hypertrophic scar-derived fibroblasts through inhibiting Smad2/3 phosphorylation. WG449E inhibited the proliferation, migration and contraction of fibroblasts in vitro and in vivo. In addition, WG449E induced cell apoptosis through the activation of cleaved-caspase3. Moreover, WG449E significantly attenuated hypertrophic scar formation and collagen deposition in a mechanical load-induced mouse model. CONCLUSIONS: WG449E is a potential candidate for the treatment of hypertrophic scars.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31627161

RESUMO

Xiao Chai Hu Tang (XCHT) is sold as traditional medicine or dietary supplement in worldwide. To understand metabolism profile of traditional medicine is key point in their logical pharmacological research and clinical application. Based on our previous research of the chemical and absorption signature of XCHT in vitro, we proposed a novel strategy to identify the bioactive components of XCHT in vivo. This strategy have two steps: firstly, based on the parents' database in vitro, built-in and editable biotransformations for phase I and phase II metabolism reactions with MassHunter Metabolite ID software (building metabolites database). Secondly, mouse plasma, bile and urine samples were analyzed by UHPLC-ESI-Q-TOF/MS technique, and the absorbed parents and metabolites were compared and identified with the XCHT's digital library using MassHunter Metabolite ID software. In total, 27 parent compounds and 26 metabolites of XCHT were identified in vivo, 2'-O-xylosyl saikosaponin b2 or b1 was reported for the first time. Saponins and their related metabolites were predominantly excreted into the bile, but flavonoids were excreted by both hepatic as well as renal excretion. Flavonoids, saponins, gingerol and their related metabolites were the absorbed components in cardiovascular system and bioactive components of XCHT. Phase I reactions (hydrolysis, hydroxylation and oxidation) and phase II reactions (glucuronidation) were identified and involved in the mouse metabolism of XCHT.

13.
J Appl Clin Med Phys ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633877

RESUMO

Validate that a two-dimensional (2D) ionization chamber array (ICA) combined with a double-wedge plate (DWP) can track changes in electron beam energy well within 2.0 mms as recommended by TG-142 for monthly quality assurance (QA). Electron beam profiles of 4-22 MeV were measured for a 25 × 25 cm2 cone using an ICA with a DWP placed on top of it along one diagonal axis. The relationship between the full width half maximum (FWHM) field size created by DWP energy degradation across the field and the depth of 50% dose in water (R50 ) is calibrated for a given ICA/DWP combination in beams of know energies (R50 values). Once this relationship is established, the ICA/DWP system will report the R50 FWHM directly. We calibrated the ICA/DWP on a linear accelerator with energies of 6, 9, 12, 16, 20, and 22 MeV. The R50 FWHM values of these beams and eight other beams with different R50 values were measured and compared with the R50 measured in water, that is, R50 Water. Resolving changes of R50 up to 0.2 cm with ICA/DWP was tested by adding solid-water to shift the energy and was verified with R50 Water measurements. To check the long-term reproducibility of ICA/DWP we measured R50 FWHM on a monthly basis for a period of 3 yr. We proposed a universal calibration procedure considering the off-axis corrections and compared calibrations and measurements on three types of linacs (Varian TrueBeam, Varian C-series, and Elekta) with different nominal energies and R50 values. For all 38 beams on same type of linac with R50 values over a range of 2-8.8 cm, the R50 FWHM reported by the ICA/DWP system agreed with that measured in water within 0.01 ± 0.03 cm (mean ± 1σ) and maximum discrepancy of 0.07 cm. Long-term reproducibility results show the ICA/DWP system to be within 0.04 cm of their baseline over 3 yr. With the universal calibration the maximum discrepancy between R50 FWHM and R50 Water for different types of linac reduced from 0.25 to 0.06 cm. Comparison of R50 FWHM values and R50 Water values and long-term reproducibility of R50 FWHM values indicates that the ICA/DWP can be used for monitoring of electron beam energy constancy well within TG-142 recommended tolerance.

15.
Nat Commun ; 10(1): 4914, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664033

RESUMO

Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.

16.
Chemistry ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31647595

RESUMO

Transition-metal-based phosphides (TMPs) have been considered as attractive electrocatalysts for water splitting due to their earth-abundance and remarkable catalytic activity. As a representative type of precursors, metal-organic frameworks (MOFs) provide ideal plateaus for the design of nanostructured TMPs. In this work, the hierarchically structured iron phosphide nanobundles (FeP-500) were fabricated by one-step phosphorization of an iron-based MOF (MET(Fe)) precursor. The derived FeP-500 nanobundles were constructed by quasi-paralleled one-dimensional nanorods with uneven surface, which provided channels for electrolyte penetration, mass transport, and effective exposure of active sites during the water-splitting process. With the addition of conductive Super P, the obtained FeP-500-S exhibited a good electrocatalytic performance towards the hydrogen evolution reaction in alkaline electrolyte (1 mol L-1 KOH). Furthermore, to investigate the influence of secondary metal doping, a series of isoreticular MOF precursors and bimetallic TMPs were fabricated. The results indicated that the catalytic performance is structure dominated.

17.
Mol Ther ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31611143

RESUMO

Stargardt disease (STGD) is an autosomal recessive retinal disorder caused by a monogenic ABCA4 mutation. Currently, there is no effective therapy to cure Stargardt disease. The replacement of mutated ABCA4 with a functional gene remains an attractive strategy. In this study, we have developed a non-viral gene therapy using nanoparticles self-assembled by a multifunctional pH-sensitive amino lipid ECO and a therapeutic ABCA4 plasmid. The nanoparticles mediated efficient intracellular gene transduction in wild-type (WT) and Abca4-/- mice. Specific ABCA4 expression in the outer segment of photoreceptors was achieved by incorporating a rhodopsin promoter into the plasmids. The ECO/pRHO-ABCA4 nanoparticles induced substantial and specific ABCA4 expression for at least 8 months, 35% reduction in A2E accumulation on average, and a delayed Stargardt disease progression for at least 6 months in Abca4-/- mice. ECO/plasmid nanoparticles constitute a promising non-viral gene therapy platform for Stargardt disease and other visual dystrophies.

18.
Oncogene ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530934

RESUMO

Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87%. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction-oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.

19.
AAPS PharmSciTech ; 20(7): 301, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31485857

RESUMO

Huperzine A (hup A), extracted from the Chinese medicinal plant Huperzia serrata, is a reversible and highly selective second-generation acetylcholine esterase (AchE) inhibitor for treating Alzheimer's disease (AD), but it suffers from low bioavailability in the brain. This study aimed to develop a nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of hup A (hup A-M-TPISG). The optimal formulation was obtained by central composite design and response surface methodology. The optimized mucoadhesive formulation, hup A-M-TPISG, was composed of pluronic F127 (20.80%), pluronic F68 (2.8%), and chitosan (0.88%) as the gel matrix, which could gelatinize under physiological conditions (29-34°C, pH 6.5) because of its temperature and pH responsiveness. The optimized hup A-M-TPISG formulation was further evaluated by in vitro release and in vivo pharmacokinetic studies via microdialysis. The in vitro release study showed continuous and steady drug release from hup A-M-TPISG, which was in accordance with the first-order model. Moreover, the pharmacokinetic results revealed that the optimized formulation for nasal administration, with convenient administration and improved patient compliance, could achieve similar brain-targeting properties as intravenous administration. In conclusion, the hup A-M-TPISG for intranasal administration, as an effective and safe vehicle, could enhance the absorption of hup A in vivo and would be a promising noninvasive alternative for partially improving brain-targeting therapy.


Assuntos
Alcaloides/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Sistemas de Liberação de Medicamentos , Sesquiterpenos/administração & dosagem , Administração Intranasal , Alcaloides/química , Alcaloides/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Composição de Medicamentos , Emulsões , Géis , Concentração de Íons de Hidrogênio , Masculino , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Temperatura Ambiente
20.
J Appl Clin Med Phys ; 20(10): 92-100, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31541526

RESUMO

PURPOSE: Kilo-voltage cone-beam computed tomography (CBCT) is widely used for patient alignment, contour propagation, and adaptive treatment planning in radiation therapy. In this study, we evaluated the accuracy of deformable image registration (DIR) for CBCT under various imaging protocols with different noise and patient dose levels. METHODS: A physical phantom previously developed to facilitate end-to-end testing of the DIR accuracy was used with Varian Velocity v4.0 software to evaluate the performance of image registration from CT to CT, CBCT to CT, and CBCT to CBCT. The phantom is acrylic and includes several inserts that simulate different tissue shapes and properties. Deformations and anatomic changes were simulated by changing the rotations of both the phantom and the inserts. CT images (from a head and neck protocol) and CBCT images (from pelvis, head and "Image Gently" protocols) were obtained with different image noise and dose levels. Large inserts were filled with Mobil DTE oil to simulate soft tissue, and small inserts were filled with bone materials. All inserts were contoured before the DIR process to provide a ground truth contour size and shape for comparison. After the DIR process, all deformed contours were compared with the originals using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). Both large and small volume of interests (VOIs) for DIR volume selection were tested by simulating a DIR process that included whole patient image volume and clinical target volumes (CTV) only (for CTVs propagation). RESULTS: For cross-modality DIR registration (CT to CBCT), the DSC were >0.8 and the MDA were <3 mm for CBCT pelvis, and CBCT head protocols. For CBCT to CBCT and CT to CT, the DIR accuracy was improved relative to the cross-modality tests. For smaller VOIs, the DSC were >0.8 and MDA <2 mm for all modalities. CONCLUSIONS: The accuracy of DIR depends on the quality of the CBCT image at different dose and noise levels.

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