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Objective :To explore therapeutic effect of upper and lower extremity active and passive rehabilitation treadmill combined occupational therapy on patients with chronic obstructive pulmonary disease (COPD) during sta—ble period .Methods : A total of 92 COPD patients were randomly and equally divided into occupational therapy group and treadmill + occupational therapy group .Both groups received routine nursing care ,treatment and com—prehensive rehabilitation therapy ,occupational therapy group also received occupational therapy ,while treadmill +occupational therapy group received upper and lower extremity active and passive treadmill training based on occupa—tional therapy group .After eight—week treatment ,pulmonary function ,exercise function ,daily living capacity and quality of life were analyzed and compared between two groups .Results : Compared with before treatment ,after treatment ,there were significant improvements in pulmonary function ,exercise function ,score of activity of daily living scale (ADL) and quality of life (SGRQ) in two groups , P＜ 0. 05 or ＜ 0. 01. Compared with occupational therapy group after treatment ,there was significant reduction in modified Medical Research Council dyspnea scale (mMRC) [ (2. 7 ± 0. 4) grade vs.(2. 4 ± 0.6) grade] ,and significant rise in 6min walking distance [ (291. 4 ± 28. 9) m vs.(307. 8 ± 30. 4) m] and ADL score [(56.0 ± 11.4) scores vs .(62. 0 ± 10.9) scores] in treadmill + occupation—al therapy group ( P＜0.05 or ＜0. 01) ,but there were no significant differences in pulmonary function indexes and quality of life (SGRQ) between two groups , P＞0.05 all.Conclusion : Upper and lower extremity active and passive treadmill training combined occupational therapy can significantly improve pulmonary function and exercise function and daily living capacity in patients with chronic obstructive pulmonary disease .
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OBJECTIVE To investigate the protective effect of sGC003,a novel agonist of soluble guanylate cyclase,on endothelin-1(ET-1)-induced cardiomyocyte hypertrophy. METHODS Cardiomy?ocytes were isolated from neonatal Sprague-Dawley rats using serial enzymatic digestion and then incubated with ET-1 10 nmol·L-1 in the absence or presence of sGC003 0.01,0.1 and 1.0μmol·L-1. Hyper?trophic responses including the cardiomyocyte area(Image-Pro Plus 6.0),the expression of atrial natri?uretic peptide gene(ANP)mRNA(RT-PCR method)and total protein content(BCA method)were detect?ed. RESULTS After 48 h stimulation with ET-1 10 nmol·L-1,the cardiomyocyte area increased by 80%(P<0.01),the total protein content increased by 120%(P<0.01) and the expression of ANP mRNA up-regulated by 140%(P<0.01). sGC003 0.01,0.1 and 1.0μmol · L-1 elicited antihypertrophic actions, including inhibition of ET-1-mediated increase in the cardiomyocyte area(P<0.01),raised total protein content(P<0.05)and upregulation of ANP mRNA(P<0.05). CONCLUSION sGC003 has protective,car?diomyocyte-selective antihypertrophic effects in vitro.
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OBJECTIVE To establish a new cell line that can stably express humanα2A-adrenoceptor (α2A- AR). METHODS Recombinant plasmid of α2A- AR with hygromycin B (Hygro) resistance (pcDNA3.1/Hygro-HA-α2A-AR)was stably transfected into Chinese hamster ovary(CHO)cells which had expressed protein kinase A catalytic subunits(PKAcat) with labeling of enhanced green fluorescent protein(EGFP)by a Lipofectamine based method. A single positive clone expressingα2A-AR was selected through cultivation in the presence of 200 mg · L-1 hygromycin B followed by PKA redistribution assay. The transcriptional expression ofα2A-AR was detected by quantitative real-time PCR(qRT-PCR). Time-resolved fluorescence resonance energy transfer immunoassay was used to identify the function of inhibiting cAMP accumulation of α2A-AR. RESULTS The CHO-PKAcat-α2A-AR cell line No.7 exhibited stable response in PKA redistribution assay. qRT-PCR analysis demonstrated that the high expression ofα2A-AR in the cell line remained stable after a few generations compared with CHO-PKAcat-EGFP cells (P<0.01). The cAMP accumulation caused by forskolin was significantly inhibited by α2A-AR agonist in CHO-PKAcat-α2A-AR cells(P<0.01). CONCLUSION CHO-PKAcat-α2A-AR cell line is constructed successfully, which provides an effective model for drug screening and studies of mechanisms.
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OBJECTIVE To analyze impulsive-like behaviors of SD rats induced by pramipexole in Y-maze avoidance tasks. METHODS Behaviors of SD rats in Y-maze avoidance tasks were recorded with a camera and analyzed by Noldus Etho Vision XT8 software after acute subcutaneous injection of pramipexole(0.1,1 and 10 mg · kg-1),including right reaction numbers of 20 consecutive avoidance tasks,shuttle number of times between the three arms of Y-maze, distance covered in Y-maze and time spent in safe arms during 20 consecutive avoidance tasks. Then,the prepulse inhibition(PPI)of the startle reflex test was used to assess the effect of pramipexole on sensorimotor gating (SG). Effects of pramipexole on the dialyzed content of monoamine neurotransmitter and its metabolites in the striatum and amygdala of SD rats were measured by microdialysis in vivo. RESULTS Compared with normal control group,the rats of pramipexole group showed a significant increase in the shuttle number of times and distance covered in Y-maze between Y-maze avoidance tasks(P<0.01),but a statistically significant decrease in the time spent in safe arms(P<0.01),while the number of right reactions in Y-maze avoidance tasks was not changed. Such premature responses were quite similar to certain impulsive-compulsive behaviors in rodent models,such as five-choice serial reaction time tasks. In the PPI test,pramipexole displayed an impairing effect on SG(P<0.01). The microdialysis results showed that there was an increase of dopamine and 5-hydroxytryptamine in the striatum of pramipexole group, but not statistically significant. Monoamine neurotransmitters and their metabolites were not significantly changed in the amygdala. CONCLUSION Pramipexole can induce impulsive-compulsive behaviors in Y-maze avoidance tasks,which might be attributed to impaired SG.
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Objective To investigate the effects of inhibiting vesicular glutamate transporters (VGLUT) on pain behaviors in animals. Methods The latency in hot plate test, number of writhes in acetic acid and licking time in formeldehyde solution (formalin) tests were recorded to determine the analgesic effect of Chicago sky blue 6B (CSB6B), a selective VGLUT inhibitor. Results Intraperitoneal administration of CSB6B did not affect the acute thermal pain responses in hot plate test. In acetic acid writhing, compared with control group (26.50 ±2.97), CSB6B (2.5 mg/kg, ip) significantly attenuated the acetic acid-induced writhing (8.22±1.90) 30 min after administration (P<0.01);CSB6B (2.5 mg/kg, ip) significantly reduced the acetic acid-induced writhing(9.60±1.84) 60 min after administration(P<0.01). In Formalin test, compared with control group(139.40±21.02), CSB6B (0.5 mg/kg, ip) significantly reduced the licking time(75.10±19.45) 30 min after administration(P<0.05) during the second phase, but not during the first phases. CSB6B(ip) did not affect the licking time 2 h after administration during the first and second phases. Conclusion Inhibition of VGLUTs activity is sufficient to attenuate the inflammatory pain and this finding suggests that VGLUT participate in regulation of inflammatory pain and be a novel therapeutic strategy for treatment of pain.
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Aims To establish several behavioral paradigms to characterize the psychotropic effects of hallucinogens which ze-brafish was utilized as a model animal, and then to investigate the effects of potent hallucinogenic drugs on these models. Methods With the video record and track system, the behavior was recorded and quantified automatically. In the experiments, the bottom dwelling test, social behavior and mirror test were performed to test the hallucinogenic effects of drugs. Metham-phetamine (METH, 2 mg·L-1) and ketamine (20 mg·L-1) were selected as experimental challenges. The 30 min pre-treat-ment time was chosen based on our prior experience in zebrafish models. Results Compared to the normal group, in dwelling test, acute exposure of zebrafish to METH and ketamine de-creased transitions significantly, and in mirror reflection test, the drug-treated fish changed the preference for mirror zone, and ex-hibited aggressive for their mirror images. The pretreatment of METH and ketamine significantly reduced the contact durations, and the ketamine inhibited the contact frequency each other, the results indicated that the social interaction of zebrafish was im-paired. Conclusion The results confirm high sensitivity of ze-brafish models to hallucinogenic compounds with complex behav-ioral and physiological effects.
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Vesicular glutamate transporter(VGLUT), located on the vesicular membrane, is a highly specific marker of glut-amatergic neurons. VGLUT selectively transports glutamate in the cytoplasm into vesicles. VGLUT1, VGLUT2 and VGLUT3 are three subtypes of VGLUT. The VGLUT can influence the glutamatergic synaptic transmission through mediating sequestration, storage and release of glutamate. The number and activity of VGLUT can change the level of glutamate in synapse cleft through mediating sequestration,storage and release of glutamate,then influence the glutamatergic synaptic transmission. To improve this pathological situation and maintain glutamate at the physiologically relevant concentration, VGLUT inhibition is required. Several classes of competitive VGLUT inhibitors have emerged including azo dyes, substituted quinolines, fatty acids and alkaloids. This article provides a brief review on the structure and function of these potential VGLUT inhibitors.
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Objective To investigate rats reared in social isolation as a model of behavioral symptoms of neurodevelop-mental psychiatric disorders including schizophrenia.Methods Male rat pups were housed in individual cages from post-weaning to adulthood.Locomotor activity detection, Morris water maze test and social interaction test were performed. Results Compared with controls, the social isolation-reared rats got more body mass, showed locomotor hyperactivity and increased social interaction, but significant spatial learning changes were not observed in Morris water maze test.Conclu-sion Exposing rats to social isolation can profoundly affect behavior in adulthood, which can be used to build animal mod-els of neurodevelopmental psychiatric disorders including schizophrenia.
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Objective: To explore value of 6-minute walking in rehabilitation therapy of patients with chronic heart failure (CHF). Methods: A total of 78 CHF patients were selected from department of geriatrics of our hospital. They were randomly and equally divided into 6min walking test (6MWT) group (received 6-min walking training based on routine treatment, twice/d) and routine treatment group. After six weeks, 6min walking distance (6MWD), heart rate and left ventricular ejection fraction (LVEF) were compared between two groups before and after treatment. Results: After six weeks, there were significant improvements in related indexes in both groups, P<0.05 all; compared with routine treatment group, there were significant increase in 6MWD [(307.6±39.3) m vs. (503.4±44.4) m] and LVEF [(45.3±17.9) % vs. (58.7±19.2) %], and significant decrease in heart rate of recovery period after 6MWT [(73.3±2.9) times/min vs. (65.7±2.1) times/min] in 6MWT group, P<0.05 all. Conclusion: Six-minute walking can significantly improve symptoms of heart failure and enhance exercise tolerance, and it possesses important value for recovery of heart function in these patients.
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Schizophrenia, described as the worst disease affecting mankind, is a severe and disabling mental disorder. Schizophrenia is characterized by complicated symptoms and still lacks a diagnostic neuropathology, so developing schizophrenia animal models which have quantifiable measures tested in a similar fashion in both humans and animals will play a key role in new therapeutic approaches. According to the symptoms of cognitive impairment and emotional disorder, the N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 was applied to induce schizophrenia-like behavior in mice. Locomotor activity and prepulse inhibition (PPI) were selected as indices and the effect of clozapine was also investigated in this model. The results showed that compared with the normal group, MK-801-treated mice exhibited significantly increased locomotor activity and impaired PPI, and pre-exposure to clozapine could ameliorate the abnormality and make it back to normal level. These findings suggest that the model we established could be a useful tool for antipsychotic drug screening.
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This study investigates whether kappa-opioid receptor and ORL1 receptor may interact to form a heterodimer. In immunofluorescence and co-immunoprecipitation experiments, differentially epitope-tagged receptors, colocalization and heterodimerization of kappa-opioid receptor and ORL1 receptor were used and examined in primary culturing rat neurons, Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. The results show that fluorescence of both kappa-opioid receptor and ORL1 receptor were overlapping in primary culturing hippocampal and cortical neurons. Similarly in co-expressing CHO or HEK293 cells, HA-KOR and Myc-ORL1 were almost exclusively confined to the membranes, revealing extensive colocalization. When Flag-KOR and Myc-ORL1 were co-expressing in CHO cells, heterodimerization was identified to have the ability to co-immunoprecipitate ORL1-receptors with kappa-opioid receptor and vice versa. In the current study, further evidence was provided for the direct interaction of two subtypes of opioid receptors, kappa-opioid receptor and ORL1-receptor, to form the heterodimerization. The finding represents the novel pharmacological mechanism for modulation of opioid receptor function as well as diversity of G protein-coupled receptors.
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Human rhinoviruses (HRVs) are the causative pathogens in more than half of viral upper respiratory tract infections. Currently, no antiviral agents that are active against HRVs are available for clinical use. Because only higher primates are susceptible to HRVs, the screening of new drug is most commonly based on the cell line model. In this study, isolated rabbit airway smooth muscles (ASM) tissue model has been established, and the airway responsiveness with different treatment has been examined. Relative to control tissues, the maximal constrictor (Tmax) response to ACh increased significantly 150% in ASM inoculated with HRV, and relaxation to isoproterenol has been attenuated to 63%. And the abnormal responsiveness can be inhibited in presence of pretreatment with several new compounds which have been exhibited effective anti-HRV activity on cell lines. The results demonstrate that the established ASM model will be applied to screening the anti-HRVs drugs.
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Aim To evaluate the antinociception of ω-SO3,a novel Omega-superfamily conotoxin,in rat formalin test.Methods Potency and duration of ω-SO3 antinociception compared with morphine were investigated in rat formalin test after acute intrathecal administration.Development of tolerance or cross tolerance to analgesia of ω-SO3 and morphine was tested in formalin test after chronic intrathecal administration.Locomotor activity of rat after acute intrathecal administration was tested to evaluate possible central side effects.Results In rat formalin test after intrathecal bolus injection,ω-SO3 produced dose-and time-dependent antinociception by suppressing acute(ED_(50),1.79 ng·g~(-1))and tonic phases(ED_(50),0.41 ng·g~(-1)),which was approximately 10-fold potency and twice longer-acting of morphine in blocking tonic phase responses.After repeated intrathecal injections twice daily for 5 consecutive days,ω-SO3 produced analgesia without loss of potency whereas morphine produced analgesia tolerance in rat formalin test;further,ω-SO3 still produced potent analgesia in morphine-tolerant rats.No changes in motor function were seen in rats receiving above antinociceptive doses.Conclusion sNovel ω-SO3 produces potent and long-acting spinal antinociception without observable motor dysfunction and after chronic intrathecal administration.ω-SO3 produces neither tolerance nor cross-tolerance to morphine analgesia.
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AIM To evaluate bioavailability, biocompa- tibility and biodegradability of an injectable microsphere sustained release preparation of naltrexone(NTX) in 4 dogs. METHODS Pharmacokinetic data of NTX and remained NTX in microspheres in injection site were studied using high performance liquid chromatography(HPLC)-electrochemical detection with naloxone(NLX) as internal standard. Biocompatibility of the microspheres was assayed by histological examination. RESULTSPharmacokinetics of NTX after an intramuscular dose of 0.5 or 1.0 mg*kg-1 NTX indicated a plasma clearance range of 0.66 to 0.73 L*min-1 and a t1/2β range of 60.0 to 67.2 min. After a 1-week washout period without medication, NTX microspheres injection period about 4 weeks followed. After injection of 1.0 g of microspheres containing (296.5±2.1)mg of NTX, mean blood concentrations of NTX exceeded 1 μg*L-1 for 26-28 d, and cmax per dose (mg*kg-1) was only 1% of that after NTX dosing. It was estimated that approximately (93.0±4.1)% of the administered dose was absorbed after microspheres injection in 4 dogs. There were no serious adverse effects other than light tissue irritation. CONCLUSIONThis NTX microspheres preparation provides a safe, complete and sustained release of the drug for about one month.
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The addiction potential of abused drugs can be different although their pharmacodynamics characteristics are quite similar.In this article, the influence of pharmacokinetics characteristics of a drug on its addiction potential was discussed. A more rapid rate of onset had been shown to result in greater propensity to addiction. Although prolonging the duration of action could reduce the responding rate in animal self-administration experiments, it might not influence the strength of a drug. Understanding the relationship between the pharmacokinetics characteristics and addiction potential may contribute to the rational use and development of these kinds of drugs.
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Aim To investage the effects of ?、?、?-receptor on hyperlocomotor and analgesia in mice.Methods Locomotor activity experiment and hot-plate pain experiment were measured.Results Oxycodone dose-dependently enhanced locomotor response in mice.Naloxone,a unselective opioid receptor antagonists and naltrindole(?-selective opioid receptor antagonist)could attenuate the increase of locomotor acitivity induced by oxycodone,but naloxonazine,a ?-receptor antagonist had no such effect.?-receptor antagonist nor-Binltorphimine increased hyperlocomotion induced by oxycodone.In antinociceptive experiment,naloxonazine and naltrindole could not attenuate the that of oxycodone,but nor-Binaltorphimine could attenuate the antinociceptive effects of oxycodone.Conclusion Oxycodone-hyperlocomotor is probably mediated by ? opioid receptor,and antinocieptive effects of oxycodone is probably mediated by ? opioid receptor.
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ORL1(Opioid receptor-like 1)receptor and its endogenous ligand,nociceptin/orphanin FQ,belong to G protein-coupled receptor super family with multiple functions.ORL1 is not only endowed with anti-opioid properties(it suppresses opioid-mediated analgesia),but also involved in cognitive processes,emotion,cardioprotection and neuroendocrine secretion.The research on ORL1 and N/OFQ will certainly be helpful to develop new therapeutic drugs and to find drug targets of clinical application.
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Cardiac hypertrophy is a major adaptational mechanism in stresses such as pressure overload and neurohumoral stimulation.As powerful vasoconstrictor peptides in cardiovascular system,especially the vascular endothelium,smooth muscle cells and cardiocyte,ETs play important physiological roles in the regulation of normal cardiovascular function.Excessive generation of ETs in local cardiac muscle has been linked to myocardial hypertrophy.Endothelin-1(ET-1) in cardiac muscle exerts its actions in the development of myocardial hypertrophy through binding to specific receptors and interacting with other vasoactive substance of local tissues.ET-1 can induce the hypertrophy for cardiocytes and the proliferation for cardiac fibroblasts by ETA.ETB receptors are implicated both in initiating and maintaining myocardial hypertrophy.As a new target of drug,ET receptors have become the research focus,and great progress has been made on the development of the ET antagonists.
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Aim Series of compounds,which were considered to be the antagonists of ET-1 receptor,were synthesized by Beijing Institute of Pharmacology and Toxicology.The biological activity of these compounds was screened and some active compounds were selected for further pharmacological characterization on pulmonary hypertension.Methods Radioligand binding assay was performed to study the binding affinity of compounds for ETA and ETB receptors.The biological activity of compounds was evaluated in isolated rat aortic ring and in systemic arterial pressure(SAP)of anesthetized rat experiments.In addition,hypotensive effect of compounds was investigated on monocrotaline induced pulmonary hypertension in rats.Results Compounds bind to ETA receptor had over 10 000 fold higher affinity than to ETB receptor.Contraction induced by ET-1 in isolated rat aortic ring was inhibited by compounds,and 1 ?mol?L-1 ETP-508 shifted the cumulative concentration-contraction response curve to ET-1 to right with no change in the maximal response.In vivo,the increase in SAP induced by ET-1 〔3.7 ?g?(0.5 ml)-1?kg-1〕 was inhibited by 2 mg?kg-1 compounds by intravenous infusion.Furthermore,BQ-485 and ETP-508 by intravenous infusion(0.4 mg?h-1)significantly inhibited 80 mg?kg-1(sc)monocrotaline induced pulmonary hypertension in rats.Conclusions These results indicate that ETP-508 and BQ-485 are highly selective ETA receptor antagonists and significantly inhibite monocrotaline induced pulmonary hypertension in rats.
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The C-terminal tail of opioid receptor is important for opioid receptor phosphorylation,desensitization and internalization after opioid agonists treatment.The C-terminal point mutant and truncated mutant of amino acid residues of ?opioid receptors such as T394A,T383A,T357A,S355A affect the function of the opioid receptor obviously.The identical results could be seen in the C-terminal point mutant S363A of ?opioid receptor and S369A of ?opioid receptor.It is well known that opioid receptor requires interaction with other proteins for function,regulation and trafficking.Although proteins such as PPL,FilaminA,PLD2,PKCI,GASP and EBP50/NHERF have been identified to interact with C-terminals of opioid receptors,the role of interaction of these proteins with opioid receptor in the dependence,tolerance and addiction of opioids is dubious.Therefore,looking for the proteins specifically interacting with the C-terminals of opioid receptor may be important to understand the mechanism of opioids addiction.