RESUMO
The transient receptor potential polycystin-2 (TRPP2) is encoded by the Pkd2 gene, and mutation of this gene can cause autosomal dominant polycystic kidney disease (ADPKD). Some patients with ADPKD experience extrarenal manifestations, including radiologic and clinical bronchiectasis. We hypothesized that TRPP2 may regulate airway smooth muscle (ASM) tension. Thus, we used smooth muscle-Pkd2 conditional knockout (Pkd2SM-CKO) mice to investigate whether TRPP2 regulated ASM tension and whether TRPP2 deficiency contributed to bronchiectasis associated with ADPKD. Compared with wild-type mice, Pkd2SM-CKO mice breathed more shallowly and faster, and their cross-sectional area ratio of bronchi to accompanying pulmonary arteries was higher, suggesting that TRPP2 may regulate ASM tension and contribute to the occurrence of bronchiectasis in ADPKD. In a bioassay examining isolated tracheal ring tension, no significant difference was found for high-potassium-induced depolarization of the ASM between the two groups, indicating that TRPP2 does not regulate depolarization-induced ASM contraction. By contrast, carbachol-induced contraction of the ASM derived from Pkd2SM-CKO mice was significantly reduced compared with that in wild-type mice. In addition, relaxation of the carbachol-precontracted ASM by isoprenaline, a ß-adrenergic receptor agonist that acts through the cAMP/adenylyl cyclase pathway, was also significantly attenuated in Pkd2SM-CKO mice compared with that in wild-type mice. Thus, TRPP2 deficiency suppressed both contraction and relaxation of the ASM. These results provide a potential target for regulating ASM tension and for developing therapeutic alternatives for some ADPKD complications of the respiratory system or for independent respiratory disease, especially bronchiectasis.
Assuntos
Brônquios/metabolismo , Bronquiectasia/genética , Músculo Liso/metabolismo , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Bronquiectasia/metabolismo , Bronquiectasia/fisiopatologia , Broncodilatadores/antagonistas & inibidores , Broncodilatadores/farmacologia , Cálcio/metabolismo , Carbacol/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Contração Isométrica/efeitos dos fármacos , Contração Isométrica/fisiologia , Isoproterenol/antagonistas & inibidores , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Knockout , Mióticos/farmacologia , Tono Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Respiração/efeitos dos fármacos , Transdução de Sinais , Canais de Cátion TRPP/deficiência , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/fisiopatologiaRESUMO
Defective autophagy in vascular smooth muscle cells (VSMCs) is the principal cause of atherosclerosis. This study aimed to investigate the effect of astragaloside IV (AS-IV) on VSMCs autophagy. In vivo, ApoE-/- mice were fed with high-fat diet ad libitum for eight weeks, with or without AS-IV (25â¯mg/kg, daily). In vitro, human VSMCs were cultured and treated with ß-Glycerophosphate (10â¯mmol/L) and AS-IV (50⯵g/ml). VSMCs autophagy, mineralization, expression of p-ERK1/2, p-mTOR, and autophagy-related proteins (LC3 II/I, p62, and Beclin 1) were detected. Increased autophagy and mineralization was observed in VSMCs in thoracic aorta of mice and in in vitro VSMCs model of atherosclerosis. AS-IV administration attenuated the autophagy and mineralization in VSMCs. Reverse expression profiles of H19 and DUSP5 were observed. AS-IV inhibited DUSP5 and autophagy-related proteins and increased expression of H19, level of p-ERK1/2 and p-mTOR. Further, autophagy and mineralization level in VSMCs were in line with DUSP5 expression level, but in contrast to H19, p-ERK1/2, and p-mTOR profiles. We demonstrated that AS-IV could attenuate autophagy and mineralization of VSMCs in atherosclerosis, which may be associated with H19 overexpression and DUSP5 inhibition.
Assuntos
Aterosclerose/prevenção & controle , Autofagia/efeitos dos fármacos , Fosfatases de Especificidade Dupla/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Calcificação Vascular/prevenção & controle , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fosforilação , Placa Aterosclerótica , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Calcificação Vascular/enzimologia , Calcificação Vascular/genética , Calcificação Vascular/patologiaRESUMO
BACKGROUND: Daratumumab is widely used in multiple myeloma (MM) and light chain amyloidosis (AL amyloidosis). The purpose of this study was to identify adverse event (AE) signals for daratumumab through the FDA Adverse Event Reporting System (FAERS) database to assess its safety in a large sample of people. METHODS: Based on data from the FAERS database, three disproportionality analysis methods were used to mine AE signals for daratumumab, including reporting odd ratio (ROR), proportional reporting ratio (PRR), and bayesian configuration promotion neural network (BCPNN). RESULTS: A total of 9220 AE reports with daratumumab as the primary suspect drug were collected, containing 23,946 AEs. Within these reports, 252 preferred terms (PT) levels, 73 high level term (HLT) levels and 11 system organ class (SOC) levels of AE signals were detected, along with some new AEs. Most AEs occurred within the first month after drug administration. CONCLUSION: Our findings were consistent with the results of established studies that daratumumab has a good safety profile. The newly identified AEs are of concern and prospective clinical studies are needed to confirm whether they are causally related to daratumumab. This study provided an early warning for the safe use of daratumumab and also provided guidance for further safety studies.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Anticorpos Monoclonais , Bases de Dados Factuais , Mieloma Múltiplo , Farmacovigilância , Humanos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estados Unidos , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , United States Food and Drug Administration , Adolescente , Adulto Jovem , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Fatores de Tempo , Teorema de BayesRESUMO
In the title compound, C19H22N2, both the benzimidazole unit and the 2,6-diiso-propyl-phenyl group are essentially planar [maximum deviations from the least-squares planes of 0.005â (1) and 0.009â (1)â Å, respectively]. The dihedral angle between the two planes is 79.6â (7)°. In the crystal, mol-ecules are linked into chains along the a-axis direction by weak C-Hâ¯N inter-actions. The crystal structure also features C-Hâ¯π inter-actions, which link the chains into a three-dimensional network.
RESUMO
In order to improve the construction efficiency of piers and reduce the local damage of piers, concrete-filled steel tubes (CFST) are used to precast pier segments. Aiming at the problems of the poor integrity and insufficient energy dissipation capacity of dry joint segmental assembled piers, segmental assembled concrete-filled steel tubular piers with external replaceable energy dissipators are being developed. Based on the low cyclic test of a segmental assembled CFST pier, the finite element numerical simulation model of a CFST pier is established based on ABAQUS software, and the validity of the numerical model is verified by the experimental results. The effects of the section ratio, axial compression ratio, and initial prestress on the seismic performance of piers are studied through a pseudostatic analysis. The results show that an increase in the section ratio can improve the lateral bearing capacity and energy dissipation capacity of the pier. When the section ratio is increased to 4%, the energy dissipation capacity of a CFST pier is increased by 77.8% and the lateral bearing capacity is increased by 33.9% compared with a section ratio of 2%, but the residual displacement of the pier top also increases. With an increase in the axial compression ratio, the energy dissipation capacity of the pier is significantly improved; when the axial compression ratio is increased to 0.30, the energy dissipation capacity of CFST piers is increased by 27.5% compared with a section ratio of 0.05, the residual displacement of the pier top is reduced, and the self-resetting effect of the pier is improved. A change in the initial prestress has no effect on the energy dissipation capacity of piers. Finally, based on an analysis of mechanical theory, a formula of bending capacity suitable for this type of pier is proposed, and the error is within 10%.
RESUMO
In order to further promote the application of segment-assembled bridge piers in medium- and high-intensity areas, and to reduce the post-earthquake damage and repair cost of bridge piers, in this paper, a precast segmental concrete-filled steel-tube bridge pier (PSCFSTBP) with an external arched energy dissipation device (AEDD) is proposed. Firstly, the effectiveness of the finite-element analysis software ABAQUS 6.14-4 is proved by the test results of the PSCFSTBP and the corresponding finite-element model analysis results. Secondly, ABAQUS 6.14-4 was used to establish four-segment PSCFSTBP models with four different structural forms (non-energy dissipation device, external arch steel plate, external vertical steel plate, and external AEDD), and the seismic performance of each model was compared and analyzed under reciprocating displacement loading. The results show that compared with the PSCFSTBP with an external AEDD, the lateral bearing capacity of the PSCFSTBP with an external vertical steel plate is increased by about 11.9%, and the initial stiffness is increased by about 2.5%. Compared with the PSCFSTBP with an external arch steel plate, the lateral bearing capacity, initial stiffness, and energy dissipation capacity are increased by 28.8%, 4.6%, and 13 times, respectively. Compared with the PSCFSTBP without an energy dissipation device, its lateral bearing capacity, initial stiffness, and energy dissipation capacity are increased by 39.4%, 10.4%, and 18 times, respectively. The residual displacement of the PSCFSTBP with an external AEDD is kept within 1 mm in the whole displacement loading stage, the offset rate is less than 1%, and the pier damage is controllable, which can realize rapid repair after an earthquake. Finally, the multi-level energy consumption and local replacement of the AEDD are also explored.
RESUMO
BACKGROUND: The elderly population is at risk of osteoarthritis (OA), a common, multifactorial, degenerative joint disease. Environmental, genetic, and epigenetic (such as DNA hydroxymethylation) factors may be involved in the etiology, development, and pathogenesis of OA. Here, comprehensive bioinformatic analyses were used to identify aberrantly hydroxymethylated differentially expressed genes and pathways in osteoarthritis to determine the underlying molecular mechanisms of osteoarthritis and susceptibility-related genes for osteoarthritis inheritance. METHODS: Gene expression microarray data, mRNA expression profile data, and a whole genome 5hmC dataset were obtained from the Gene Expression Omnibus repository. Differentially expressed genes with abnormal hydroxymethylation were identified by MATCH function. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the genes differentially expressed in OA were performed using Metascape and the KOBAS online tool, respectively. The protein-protein interaction network was built using STRING and visualized in Cytoscape, and the modular analysis of the network was performed using the Molecular Complex Detection app. RESULTS: In total, 104 hyperhydroxymethylated highly expressed genes and 14 hypohydroxymethylated genes with low expression were identified. Gene ontology analyses indicated that the biological functions of hyperhydroxymethylated highly expressed genes included skeletal system development, ossification, and bone development; KEGG pathway analysis showed enrichment in protein digestion and absorption, extracellular matrix-receptor interaction, and focal adhesion. The top 10 hub genes in the protein-protein interaction network were COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL6A1, COL8A1, COL11A1, and COL24A1. All the aforementioned results are consistent with changes observed in OA. CONCLUSION: After comprehensive bioinformatics analysis, we found aberrantly hydroxymethylated differentially expressed genes and pathways in OA. The top 10 hub genes may be useful hydroxymethylation analysis biomarkers to provide more accurate OA diagnoses and target genes for treatment of OA.
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Intracellular Ca2+ is critical for regulating airway smooth muscle (ASM) tension. A rapid rise in the intracellular Ca2+ concentration ([Ca2+]i) of ASM cells is crucial for modulating the intensity and length of the ASM contraction. Because this rapid increase in [Ca2+]i largely depends on the balance between Ca2+ released from intracellular Ca2+ stores and extracellular Ca2+ entry, exploring the mechanisms mediating Ca2+ transport is critical for understanding ASM contractility and the pathogenesis of bronchial contraction disorders. Transient receptor potential vanilloid 4 (TRPV4) is a highly Ca2+-permeable non-selective cation channel that mediates Ca2+ influx to increase [Ca2+]i, which then directly or indirectly regulates the contraction and relaxation of ASM. The [Ca2+]i returns to basal levels through several uptake and extrusion pumps, such as the sarco(endo)plasmic reticulum Ca2+ ATPase and inositol 1,4,5-trisphosphate receptors (IP3Rs), the plasmalemmal Ca2+ ATPase, and the plasma membrane Na+/Ca2+ exchanger (NCX). Thus, to further understand ASM tension regulation in normal and diseased tissue, the present study examined whether an interaction exists among TRPV4, IP3Rs, and NCX. The TRPV4-specific and potent agonist GSK1016790A increased [Ca2+]i in mouse ASM cells, an effect that was completely blocked by the TRPV4-specific antagonist HC067047. However, GSK1016790A induced relaxation in mouse tracheal rings precontracted with carbachol in vitro. To determine the mechanism underlying this TRPV4-induced relaxation of ASM, we blocked specific downstream molecules. We found that the GSK1016790A-induced relaxation was abolished by the NCX inhibitors KB-R7943 and LiCl but not by specific inhibitors of the Ca2+-activated large-, intermediate-, or small-conductance K+ channels (BKCa, IK, and SK3, respectively). The results of co-immunoprecipitation (co-IP) assays showed an interaction of TRPV4 and IP3R1 with NCXs. Taken together, these findings support a physical and functional interaction of TRPV4 and IP3R1 with NCXs as a novel TRPV4-mediated Ca2+ signaling mechanism and suggest a potential target for regulation of ASM tension and treatment of respiratory diseases, especially tracheal spasm.
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Atherosclerosis, the leading cause of cardiovascular diseases in the world, is a chronic inflammatory disorder characterized by the dysfunction of arteries. Oleanolic acid (OA) is a bioactive nature product which exists in various plants and herbs. Previous studies have demonstrated that OA was involved in numerous of biological processes, including atherosclerosis. However, the exact mechanisms of the anti-atherosclerosis effects of OA remain unknown. Here, in our study, we analyzed the effects and possible underlying mechanisms of OA in atherosclerosis depending a cell model and an animal model of atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL, 100 µg/mL) for 24 h to establish an atherosclerotic cell model. New Zealand white (NZW) rabbits were fed with high-fat (HF) diets for three months to establish an atherosclerotic animal model. Then, cell viability and expression of cytokines (ANG, NO, eNOS, IL-1ß, TNF-α, and IL-6) were measured with CCK-8 assay and ELISA kits, cell apoptosis and cell cycle distribution were analyzed by flow cytometry in the atherosclerotic cell model. Results showed that ox-LDL induced effects of anti-proliferation, cytokines alterations, and cell apoptosis were abolished by the application of OA or Ang (1-7). Further study indicated that OA increased the expression of ANG by upregulating the FXR expression in the ox-LDL induced HUVECs arthrosclerosis model. And the in vivo experiment in the HF diet induced animal model suggested that OA may inhibit the development of atherosclerosis. The atherosclerosis of aortas was assessed by Hematoxylin Eosin (HE), Oil Red O and Picrosirius Red staining; the expression levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were determined by the fully automatic biochemical analyzer, in the atherosclerotic animal model. All the results showed that OA treatment improved the cell viability in the cell model, inhibited the atherosclerosis development in the animal model. OA play as an anti-atherosclerosis agent in both the cell model and animal model by upregulating the production of Angiotensin (Ang)-(1-7) through FXR.
Assuntos
Angiotensinas/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Ácido Oleanólico/uso terapêutico , Substâncias Protetoras/uso terapêutico , Receptores Citoplasmáticos e Nucleares/metabolismo , Regulação para Cima , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/patologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas LDL/metabolismo , Ácido Oleanólico/farmacologia , Substâncias Protetoras/farmacologia , Coelhos , Regulação para Cima/efeitos dos fármacosRESUMO
The safety of measles vaccination is of great interest and importance to public health practice and the general society. We have analyzed the adverse events following immunization (AEFIs) of currently used measles-containing vaccines (including live attenuated measles vaccine, live attenuated measles and rubella combined vaccine, live attenuated measles and mumps combined vaccine, live attenuated Measles, Mumps and Rubella Combined Vaccine) in Anhui Province, China. From 2009 to 2014, 9.9 million doses of measles-containing vaccines were administrated and 1893 AEFIs were found (191.4 per million doses), of which, 33 serious AEFIs (3.3 per million vaccine doses) were reported. 59.4% (1124 cases) were male cases, and 85.1% (1611 cases) occurred in persons aged < 1 year. 93.3% (1766 cases) occurred at the first dose of vaccination and 95.9% (1815 cases) were found within 3 days after vaccination. This study presents up-to-date data and suggests that the measles-containing vaccines used in Anhui Province of China are safe.
Assuntos
Imunização/métodos , Vacina contra Sarampo/imunologia , Sarampo/imunologia , Vigilância de Produtos Comercializados/métodos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Anafilaxia/etiologia , Povo Asiático , China , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etnologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Encefalite/etiologia , Humanos , Imunização/efeitos adversos , Sarampo/etnologia , Sarampo/prevenção & controle , Vacina contra Sarampo/administração & dosagem , Vacina contra Sarampo/normas , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/normas , Vigilância de Produtos Comercializados/normas , Convulsões/etiologia , Trombocitopenia/etiologia , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/normas , Vacinas Combinadas/imunologia , Vacinas Combinadas/normasRESUMO
Anflu® is a seasonal trivalent inactivated split-virion influenza vaccine manufactured by Sinovac Biotech Co., Ltd. The objectives of this study were to evaluate the safety of Anflu® (2013-14 formulation: H1N1, H3N2 and BYAM) in infants and adults and its immunogenicity and cross-reactivity against mismatched influenza B lineage and avian influenza A(H7N9) viruses (hereafter BVIC and H7N9, respectively) in adults. In this phase IV open label trial, infants 6-35 months old (n=61) each received two injections with 28 days apart; adults 18-60 yrs old (n=60) and elderly >60 yrs old (n=61) each received one injection. Information of adverse events was collected through safety observation and follow-up visits. Pre- and post-immune blood samples (day 0 and 21) were collected from subjects ≥18 yrs old to detect hemagglutination inhibition antibody titers and calculate seroprotection rates (SPRs) and seroconversion rates (SCRs). The overall adverse reaction incidence was 1.6% (3/182), and no serious adverse event was reported during the study period. For subjects ≥18 yrs old, the SCRs, SPRs, and the geometric mean titers (GMTs) met the European criteria for all three strains. In addition, the point estimations of SCR, SPR and GMT for BVIC also met the European criteria. Six subjects were seroconverted against H7N9; however the serological results did not meet the European criteria. In conclusion, the results showed a satisfactory safety and immunogenicity profile of Anflu® and cross-reactivity against BVIC, but did not demonstrate cross-reactivity against H7N9 (Clinicaltrials.gov ID: NCT02269852).
Assuntos
Imunogenicidade da Vacina , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Adolescente , Adulto , Anticorpos Antivirais/sangue , Pré-Escolar , Reações Cruzadas , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Incidência , Lactente , Subtipo H7N9 do Vírus da Influenza A/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Estações do Ano , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Adulto JovemRESUMO
Diabetes mellitus is a chronic disease that is associated with depression. Also, depression is common in adults with type 2 diabetes mellitus (T2DM). Translocator protein (18kDa) (TSPO) and allopregnanolone play an important role in the depression treatment. However, few studies have evaluated TSPO and allopregnanolone in the treatment of depression in T2DM. AC-5216, a ligand for TSPO, produces anxiolytic- and antidepressant-like effects in animal models. The present study aimed to explore antidepressant-like effects of AC-5216 on diabetic rats. Following the development of diabetic model induced by high fat diet (HFD) feeding and streptozotocin (STZ), AC-5216 (0.3 and 1 mg/kg, i.g.) elicited the antidepressant-like effects in behavioral tests while these activities were blocked by TSPO antagonist PK11195 (3 mg/kg, i.p.). The levels of allopregnanolone in the prefrontal cortex and hippocampus were increased by AC-5216 (0.3 and 1 mg/kg, i.g.), which was antagonized by PK11195 (3 mg/kg, i.p.). The increased plasma glucose (PG) and decreased insulin (INS) in HFD-STZ rats were reversed by AC-5216 (0.3 and 1 mg/kg, i.g.). This study indicates that the antidepressant-like effects of AC-5216 on HFD-STZ rats, suggesting that TSPO may represent a novel therapeutic target for depression in T2DM.
Assuntos
Proteínas de Transporte/metabolismo , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Purinas/farmacologia , Receptores de GABA-A/metabolismo , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/química , Depressão/etiologia , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Isoquinolinas/farmacologia , Ligantes , Masculino , Peso Molecular , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pregnanolona/metabolismo , Ratos Sprague-Dawley , Receptores de GABA-A/químicaRESUMO
Post-traumatic stress disorder (PTSD) is a severe psychiatric condition defined as a "trauma and stress-related disorder". Dampened allopregnanolone biosynthesis has been implicated as a possible contributor to PTSD aetiology. Free and Easy Wanderer Plus (FEWP) is a traditional Chinese medicine previously shown to be effective in PTSD treatment. However, little is known about the role of allopregnanolone in the anti-PTSD effects of FEWP. To evaluate this, the single prolonged stress (SPS) model was used in the present study. SPS-induced rats were administered FEWP (at doses of 2.5, 5.0 and 10.0 mg/kg, p.o.) after induction of SPS from days 2 through 15. After exposure to SPS, behavioral assessments were determined, including the open-field test, the contextual fear paradigm, and the elevated plus-maze test. The experimental model rats were decapitated at the end of the behavioral tests and the level of allopregnanolone in the prefrontal cortex, hippocampus and amygdala was measured by enzyme linked immunosorbent assay (ELISA). The behavioral deficits of the SPS-induced rats were significantly reversed by FEWP (at doses of 5.0 and 10.0 mg/kg, p.o.). The level of allopregnanolone was increased by administration of FEWP. In summary, this study indicated that the anti-PTSD effects of FEWP were associated with allopregnanolone biosynthesis.
Assuntos
Comportamento Animal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Pregnanolona/biossíntese , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Medo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologiaRESUMO
The translocator protein (18 kDa) (TSPO) plays an important role in stress-related disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD), caused by neurosteroids (e.g. allopregnanolone). The present study sought to evaluate the significance of TSPO in anxiolytic and antidepressant effects induced by midazolam. The animals were administrated midazolam (0.25, 0.5 and 1 mg/kg, i.p.) and subjected to behavioral tests, including Vogel-type conflict test, elevated plus-maze test, forced swimming test. Midazolam produced anxiolytic- and antidepressant-like effects Vogel-type conflict test (1 mg/kg, i.p.), elevated plus-maze test (0.5 and 1 mg/kg, i.p.), and forced swimming test (0.5 and 1 mg/kg, i.p.). These effects of Midazolam were totally blocked by the TSPO antagonist PK11195 (3 mg/kg, i.p.). To evaluate the role of allopregnanolone in the anxiolytic- and antidepressant-like effects of midazolam, the animals were decapitated at the end of the behavioral tests. The allopregnanolone levels of the prefrontal cortex and hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The allopregnanolone level of the prefrontal cortex and hippocampus was increased by midazolam (0.5, 1 mg/kg, i.p.) and the increase was reversed by PK11195 (3 mg/kg, i.p.). Overall, the results indicated that the anxiolytic- and antidepressant-like effects of midazolam were mediated by TSPO, via stimulation of allopregnanolone biosynthesis.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Proteínas de Transporte/fisiologia , Midazolam/farmacologia , Receptores de GABA-A/fisiologia , Animais , Ansiolíticos/administração & dosagem , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Isoquinolinas/farmacologia , Masculino , Midazolam/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pregnanolona/metabolismo , RatosRESUMO
Anxiety disorders are the serious and burdensome psychiatric illnesses, which are closely correlated with allopregnanolone. The down-regulation of allopregnanolone biosynthesis has been implicated as the possible contributor to the aetiology of anxiety disorders. Free and easy wanderer plus (FEWP) is a well-known traditional Chinese medicine that had been shown to be effective in various mood disorders. The purpose of the present study was to evaluate the anxiolytic-like effect of FEWP and its association with the level of allopregnanolone in the brain. The animal behavioral tests were processed by the acute FEWP (2.5, 5 and 10mg/kg, p.o.) treatment. It had been shown that FEWP produced anxiolytic-like effects in behavioral models, including novelty suppressed feeding (5, 10mg/kg, p.o.), Vogel-type conflict test (10mg/kg, p.o.), elevated plus-maze test (5, 10mg/kg, p.o.). The animals were decapitated after the end of the behavioral tests and measured the allopregnanolone level of the prefrontal cortex and hippocampus by enzyme-linked immunosorbent assay (ELISA). The allopregnanolone level of the prefrontal cortex and hippocampus was increased by administration of FEWP (5, 10mg/kg, p.o.). Overall, these results indicated that FEWP exerts anxiolytic-like effects that were associated with the stiumlation of the allopregnanolone biosynthesis.
Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Pregnanolona/biossíntese , Animais , Ansiedade/psicologia , Conflito Psicológico , Comportamento Alimentar/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos ICR , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacosRESUMO
In this study, the scope of CFRP cables in cable-stayed bridges is studied by establishing a numerical model of a 1400-m span of the same. The mechanical properties and characteristics of CFRP stay cables and of a cable-stayed bridge with CFRP cables are here subjected to comprehensive analysis. The anomalies in the damping properties of free vibration, nonlinear parametric vibration and wind fluctuating vibration between steel cables and CFRP cables are determined. The structural stiffness, wind resistance and traffic vibration of the cable-stayed bridge with CFRP cables are also analyzed. It was found that the static performances of a cable-stayed bridge with CFRP cables and steel cables are basically the same. The natural frequencies of CFRP cables do not coincide with the major natural frequencies of the cable-stayed bridge, so the likelihood of CFRP cable-bridge coupling vibration is minuscule. For CFRP cables, the response amplitudes of both parametric vibration and wind fluctuating vibration are smaller than those of steel cables. It can be concluded from the research that the use of CFRP cables does not change the dynamic characteristics of the vehicle-bridge coupling vibration. Therefore, they can be used in long-span cable-stayed bridges with an excellent mechanical performance.
RESUMO
OBJECTIVE: To introduce exponent curve model methods in the study of the hepatitis B vaccine antibody level. METHODS: After the China made vaccine of hepatitis B DNA recombinant yeast derived vaccine (YDV) had been carried out for 5 years, data on the anti-HBsAg's titer were used to construct an exponent curve model. When the vaccination program had been carried out for 8 years, the predicating results of the model were further tested by observed number. RESULTS: The exponent curve model was Y = 165.67 exp (-0.019X) and the R(2) was 0.98. After 8 years, the practical observed number became 35 mIU/ml, and the predicating result of the model was 27 mIU/ml, 8 mIU/ml lower than the observed number. When the vaccine had been carried out for 12 years, the predicating results of the model became 10.74 mIU/ml, still higher than 10 mIU/ml but was still in the effective range. CONCLUSION: An exponent curve model could be constructed, as long as the data of the antibody's titer was in accordance with the tendency of exponent curve. The model could be used to predict the persistence lever of vaccine antibody under certain conditions. The results showed that after 8 years, the predicting results of the model were reliably lower than the observed number.