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1.
J Sci Food Agric ; 104(6): 3570-3584, 2024 Apr.
Article En | MEDLINE | ID: mdl-38150568

BACKGROUND: Tea pests pose a significant threat to tea leaf yield and quality, necessitating fast and accurate detection methods to improve pest control efficiency and reduce economic losses for tea farmers. However, in real tea gardens, some tea pests are small in size and easily camouflaged by complex backgrounds, making it challenging for farmers to promptly and accurately identify them. RESULTS: To address this issue, we propose a real-time detection method based on TP-YOLOX for monitoring tea pests in complex backgrounds. Our approach incorporates the CSBLayer module, which combines convolution and multi-head self-attention mechanisms, to capture global contextual information from images and expand the network's perception field. Additionally, we integrate an efficient multi-scale attention module to enhance the model's ability to perceive fine details in small targets. To expedite model convergence and improve the precision of target localization, we employ the SIOU loss function as the bounding box regression function. Experimental results demonstrate that TP-YOLOX achieves a significant performance improvement with a relatively small additional computational cost (0.98 floating-point operations), resulting in a 4.50% increase in mean average precision (mAP) compared to the original YOLOX-s. When compared with existing object detection algorithms, TP-YOLOX outperforms them in terms of mAP performance. Moreover, the proposed method achieves a frame rate of 82.66 frames per second, meeting real-time requirements. CONCLUSION: TP-YOLOX emerges as a proficient solution, capable of accurately and swiftly identifying tea pests amidst the complex backgrounds of tea gardens. This contribution not only offers valuable insights for tea pest monitoring but also serves as a reference for achieving precise pest control. © 2023 Society of Chemical Industry.


Algorithms , Trees , Humans , Farmers , Gardening , Tea
2.
Gait Posture ; 99: 9-13, 2023 01.
Article En | MEDLINE | ID: mdl-36283302

BACKGROUND: Selective motor control (SMC) is a fundamental component of typical human motion. As a result of brain damage, impaired SMC often leads to difficulties with coordination, balance, gait efficiency and symmetry. RESEARCH QUESTION: What is the association between impaired SMC and lower limb motor ability, functional balance and gait performance in children with bilateral spastic cerebral palsy (CP)? METHODS: Thirty-six children (aged 5-16 years) with spastic bilateral CP in Gross Motor Function Classification System (GMFCS) level I to II were included in this study. SMC was assessed using Selective Control Assessment of the Lower Extremity (SCALE). Gross motor function was assessed using Gross Motor Function Measure-88 items D and E dimension (GMFM-88 D&E). Functional balance was assessed using Pediatric Balance Scale (PBS) and Timed Up and Go Test (TUG). Gait quality was assessed using Edinburg Visual Gait Score (EVGS) and 10-Meter Walk Test (10MWT). Spearman's rank correlation analyses were used to determine the association between SMC and other factors. RESULTS: Correlation analyses showed that SCALE was strongly positively correlated with GMFM-88 (D&E) (rs=0.756, p < 0.001), PBS (rs=0.769, p < 0.001), and height-normalized fast walking speed (rs=0.632, p < 0.001), and strongly negatively correlated with TUG (rs=-0.766, p < 0.001) and EVGS (rs=-0.893, p < 0.001). SIGNIFICANCE: Lower extremity SMC deficits are associated with poor gross motor function and balance control, more severe overall gait deviations and decreased fast walking speed in children with bilateral spastic CP. Physical therapy should include interventions that promote selective motor control in order to improve overall functional ability.


Cerebral Palsy , Child , Humans , Postural Balance , Muscle Spasticity , Time and Motion Studies , Gait
3.
Neurol Sci ; 38(1): 33-40, 2017 Jan.
Article En | MEDLINE | ID: mdl-27785579

Dozens of observational studies and two meta-analyses have investigated the association of migraine with the risk of stroke, but their results are inconsistent. We aimed to quantitatively evaluate the relationship between migraine and stroke risk by performing a meta-analysis of prospective cohort studies. PubMed and Embase were searched through July 2016 to identify studies that met pre-stated inclusion criterion and reference lists of retrieved articles were also reviewed. Information on the characteristics of the included study, risk estimates, and control for possible confounding factors were extracted independently by two authors. The random-effects model was used to calculate the pooled risk estimates. Eleven prospective cohort studies involving 3371 patients with stroke and 2,221,888 participants were included in this systematic review. Compared with non-migraineurs, the pooled relative risks of total stroke, hemorrhagic stroke, and ischemic stroke for migraineurs were 1.55 [95% confidence interval (CI) 1.38-1.75], 1.15 (95% CI 0.85-1.56), and 1.64 (95% CI 1.22-2.20), respectively. Exception of any single study did not materially alter the combined risk estimate. Integrated epidemiological evidence supports that migraine should be associated with the increased risk of total stroke and ischemic stroke, but the relationship between migraine and the risk of hemorrhagic stroke is not of certainty.


Migraine Disorders/epidemiology , Stroke/epidemiology , Humans , Incidence , Risk
4.
Carbohydr Polym ; 154: 1-7, 2016 Dec 10.
Article En | MEDLINE | ID: mdl-27577889

This paper addressed the application of hydroxyethyl pachyman (HEP) as a novel matrix for sustained - release tablets, using diclofenac sodium (DS) as a model drug. The studies showed the HEP tablets prepared by wet granulation had much slower drug release as compared to those prepared by direct compression. Meanwhile, increasing the percentage of HEP in the formulations caused a decrease in drug release rates. Moreover, DS release from the HEP tablets was much higher at high pH (6.8) than that at low pH (1.2). Morphology studies proved the HEP tablet formed a continuous gel layer with porous inner structure in the dissolution media. Analysis of DS release profiles revealed that diffusion and matrix erosion occurred in simulated intestinal fluid(SIF, pH=6.8) for all the tablets. The experimental results predict HEP has a potential as a hydrophilic matrix in tablets to prolong drug release.


Excipients/chemistry , Glucans/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Delayed-Action Preparations/chemistry , Diclofenac/chemistry , Drug Liberation , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Tablets
5.
Nanomedicine ; 12(7): 1795-1803, 2016 10.
Article En | MEDLINE | ID: mdl-27184095

Alginate/chitosan nanocomposite particles (GSNO-acNCPs), i.e. S-nitrosoglutathione (GSNO) loaded polymeric nanoparticles incorporated into an alginate and chitosan matrix, were developed to increase the effective GSNO loading capacity, a nitric oxide (NO) donor, and to sustain its release from the intestine following oral administration. Compared with free GSNO and GSNO loaded nanoparticles, GSNO-acNCPs promoted 2.7-fold GSNO permeation through a model of intestinal barrier (Caco-2 cells). After oral administration to Wistar rats, GSNO-acNCPs promoted NO storage into the aorta during at least 17h, as highlighted by (i) a long-lasting hyporeactivity to phenylephrine (decrease in maximum vasoconstrictive effect of aortic rings) and (ii) N-acetylcysteine (a thiol which can displace NO from tissues)-induced vasodilation of aorxxtic rings preconstricted with phenylephrine. In conclusion, GSNO-acNCPs enhance GSNO intestinal absorption and promote the formation of releasable NO stores into the rat aorta. GSNO-acNCPs are promising carriers for chronic oral application devoted to the treatment of cardiovascular diseases.


Nanocomposites , Nitric Oxide/metabolism , Polymers , S-Nitrosoglutathione/pharmacokinetics , Animals , Aorta , Caco-2 Cells , Humans , Intestinal Absorption , Rats , Rats, Wistar
6.
Chem Biol Drug Des ; 87(5): 773-83, 2016 May.
Article En | MEDLINE | ID: mdl-26684806

Neuromuscular blocking agents are widely used as an anesthesia auxiliary in surgery, which induce relaxation of skeletal muscles by blocking signal transmission at the neuromuscular junction. Many neuromuscular blocking agents s were developed over the past decades, but none of them fully meets the needs of the clinic by various reasons. In this study, a series of quaternary ammonium steroidal neuromuscular blocking agents were synthesized and evaluated on isolated mouse phrenic nerve-hemidiaphragms for their bioactivities. The initial separation of mono- and bis-quaternary ammonium compounds turned out to be very challenging on regular silica gel chromatography. Therefore, a facile purification method, in which the silica gel was pretreated with methanolic sodium bromide solution, was finally achieved. Compounds 3g (0.36 µm) and 4g (0.37 µm) exhibited excellent neuromuscular blocking activities, which were about sixfold to sevenfold higher in potency than that of rocuronium (2.50 µm). In addition, other bis-quaternized compounds also showed good potencies close to that of rocuronium. Furthermore, the preliminary structure-activity relationship of this series was also elucidated. Benzyl group was found to be a promising quaternary group in this series.


Ammonium Compounds/pharmacology , Neuromuscular Blocking Agents/pharmacology , Steroids/pharmacology , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization
7.
Nat Mater ; 15(2): 235-42, 2016 Feb.
Article En | MEDLINE | ID: mdl-26595119

Fluorescent imaging of biological systems in the second near-infrared window (NIR-II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (∼90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)-a clinically approved NIR-I dye-in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ∼4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti-EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery.


Benzopyrans/pharmacology , Carcinoma, Squamous Cell/pathology , Fluorescent Dyes/pharmacology , Indoles/pharmacology , Neoplasms, Experimental/pathology , Phenylpropionates/pharmacology , Thiadiazoles/pharmacology , Animals , Benzopyrans/chemistry , Benzopyrans/urine , Cell Line, Tumor , Diagnostic Imaging/methods , Female , Humans , Indoles/chemistry , Indoles/urine , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Spectroscopy, Near-Infrared
8.
BMC Pregnancy Childbirth ; 15: 343, 2015 Dec 22.
Article En | MEDLINE | ID: mdl-26694165

BACKGROUND: Few studies on cluster-based synthetic effects of multiple risk factors for birth defects have been reported. The present study aimed to identify maternal exposure clusters, explore the association between clusters of risk factors and birth defects, and further screen women with high risk for birth defects among expectant mothers. METHODS: Data were drawn from a large-scale, retrospective epidemiological survey of birth defects from 2006 to 2008 in six counties of Shanxi Province, China, using a three-level stratified random cluster sampling technique. Overall risk factors were extracted using eight synthetic variables summed and examined as a total risk factor score: maternal delivery age, genetic factors, medical history, nutrition and folic acid deficiency, maternal illness in pregnancy, drug use in pregnancy, environmental risk factors in pregnancy, and unhealthy maternal lifestyle in pregnancy. Latent class cluster analysis was used to identify maternal exposure clusters based on these synthetic variables. Adjusted odds ratios (AOR) were used to explore associations between clusters and birth defects, after adjusting for confounding variables using logistic regression. RESULTS: Three latent maternal exposure clusters were identified: a high-risk (6.15%), a moderate-risk (22.39%), and a low-risk (71.46%) cluster. The prevalence of birth defects was 14.08%, 0.85%, and 0.52% for the high-, middle- and low-risk clusters respectively. After adjusting for maternal demographic variables, women in the high-risk cluster were nearly 31 times (AOR: 30.61, 95% CI: [24.87, 37.67]) more likely to have an infant with birth defects than low-risk women. CONCLUSIONS: A high-risk group of mothers in an area with a high risk for birth defects were screened in our study. Targeted interventions should be conducted with women of reproductive age to improve neonatal birth outcomes in areas with a high risk of birth defects.


Congenital Abnormalities/epidemiology , Congenital Abnormalities/etiology , Folic Acid Deficiency , Maternal Age , Maternal Exposure , Pregnancy Complications , Adult , China , Cluster Analysis , Female , Humans , Infant , Life Style , Logistic Models , Mass Screening , Odds Ratio , Pregnancy , Retrospective Studies , Risk Factors
9.
Molecules ; 20(9): 17585-600, 2015 Sep 23.
Article En | MEDLINE | ID: mdl-26404228

A novel series of benzenesulfonamide derivatives containing 4-aminobenzenesul-fonamide and α-amides branched valproic acid or 2,2-dimethylcyclopropanecarboxylic acid moieties were synthesized and screened for their anticonvulsant activities in mice maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) test. The activity experimental study showed that 2,2-dipropyl-N¹-(4-sulfamoylphenyl)malonamide (18b) had the lowest median effective dose (ED50) of 16.36 mg/kg in MES test, and 2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12c) had the lowest ED50 of 22.50 mg/kg in scPTZ test, which resulted in the protective indexe (PI) of 24.8 and 20.4, respectively. These promising data suggest the new compounds have good potential as new class of anticonvulsant agents with high effectiveness and low toxicity for the treatment of epilepsy.


Anticonvulsants/chemical synthesis , Seizures/drug therapy , Sulfonamides/chemical synthesis , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemistry , Disease Models, Animal , Male , Mice , Molecular Structure , Seizures/etiology , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemistry , Benzenesulfonamides
10.
Int J Pharm ; 495(1): 354-361, 2015 Nov 10.
Article En | MEDLINE | ID: mdl-26319632

S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor with therapeutic potential for cardiovascular disease treatment. Chronic oral treatment with GSNO is limited by high drug sensitivity to the environment and limited oral bioavailability, requiring the development of delivery systems able to sustain NO release. The present work describes new platforms based on polymer nanocomposite particles for the delivery of GSNO. Five types of optimized nanocomposite particles have been developed (three based on chitosan, two based on alginate sodium). Those nanocomposite particles encapsulate GSNO with high efficiency from 64% to 70% and an average size of 13 to 61 µm compatible with oral delivery. Sustained release of GSNO in vitro was achieved. Indeed, chitosan nanocomposites discharged their payload within 24h; whereas alginate nanocomposites released GSNO more slowly (10% of GSNO was still remaining in the dosage form after 24h). Their cytocompatibility toward intestinal Caco-2 cells (MTT assay) was acceptable (IC50: 6.07 ± 0.07-9.46 ± 0.08 mg/mL), demonstrating their suitability as oral delivery systems for GSNO. These delivery systems presented efficient GSNO loading and sustained release as well as cytocompatibility, showing their promise as a means of improving the oral bioavailability of GSNO and as a potential new treatment.


Alginates/chemistry , Chitosan/chemistry , Nanocomposites/chemistry , Nitric Oxide Donors/administration & dosage , S-Nitrosoglutathione/administration & dosage , Administration, Oral , Caco-2 Cells , Chemistry, Pharmaceutical/methods , Delayed-Action Preparations , Drug Carriers/chemistry , Drug Liberation , Drug Stability , Glucuronic Acid/chemistry , Hexuronic Acids/chemistry , Humans , Particle Size
11.
Drug Des Devel Ther ; 9: 1805-13, 2015.
Article En | MEDLINE | ID: mdl-25848217

BACKGROUND: The objective of this study was to develop a novel polydatin (PLD)-loaded liposome system using the thin film hydration technique. METHODS: The delivery system was characterized in terms of morphology, size, zeta potential, encapsulation efficiency, and in vitro release. In addition, a pharmacokinetic study was carried out in rats after oral administration of PLD-loaded liposomes in vivo. RESULTS: Transmission electron microscopy revealed that the PLD-loaded liposomes had a homogeneous size and spherical shape. Dynamic light scattering showed that the PLD-loaded liposomes had a smaller size with a mean value of 80.2±3.7 nm and a polydispersity index of 0.12±0.06. The encapsulation efficiency of the prepared liposomes was 88.4%±3.7%. During the release process, liposome showed two distinct phases. The first was characterized by rapid release during the first 2 hours, which could be related to the release of the drug adsorbed on the surface of liposomes. In the second phase, the release rate slowed down, demonstrating a typical sustained and prolonged drug-release behavior. The release kinetic model for the PLD-loaded liposomes fitted well with the Weibull distribution equation. In vivo, relative oral bioavailability of the encapsulated PLD was 282.9%, ie, significantly enhanced (P<0.05) compared with the free drug. No histological changes occurred in the organs after administration of PLD-loaded liposomes. CONCLUSION: PLD-loaded liposomes could significantly prolong the drug circulation time in vivo and increase the oral bioavailability of the drug.


Drug Delivery Systems , Glucosides/administration & dosage , Glucosides/pharmacokinetics , Nanoparticles/chemistry , Stilbenes/administration & dosage , Stilbenes/pharmacokinetics , Administration, Oral , Animals , Glucosides/chemistry , Liposomes , Male , Molecular Structure , Particle Size , Rats , Rats, Sprague-Dawley , Stilbenes/chemistry
12.
Angew Chem Int Ed Engl ; 54(20): 5981-4, 2015 May 11.
Article En | MEDLINE | ID: mdl-25800807

Small-molecule-based multimodal and multifunctional imaging probes play prominent roles in biomedical research and have high clinical translation ability. A novel multimodal imaging platform using base-catalyzed double addition of thiols to a strained internal alkyne such as bicyclo[6.1.0]nonyne has been established in this study, thus allowing highly selective assembly of various functional units in a protecting-group-free manner. Using this molecular platform, novel dual-modality (PET and NIRF) uPAR-targeted imaging probe: (64)Cu-CHS1 was prepared and evaluated in U87MG cells and tumor-bearing mice models. The excellent PET/NIRF imaging characteristics such as good tumor uptake (3.69%ID/g at 2 h post-injection), high tumor contrast, and specificity were achieved in the small-animal models. These attractive imaging properties make (64)Cu-CHS1 a promising probe for clinical use.


Alkynes/chemistry , Cyclooctanes/chemistry , Molecular Imaging , Molecular Probes/chemistry , Neoplasms, Experimental/diagnosis , Alkynes/pharmacokinetics , Animals , Cell Line, Tumor , Cyclooctanes/pharmacokinetics , Disease Models, Animal , Humans , Mice , Molecular Probes/pharmacokinetics , Molecular Structure , Positron-Emission Tomography , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacokinetics
13.
Br J Pharmacol ; 172(14): 3495-509, 2015 Jul.
Article En | MEDLINE | ID: mdl-25816897

BACKGROUND AND PURPOSE: Transient receptor potential canonical (TRPC) channels play important roles in a broad array of physiological functions and are involved in various diseases. However, due to a lack of potent subtype-specific inhibitors the exact roles of TRPC channels in physiological and pathophysiological conditions have not been elucidated. EXPERIMENTAL APPROACH: Using fluorescence membrane potential and Ca(2+) assays and electrophysiological recordings, we characterized new 2-aminobenzimidazole-based small molecule inhibitors of TRPC4 and TRPC5 channels identified from cell-based fluorescence high-throughput screening. KEY RESULTS: The original compound, M084, was a potent inhibitor of both TRPC4 and TRPC5, but was also a weak inhibitor of TRPC3. Structural modifications of the lead compound resulted in the identification of analogues with improved potency and selectivity for TRPC4 and TRPC5 channels. The aminobenzimidazole derivatives rapidly inhibited the TRPC4- and TRPC5-mediated currents when applied from the extracellular side and this inhibition was independent of the mode of activation of these channels. The compounds effectively blocked the plateau potential mediated by TRPC4-containing channels in mouse lateral septal neurons, but did not affect the activity of heterologously expressed TRPA1, TRPM8, TRPV1 or TRPV3 channels or that of the native voltage-gated Na(+) , K(+) and Ca(2) (+) channels in dissociated neurons. CONCLUSIONS AND IMPLICATIONS: The TRPC4/C5-selective inhibitors developed here represent novel and useful pharmaceutical tools for investigation of physiological and pathophysiological functions of TRPC4/C5 channels.


Benzimidazoles/pharmacology , TRPC Cation Channels/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Cells, Cultured , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Sequence Data , Molecular Structure , Structure-Activity Relationship , TRPC Cation Channels/metabolism
14.
Steroids ; 96: 103-14, 2015 Apr.
Article En | MEDLINE | ID: mdl-25637675

Neuromuscular blocking agents (NMBAs) are widely used in surgery to achieve skeleton muscles relaxation under light anesthesia status. In this work, we synthesized a series of 3,16-bisquaternary ammonium steroidal NMBAs. Among them, three compounds exhibited higher in vitro activities than the commenced drug rocuronium. In addition, structure-activity relationship was unveiled. We found that the intact acetylcholine-like moiety in D-ring was not necessary for maintaining activity but both the acetyl group and the quaternary nitrogen were very essential.


Neuromuscular Blocking Agents/chemical synthesis , Neuromuscular Blocking Agents/pharmacology , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/pharmacology , Steroids/chemistry , Animals , Chemistry Techniques, Synthetic , Male , Mice , Neuromuscular Blocking Agents/chemistry , Quaternary Ammonium Compounds/chemistry , Structure-Activity Relationship
15.
Drug Des Devel Ther ; 9: 791-8, 2015.
Article En | MEDLINE | ID: mdl-25709403

BACKGROUND: A novel lovastatin (LVT)-loaded poly(lactic acid) microsphere suitable for oral administration was developed in this study, and in vitro and in vivo characteristics were evaluated. METHODS: The designed microspheres were obtained by an improved emulsion-solvent evaporation method. The morphological examination, particle size, encapsulation ratio, drug loading, and in vitro release were characterized. Pharmacokinetics studies were used to show that microspheres possess more advantages than the conventional formulations. RESULTS: By using the emulsion-solvent evaporation method, it was simple to prepare microspheres and easy to scale up production. The morphology of formed microspheres showed a spherical shape with a smooth surface, without any particle aggregation. Mean size of the microspheres was 2.65±0.69 µm; the encapsulation efficiency was 92.5%±3.6%, and drug loading was 16.7%±2.1%. In vitro release indicated that the LVT microspheres had a well-sustained release efficacy, and ex vivo studies showed that after LVT was loaded to microspheres, the area under the plasma concentration-time curve from zero to the last measurable plasma concentration point and the extrapolation to time infinity increased significantly, which represented 2.63-fold and 2.49-fold increases, respectively, compared to suspensions. The rate of ex vivo clearance was significantly reduced. CONCLUSION: This research proved that poly(lactic acid) microspheres can significantly prolong the drug circulation time in vivo and can also significantly increase the relative bioavailability of the drug.


Drug Delivery Systems , Lactic Acid/administration & dosage , Lovastatin/administration & dosage , Microspheres , Polymers/administration & dosage , Administration, Oral , Animals , Biological Availability , Drug Stability , Lactic Acid/chemistry , Lactic Acid/pharmacokinetics , Lovastatin/chemistry , Lovastatin/pharmacokinetics , Molecular Conformation , Particle Size , Polyesters , Polymers/chemistry , Polymers/pharmacokinetics , Rats , Surface Properties
16.
Mol Pharm ; 12(3): 675-83, 2015 Mar 02.
Article En | MEDLINE | ID: mdl-25584860

Due to overexpression of glycyrrhetinic acid (GA) receptor in liver cancer cells, glycyrrhetinic acid modified recombinant human serum albumin (rHSA) nanoparticles for targeting liver tumor cells may result in increased therapeutic efficacy and decreased adverse effects of cancer therapy. In this study, doxorubicin (DOX) loaded and glycyrrhetinic acid modified recombinant human serum albumin nanoparticles (DOX/GA-rHSA NPs) were prepared for targeting therapy for liver cancer. GA was covalently coupled to recombinant human serum albumin nanoparticles, which could efficiently deliver DOX into liver cancer cells. The resultant GA-rHSA NPs exhibited uniform spherical shape and high stability in plasma with fixed negative charge (∼-25 mV) and a size about 170 nm. DOX was loaded into GA-rHSA NPs with a maximal encapsulation efficiency of 75.8%. Moreover, the targeted NPs (DOX/GA-rHSA NPs) showed increased cytotoxic activity in liver tumor cells compared to the nontargeted NPs (DOX/rHSA NPs, DOX loaded recombinant human serum albumin nanoparticles without GA conjugating). The targeted NPs exhibited higher cellular uptake in a GA receptor-positive liver cancer cell line than nontargeted NPs as measured by both flow cytometry and confocal laser scanning microscopy. Biodistribution experiments showed that DOX/GA-rHSA NPs exhibited a much higher level of tumor accumulation than nontargeted NPs at 1 h after injection in hepatoma-bearing Balb/c mice. Therefore, the DOX/GA-rHSA NPs could be considered as an efficient nanoplatform for targeting drug delivery system for liver cancer.


Antineoplastic Agents/administration & dosage , Doxorubicin/administration & dosage , Liver Neoplasms, Experimental/drug therapy , Nanocapsules/chemistry , Animals , Antineoplastic Agents/pharmacokinetics , Doxorubicin/pharmacokinetics , Drug Delivery Systems , Glycyrrhetinic Acid/chemistry , HeLa Cells , Hep G2 Cells , Humans , Liver Neoplasms, Experimental/metabolism , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microscopy, Electron, Transmission , Nanocapsules/administration & dosage , Nanocapsules/ultrastructure , Recombinant Proteins/chemistry , Serum Albumin/chemistry , Tissue Distribution , Xenograft Model Antitumor Assays
17.
Eur J Med Chem ; 92: 370-6, 2015 Mar 06.
Article En | MEDLINE | ID: mdl-25585007

A series of new N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives (8a-i) and ethyl 2,2-dimethyl-1-(3-(2-(sulfonamido)ethyl)ureido) cyclopropanecarbox-ylate derivatives (9a-i) were designed, synthesized and evaluated for their anticonvulsant activities using maximal electroshock shock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4-fluoroben- zenesulfonamide (8f) and N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4- methylbenzenesulfonamide (8e) have shown promising anticonvulsant activities in MES model. The most active compound 8f has shown the MES-induced seizures with ED50 value of 28.05 mg/kg and TD50 value of 561 mg/kg after intraperitoneal injection to mice, which provided compound 8f with a protective index (TD50/ED50) of 20 in the MES test. Further, rotarod toxicity method was used to study the acute neurotoxicity profile of selected compounds.


Anticonvulsants/therapeutic use , Cycloheptanes/pharmacology , Drug Design , Seizures/drug therapy , Spiro Compounds/pharmacology , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Cycloheptanes/chemical synthesis , Cycloheptanes/chemistry , Electroshock , Injections, Intraperitoneal , Male , Mice , Mice, Inbred Strains , Molecular Structure , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry
18.
Eur J Pharm Biopharm ; 89: 1-8, 2015 Jan.
Article En | MEDLINE | ID: mdl-25448077

Physiological S-nitrosothiols (RSNO), such as S-nitrosoglutathione (GSNO), can be used as nitric oxide (NO) donor for the treatment of vascular diseases. However, despite a half-life measured in hours, the stability of RSNO, limited by enzymatic and non-enzymatic degradations, is too low for clinical application. So, to provide a long-lasting effect and to deliver appropriate NO concentrations to target tissues, RSNO have to be protected. RSNO encapsulation is an interesting response to overcome degradation and provide protection. However, RSNO such as GSNO raise difficulties for encapsulation due to its hydrophilic nature and the instability of the S-NO bound during the formulation process. To our knowledge, the present study is the first description of the direct encapsulation of GSNO within polymeric nanoparticles (NP). The GSNO-loaded NP (GSNO-NP) formulated by a double emulsion process, presented a mean diameter of 289 ± 7 nm. They were positively charged (+40 mV) due to the methacrylic acid and ethylacrylate polymer (Eudragit® RL) used and encapsulated GSNO with a satisfactory efficiency (i.e. 54% or 40 mM GSNO loaded in the NP). In phosphate buffer (37 °C; pH 7.4), GSNO-NP released 100% of encapsulated GSNO within 3h and remained stable still 6h. However, in contact with smooth muscle cells, maximum protein nitrosation (a marker of NO bioavailability) was delayed from 1h for free GSNO to 18h for GSNO-NP. Therefore, protection and sustained release of NO were achieved by the association of a NO donor with a drug delivery system (such as polymeric NP), providing opportunities for vascular diseases treatment.


Nanoparticles/administration & dosage , Nitrosation/drug effects , Polymers/pharmacology , Protein S/metabolism , S-Nitrosoglutathione/pharmacology , Animals , Cell Line , Drug Delivery Systems/methods , Half-Life , Nanoparticles/chemistry , Nitric Oxide/metabolism , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/pharmacology , Polymers/chemistry , Rats , S-Nitrosoglutathione/chemistry , S-Nitrosothiols/metabolism
19.
Eur J Med Chem ; 83: 466-73, 2014 Aug 18.
Article En | MEDLINE | ID: mdl-24992074

A series of 6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate derivatives were prepared to evaluate their ability of inhibiting neuraminidase (NA) of influenza A virus. All the compounds were synthesized in good yields starting from aldehyde by using a suitable synthetic strategy, which showed moderate inhibitory activity against influenza A NA. Compound 6g exhibited the strongest inhibitory activity against influenza virus A NA (IC50 = 17.64 µM), which indicated pyrimidine ring could be used as a core structure to design novel influenza NA inhibitors.


Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Influenza A virus/enzymology , Neuraminidase/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Catalytic Domain , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemistry , Models, Molecular , Neuraminidase/chemistry , Pyrimidines/chemistry
20.
Biomed Chromatogr ; 28(7): 1036-40, 2014 Jul.
Article En | MEDLINE | ID: mdl-24375717

Nifedipine is a dihydropyridine calcium channel blocker used widely in the management of hypertension and other cardiovascular disorders. In this work, a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry method was developed and validated to determine nifedipine in dog plasma using nimodipine as the internal standard. Chromatographic separation was carried out on a C8 column. The mobile phase consisted of a mixture of acetonitrile, water and formic acid (60:40:0.2, v/v/v) at a flow rate of 0.5 mL/min. Detection was performed on a triple quadrupole tandem mass spectrometer in selected reaction monitoring mode via an atmospheric pressure chemical ionization source. The method has a lower limit of quantification of 0.20 ng/mL with consumption of plasma as low as 0.05 mL. The linear calibration curves were obtained in the concentration range of 0.20-50.0 ng/mL (r = 0.9948). The recoveries of the liquid extraction method were 74.5-84.1%. Intra-day and inter-day precisions were 4.1-8.8 and 6.7-7.4%, respectively. The quantification was not interfered with by other plasma components and the method was applied to determine nifedipine in plasma after a single oral administration of two controlled-release nifedipine tablets to beagle dogs.


Chromatography, High Pressure Liquid/methods , Nifedipine/blood , Tandem Mass Spectrometry/methods , Animals , Dogs , Linear Models , Male , Nifedipine/chemistry , Nifedipine/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity
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