The primary object of this fundamental research was to survey the synergistic cardiovascular effects of iptakalim, a novel ATP-sensitive potassium channel (K(ATP)) opener, and clinical first-line antihypertensive drugs, such as calcium antagonists, thiazide diuretics and β receptor blockers by a 2 x 2 factorial-design experiment. It would provide a theoretical basis for the development of new combined antihypertensive therapy program after iptakalim is applied to the clinic. Amlodipine besylate, hydrochlorothiazide and propranolol were chosen as clinical first-line antihypertensive drugs. Blood pressure, heart rate (HR) and cardiac functions were observed in anesthetized normal rats by an eight-channel physiological recorder. The results showed that iptakalim monotherapy in a low dose could produce significant antihypertensive effect. There was no interaction between iptakalim and amlodipine on the maximal changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), the left ventricular systolic pressure (LVSP), and the left ventricular end-diastolic pressure (LVEDP) (P > 0.05). However, the effects of combination iptakalim/amlodipine on the maximal changes of SBP, DBP, MABP, LVSP and LVEDP were more obvious than those of iptakalim or amlodipine monotherapy. And there was strong positive interaction between iptakalim and amlodipine on the maximal changes of HR (P>0.05). According to the maximal changes of DBP, MABP, LVSP and LVEDP (P < 0.05) of combination iptakalim with hydrochlorothiazide, there was strong positive interaction between them. But there was no interaction between iptakalim and hydrochlorothiazide on the maximal drop of SBP and HR (P > 0.05). According to the maximal drops of DBP, MABP of combination iptakalim with propranolol, there was strong positive interaction between them (P < 0.05). But there was no interaction between iptakalim and propranolol on the maximal changes of SBP, LVSP, LVEDP and HR (P > 0.05). In conclusion, it was the first time to study the effects of amlodipine, hydrochlorothiazide or propranolol, which had different mechanisms of action from iptakalim, on cardiovascular effects of iptakalim in anesthetized normal rats. This study proved that the combination of iptakalim with hydrochlorothiazide or propranolol respectively had significant synergism on lowering blood pressure, while the combination of iptakalim/amlodipine had additive action on lowering blood pressure. Meanwhile the antihypertensive effect was explicit, stable and long-lasting. Iptakalim thus appears suitable for the clinical treatment of hypertensive people who need two or more kinds of antihypertensive agents.
Amlodipine ; pharmacology ; Animals ; Antihypertensive Agents ; pharmacology ; Blood Pressure ; drug effects ; Drug Synergism ; Heart Rate ; Hydrochlorothiazide ; pharmacology ; Hypertension ; Propranolol ; pharmacology ; Propylamines ; pharmacology ; Rats

Adult ; Female ; Humans ; Lupus Erythematosus, Systemic ; enzymology ; Male ; Middle Aged ; Peroxidase ; blood

OBJECTIVETo assess the association between brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism and clinical characteristics of first episode schizophrenia in a Chinese Han population.

METHODSGenotyping of BDNF Val66Met polymorphism was carried out for 135 schizophrenic patients and 483 healthy controls with TaqMan probe technology. The patients' psychotic symptoms were assessed using the positive and negative syndrome scale (PANSS).

RESULTSA significant difference was found in genotype distribution and allelic frequency of the Val66Met polymorphism between the two groups (P< 0.01). In patients, Met homozygotes had a significantly higher score in anxiety/depression factor, cognitive factor and total score of PANSS than Val carriers.

CONCLUSIONBDNF gene Val66Met polymorphism is associated with the pathogenesis of schizophrenia. The Met/Met genotype of BDNF Val66Met variant may be a risk factor for symptoms in first episode schizophrenia patients.

Adolescent ; Adult ; Brain-Derived Neurotrophic Factor ; genetics ; China ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Schizophrenia ; genetics ; Young Adult

Objective:To investigate the difference of brain activity intensity between abstinent methamphetamine-dependent (AMD) patients and healthy controls using amplitude of low-frequency fluctuation (ALFF).Methods:From April 2016 to March 2017, 29 male AMD patients from Pingtang compulsory rehabilitation center in Changsha City, Hunan Province and 31 healthy male controls were prospectively recruited. The general conditions of all AMD patients, including age of first use of MA, months of MA use, monthly MA consumption, MA use frequency of the last year and the last month, current months of drug withdrawal, times of drug withdrawal, self-assessment score of drug craving when taking drugs, smoking history (whether smoking and smoking years), drinking history (whether drinking and drinking years). The rest functional MRI data were collected. DPABI software package was used to preprocess the data and calculate ALFF value of each voxel in the whole brain of the subjects of two groups. Two samples t-test and alphasim multiple comparison correction were used. Nuclei with voxel level P<0.01 and voxel number>71 were considered as regions with significant differences between two groups, corresponding to corrected P<0.05. ALFF mean value was extracted for each region with significant differences. Taking smoking and drinking as covariates, the correlations between the mean ALFF values of regions with significant differences and MA use and abstinence were analyzed. Results:Compared with the healthy control group, it was found in the AMD group that ALFF value of left middle frontal gyrus was significantly lower ( t=-4.707), and that of right inferior frontal gyrus was significantly higher ( t=4.445). The results of correlation analysis showed that the ALFF value of right inferior frontal gyrus was negatively correlated with the frequency of MA use and the MA amounts used in the last month ( r=-0.396, P=0.034; r=-0.429, P=0.020). Conclusions:Abnormal brain activity intensity is found in AMD patients compared with healthy controls, with abnormalities mainly found in the prefrontal lobe, which is involved in cognitive, executive and emotion functions. The more MA is used, the more damages or alterations may exist in these regions.

Objective To investigate the changes of brain gray matter volume (GMV) and brain activity in patients with long?term methamphetamine (MA) abstinence compared with healthy controls. Methods This study included 44 abstinent MA patients and 40 demographically equivalent healthy controls. Structural magnetic resonance imaging (MRI) and resting?state functional MRI (rs?fMRI) were obtained on Siemens 3.0 T MR. Differences in GMV between abstinent MA group and control group were assessed using voxel?based morphometry (VBM) method. Within each region showed significant differences between two groups, the value of the fractional amplitude of low frequency fluctuation (fALFF) was calculated using the rs?fMRI data. Differences of fALFF between groups were also evaluated. Furthermore, partial correlation coefficients adjusted for age, years of education, smoking and drinking were calculated in the abstinent MA group to assess associations between the mean GMV and fALFF values in significant clusters and variables of MA use and abstinence. Results Compared with controls, abstinent MA group showed increased GMV in the right cerebellum crus and decreased GMV in the right calcarine. While fALFF values within bilateral cerebellum crus in abstinent MA patients were significantly increased. Moreover, GMV of the left cerebellar crus was positively correlated with the withdrawal time among abstinent MA patients. Conclusions Both structural and functional abnormalities were found in abstinent MA patients even after long?term abstinence. The positive correlation between GMV of left cerebellum crus and abstinent duration suggested that prolonged abstinence may be beneficial to brain recovery. The fALFF of the right calcarine was increased even with decreased GVM in the abstinent MA group. It indicates that the brain activity of this area is increased, which may imply that drug cue?induced craving is significant among methamphetamine patients even after long?term abstinence.

OBJECTIVE: To examine the expression of matrix metalloproteinase-9 (MMP-9) in human bronchial epithelial cells treated with calcitonin-gene-related peptide (CGRP). METHODS: RT-PCR and gelatin zymography were performed to examine the dynamic expression and activity of MMP-9 in human bronchial epithelial cells at different doses (10(-10), 10(-9), 10(-8), 10(-7), and 10(-6)mol/L) and different time points (6,12,18,24,36, and 48h) after the stimulation of CGRP. RESULTS: The unstimulated human bronchial epithelial cells only secreted a small amount of MMP-9. After the CGRP stimulation, the expression of MMP-9 presented in a concentration-dependent (10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) mol/L) and time-dependent (6,12,18,24,36, and 48 h) manners (P<0.01) in human bronchial epithelial cells. The effect of CGRP could be diminished by H-7 and W-7, an antagonist of protein kinase C (PKC) and calmodulin (CaM) (P<0.05). CONCLUSION CGRP can stimulate the secretion and expression of MMP-9 in human bronchial epithelial cells, and the signal transduction is partly via the PKC and CaM pathway.
Bronchi ; cytology ; Calcitonin Gene-Related Peptide ; pharmacology ; Calmodulin ; metabolism ; Cells, Cultured ; Epithelial Cells ; drug effects ; metabolism ; Humans ; Matrix Metalloproteinase 9 ; metabolism ; Protein Kinase C ; metabolism ; Signal Transduction

Objective:To evaluate the role of aryl hydrocarbon receptor (AhR) in the down-regulation of Clara cell secretory protein (CCSP) expression during endotoxin-induced lung injury in rats.Methods:Twenty-four clean-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 200-250 g, were divided into 4 groups ( n=6 each) using a random number table method: normal control group (group C), acute lung injury (ALI) group, ALI+ AhR antagonist group, and ALI+ vehicle group. Lipopolysaccharide(LPS) 1 mg/kg was intratracheally instilled to develop the model of lung injury, while the equal volume of normal saline was given instead in group C. At 2 h before LPS injection, AhR antagonist 6, 2′, 4′-trimethoxyflavone solution 5 mg/kg (diluted to 1 ml in dimethyl sulfoxide solution) was intraperitoneally injected in ALI+ AhR antagonist group, while dimethyl sulfoxide solution 1 ml was given in ALI+ vehicle group. The rats were sacrificed under anesthesia at 48 h after LPS administration. The left lung was lavaged and the broncho-alveolar lavage fluid (BALF) was collected for determination of the concentrations of CCSP by enzyme-linked immunosorbent assay, and the expression of CCSP in the bronchial epithelium in right lung tissues was determined by immunohistochemistry. Results:Compared with group C, the expression of CCSP in the bronchial epithelium was significantly down-regulated, and the concentrations of CCSP in BALF were decreased in the other three groups ( P<0.05 or 0.01). Compared with ALI group and ALI+ vehicle group, the histopathological injury was significantly reduced, the expression of CCSP in the bronchial epithelium was up-regulated, and the concentrations of CCSP in BALF were increased in ALI+ AhR antagonist group ( P<0.01). Conclusions:AhR partially mediates the down-regulation of CCSP expression during endotoxin-induced lung injury in rats.

OBJECTIVETo investigate the protective effects of Shengui tablet (Chinese Traditional Medicine) on experimental cerebral ischemia by acute cerebral ischemia hypoxia in mice and bilateral ligation of the carotid artery in rats.

METHODSIn the acute cerebral ischemia hypoxia model, the mice were randomly divided into control group, low-, middle- and high-dose (0.16, 0.33 and 1.00 g/kg) groups of Shengui tablet, after oral treatment for 30 d, gasping time of isolated heads of mice were observed. In bilateral ligation of the carotid artery cerebral ischemia model, the rats were randomly divided into control group, model group and low-, middle-, high-dose (0.072, 0.149 and 0.450 g/kg) groups of Shengui tablet. After oral treatment for 7 d, the cerebral index, superoxide dismutase (SOD) activity and the content of malondialdehyde (MDA) were measured.

RESULTSCompared with the control model, Shengui tablet middle- and high-dose could significantly prolong gasping time of isolate heads of mice. Compared with model group, Shengui tablet low-, middle- and high-dose could significantly decrease the cerebral index and enhance SOD activity in brain tissue; only high-dose could reduce the content of MDA.

CONCLUSIONShengui tablet has significant protective effect on the cerebral ischemia.

Animals ; Brain ; metabolism ; Brain Ischemia ; metabolism ; prevention & control ; Drugs, Chinese Herbal ; pharmacology ; Female ; Male ; Malondialdehyde ; metabolism ; Mice ; Mice, Inbred Strains ; Neuroprotective Agents ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; metabolism

AIMTo explore the effects of calcitonin-gene-related peptide (CGRP) on LPS-induced MMP-9 secretion by alveolar macrophages (AM) in vitro.

METHODSThe supernatant of LPS-induced Wistar rat AM from different intervention groups were collected to measure the activity by gelatin zymography.

RESULTS(Only secreting a small amount of MMP-9 with unstimulated AM, LPS stimulated MMP-9 production in a concentration-dependent manner (p < 0.01). (2) The activity of MMP-9 in CGRP intervention groups at different levels were significantly lower than those in non-intervention group (p < 0.01). (3) The inhibiting effects of CGRP were diminished by H-7 and W-7, an antagonist of protein kinase C (PKC) and calmodulin (CaM) (p < 0.05).

CONCLUSIONThese data suggested that CGRP involved in the MMP-9 secretion by AM, partly, via PKC and CaM pathway.

Animals ; Cells, Cultured ; Female ; Lipopolysaccharides ; adverse effects ; Macrophages, Alveolar ; secretion ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Rats ; Rats, Wistar ; Receptors, Calcitonin Gene-Related Peptide ; metabolism

OBJECTIVETo investigate the clinical utility of multiplex ligation-dependent probe amplification (MLPA) for detecting 22q11 deletion and duplication in congenital heart disease (CHD) cases and to study the incidence of 22q11 deletion and duplicaton in different kinds of CHD.

METHODSForty eight probes of which 25 located in 22q11 low copy number region (LCR 22s A-H), 7 in 22q11 surrounding region (CES, 22q13) and 16 in chromosomes 4, 8, 10 and 17 were selected to detect 22q11 deletion and duplication in 181 preoperative children with CHD and 14 fetuses with serious CHD or CHD with multiple malformations. In these cases, karyotype analysis was also performed.

RESULTSMLPA demonstrated that 7 cases had 22q11 deletion [6 cases from CLTCL1 to LZTR1(LCR A-D) and 1 case from CLTCL1 to PCQAP (LCR A-C)] and that 1 case had 22q11 duplication,spanning from ZNF74 to LZTR1(LCR B-D). The phenotypes of heart defect included ventricular septal defect, atrioventricular septal defect, pulmonary stenosis and tetralogy of Fallot. Karyotype analysis showed that 1 case had 21q deletion [46, XY, 21q], 1 case had mosaic trisomy 8 [47,XY, +8/46, XY(1:2)] and 4 cases had trisomy 21. One of the 4 cases with trisomy 21 had concurrent 22q11 duplication.

CONCLUSIONSMLPA is a rapid, sensitive, site specific and relatively inexpensive method for diagnosis of 22q11 deletion and duplication in CHD. 22q11 deletion and duplication may cause various kinds of CHD, suggesting that genetic detection should be performed routinely in CHD patients.

Adolescent ; Chromosome Deletion ; Chromosomes, Human, Pair 22 ; Female ; Gene Duplication ; Heart Defects, Congenital ; genetics ; Humans ; Infant, Newborn ; Male ; Nucleic Acid Amplification Techniques ; methods