OBJECTIVETo study the expression of bradykinin and its receptors B1R and B2R in the kidney immune injury in trichloroethylene-sensitized mouse and discuss the pathogenesis of Dermatitis Medicamentosa-like of TCE (ODMLT).

METHODSOn the first days, intradermal injection by 50% TCE and the amount of FCA mixture 100 µl for initial sensitization; on 4, 7, 10 days, painted abdominal skin by 100 µl 50% TCE for three sensitization, on 17, 19 days, painted on the back skin by 100 µl 30% TCE for initial excitation and the last challenge; 24 h before each challenge, PKSI-527+TCE group received intraperitoneal injection by inhibitor PKSI-527 (50 mg/kg); solvent control group treat without TCE and sensitization and excitation reagent the same proportion of olive oil and acetone mixture, blank control group without any treatment. Before killing the mouse, renal weight and body weight were recorded. The renals and plasma were separated at 24 h, 48 h, 72 h and 7 d after the last challenge and observed pathological of the renals. Expression of B1R and B2R in renal were examined by immunofluorescence technique. Plasma were examined by ELISA for BK.

RESULTSThe renal pathological examination revealed the apparent damage of TCE sensitized mice which compared to solvent control group showed obvious cellular infiltration, vacuolar degeneration of renal tubular epithelial cells. The renal damage of PKSI-527+TCE-sensitized groups which compared to the corresponding point of TCE-sensitized groups showed significantly reduced. The expression of BK in 24 h, 48 h and 72 h TCE-sensitized groups were significant higher than solvent control group and related TCE non-sensitized groups (P < 0.05) and 72 h point compared to the corresponding point of PKSI-527+TCE group was also increased, the difference was statistically significant (P < 0.05). The expression levels of B1R and B2R in the kidney in 24 h, 48 h, 72 h and 7 d TCE-sensitized groups were obviously higher than solvent control group and related TCE non-sensitized groups. The expression levels of B1R and B2R in the kidney in the four point of PKSI-527+TCE sensitized group were relatively lower than the corresponding point of TCE sensitized group.

CONCLUSIONKKS activation may involved in the renal immune injury of trichloroethylene-sensitized mouse and the expression change of bradykinin and its receptors B1R and B2R which may play an important role in the process.

Administration, Cutaneous ; Animals ; Bradykinin ; metabolism ; Kidney ; drug effects ; metabolism ; pathology ; Mice ; Phenylalanine ; analogs & derivatives ; Receptor, Bradykinin B1 ; metabolism ; Receptor, Bradykinin B2 ; metabolism ; Solvents ; Tranexamic Acid ; analogs & derivatives ; Trichloroethylene ; toxicity

Biopterin ; analogs & derivatives ; deficiency ; genetics ; Child ; Consensus ; Diagnosis, Differential ; Humans ; Infant ; Infant, Newborn ; Neonatal Screening ; methods ; Phenylalanine ; blood ; Phenylalanine Hydroxylase ; deficiency ; genetics ; Phenylketonurias ; classification ; diagnosis ; therapy ; Practice Guidelines as Topic ; Severity of Illness Index ; Tyrosine ; blood

Biopterin ; analogs & derivatives ; deficiency ; genetics ; Child ; Consensus ; Diagnosis, Differential ; Humans ; Infant ; Infant, Newborn ; Neonatal Screening ; Phenylalanine ; blood ; Phenylalanine Hydroxylase ; deficiency ; genetics ; Phenylketonurias ; diagnosis ; etiology ; therapy ; Practice Guidelines as Topic ; Societies, Medical

OBJECTIVETo investigate the protective effect of exogenous inhibitor of matrix metalloproteinases-9 (MMP-9), batimastat, in the lung injury induced by cardiopulmonary bypass (CPB) in dogs.

METHODSThirty healthy mongrel puppies were randomly divided into 3 groups: control group, low-dose group [batimastat 10 mg/(kg.d) for 3 days before operation] and high-dose group [batimastat 30 mg/(kg.d) for 3 days before operation]. The off-pump puppies' model of acute lung injury was established, and hemodynamic and respiratory parameters were monitored. The preoperative and postoperative alveolar-arterial oxygen difference (A-aDO(2)) and respiratory index (RI) were calculated. From the beginning of surgery, blood samples were taken at the time 0, 60, 120, and 270 min. Plasma concentrations of MMP-9 were measured by ELISA, and blood MMP-9 mRNA expressions were determined by RT-PCR. The myeloperoxidase (MPO) activity of centrifugal bronchoalveolar lavage fluid were measured by Colorimetry. And MMP-9 activity was determined by Gelatin zymography. Light and electronic microscope were used to observe the morphological changes of lung tissue. A small piece of left lung tissue was taken, weighed and baked to calculate the wet weight (W/D) index.

RESULTSAfter cardiopulmonary bypass, the concentrations of MMP-9 and mRNA expressions of the control group were increased significantly, and lung injury was apparent. At 270 min, the MMP-9 plasma concentration of high-dose group (17.36 +/- 1.18) microg/L was significant reducing than control group (30.47 +/- 2.22) microg/L (P < 0.05). After operation, A-aDO(2) and RI of high-dose group were significantly improved than control group (P < 0.05). The W/D index of the high-dose group (2.8 +/- 0.48) was significantly lower than that of control group (4.7 +/- 0.6) (P < 0.05). And the pathological changes of lung tissue were significantly improved in the high-dose group. However, there was no significant difference in the MMP-9 mRNA expression in three groups.

CONCLUSIONSBatimastat plays a role in the protection of the lung injury of CBP by reducing the concentration and activity of MMP-9, the degradation of the cell membrane and pulmonary neutrophil infiltration and reduction of pulmonary edema.

Acute Lung Injury ; etiology ; prevention & control ; Animals ; Cardiopulmonary Bypass ; Disease Models, Animal ; Dogs ; Lung ; pathology ; Matrix Metalloproteinase 9 ; metabolism ; Matrix Metalloproteinase Inhibitors ; Phenylalanine ; analogs & derivatives ; pharmacology ; Postoperative Complications ; prevention & control ; Thiophenes ; pharmacology

Animals ; Biopterin ; analogs & derivatives ; therapeutic use ; Genetic Therapy ; Humans ; Phenylalanine Ammonia-Lyase ; administration & dosage ; Phenylketonurias ; therapy

OBJECTIVETo evaluate the efficacy and safety of nateglinide, a new antidiabetic agent, in the treatment of type 2 diabetes.

METHODSA total of 219 treatment-naïve patients with type 2 diabetes from 6 centers were enrolled in this study and blindly divided into nateglinide group (n = 105) and repaglinide group (n = 114). In all patients, the disease was confirmed for at least three months. The whole observation lasted for 12 weeks. The efficacy indicators measured include glycohemoglobin A1c (HbA1c), fasting blood glucose, and 2 hours postprandial blood glucose, and the safety parameters measured included renal and hepatic function, serum lipids, and blood and urea profiles.

RESULTSSimilar decreases in fasting blood glucose, 2 hours postprandial blood glucose, and HbA1 c were found in both nateglinide group and repaglinide group without significant differences. No severe adverse events were noted. The hypoglycemia event reports were not significantly different between these two groups.

CONCLUSIONNateglinide is an effective and safe drug in treating type 2 diabetes.

Blood Glucose ; drug effects ; Cyclohexanes ; administration & dosage ; adverse effects ; therapeutic use ; Diabetes Mellitus, Type 2 ; drug therapy ; Drug Administration Schedule ; Female ; Humans ; Hypoglycemic Agents ; administration & dosage ; adverse effects ; therapeutic use ; Male ; Middle Aged ; Phenylalanine ; administration & dosage ; adverse effects ; analogs & derivatives ; therapeutic use ; Treatment Outcome

OBJECTIVETo analyze characteristics of different hyperphenylalaninemia (HPA) and to discuss the clinical difference between southern and northern Chinese patients with tetrahydrobiopterin (BH4) responsive phenylalanine hydroxylase (PAH) deficiency.

METHODS(1)BH4 (20 mg/kg) loading test was performed in all 108 HPA patients. These patients, 63 males and 45 females, were at a mean age of 7.05 months. A combined phenylalanine (Phe) and BH4 loading test was carried out in the patients who had a basic blood Phe concentration less than 600 micromol/L. The urine pterine profile analysis and the dihydropteridine reductase (DHPR) activity in dry blood filter spot were analyzed simultaneously. (2)BH4 responsive patients were divided to southern and northern groups by their parent's native place and geographic boundary determined by Changjiang River. The change of Phe concentration after BH4 loading test was compared between the two groups.

RESULTS(1)Among the 108 HPA cases, 36 patients (33.3%) were BH4 responsive PAH deficiency, 49 (45.4%) were non-BH4 no responsive phenylketonuria (PKU)and 23(21.3%)were BH4 deficiency (BH4D). The Phe concentration of patients with BH4 responsive PAH deficiency decreased by 49.24% and 65.35% at 8 h and 24 h after oral BH4, 23 in southern group and 13 in northern group among 36 patients. (2)The mean Phe concentration at 24 h after loading test in southern and northern groups were (217.02+/-189.03) micromol/L and 458.75+/-342.54 micromol/L respectively (P<0.05), although the decrease percent of plasma Phe concentration at 2 h, 4 h, 8 h, 24 h was no distinct difference between southern and northern groups (P>0.05).

CONCLUSIONMost of mild and moderate HPA patients affected by PAH deficiency show plasma Phe concentration decrease >30% in 24 h after oral BH4 20 mg/kg, few are classic PKU. The responsiveness to BH4 is no difference between southern and northern Chinese patients with BH4 responsive PAH deficiency according to the decrease percent of plasma Phe concentration, although the Phe concentration is lower in southern patients than that in northern patients.

Biopterin ; analogs & derivatives ; pharmacology ; therapeutic use ; Child, Preschool ; China ; Dihydropteridine Reductase ; blood ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Phenylalanine ; blood ; Phenylketonurias ; blood ; drug therapy ; Time Factors

OBJECTIVETo study the incidence of various enzyme deficiency in tetrahydrobiopterin (BH4) metabolism and the related gene mutation among the patients with motor disturbance and mental retardation.

METHODSOne hundred patients with unknown motor disturbance and mental retardation were referred to this study. All patients were performed by phenylalanine (Phe) and BH4 loading test, urinary pterin analysis and dihydropteridine reductase (DHPR) activity. Some patients received the dopa treatment for diagnosis of dopa-responsive dystonia (DRD). The analysis of GTP cyclohydrolase 1 gene (GCH1) mutation for DRD patients and the analysis of 6-pyruvoyl tetrahydropterin synthase (PTS) gene mutations for PTS deficient patients were done under the consent from their parents.

RESULTSSeventy of 100 patients had normal basic blood Phe levels, six (6%) patients were diagnosed as DRD. Thirty patients had hyperphenylalaninemia (HPA), eight (8%) were diagnosed as PTS deficiency and 22(22%) were diagnosed as phenylalanine hydroxylase (PAH) deficiency. All patients had normal DHPR activity. The mutation IVS5+3insT of GCH1 was found in 2 patients with DRD. Seven kinds of PTS mutations were found in 8 patients with PTS deficiency, and 75% of the mutations were 259C-->T,286G-->A and 155A-->G.

CONCLUSIONSome patients with unknown motor disturbance and mental retardation may suffer from BH4 metabolism related diseases. Theses patients are necessary to be screened for such kind of diseases in order to confirm the diagnosis.

Adolescent ; Biopterin ; analogs & derivatives ; metabolism ; Child ; Child, Preschool ; Dihydropteridine Reductase ; genetics ; metabolism ; Dystonia ; genetics ; metabolism ; Female ; GTP Cyclohydrolase ; genetics ; metabolism ; Humans ; Infant ; Intellectual Disability ; genetics ; metabolism ; Male ; Mutation ; Phenylalanine Hydroxylase ; genetics ; metabolism ; Phosphorus-Oxygen Lyases ; genetics ; metabolism

Nordy is a synthesized chrial compound. To investigate the effects of nordy (25 - 100 micromol x L(-1)) on the function of formylpeptide receptor (FPR) of malignant human glioma cells, human glioblastoma cell line U87 was used to detect its proliferation, migration, calcium mobilization, vascular endothelial growth factor (VEGF) mRNA and protein levels after activation of FPR by its agonist N-formyl-methionyl-leucyl-phenylalanine (fMLF). Cell proliferation, migration ability, VEGF mRNA, VEGF protein and calcium mobilization were evaluated by cell counting, chemotaxis assay, RT-PCR, ELISA and spectrometry. Nordy (50 - 100 micromol x L(-1)) potently inhibited the proliferation, migration and calcium mobilization of U87 cells induced by fMLF (P < 0.05). Moreover, 100 micromol x L(-1) nordy showed a significantly impaired VEGF mRNA expression and protein secretion induced by fMLF (P < 0.05). Nordy could inhibit FPR functioning in glioma cell proliferation, migration and angiogenesis, which might be a possible mechanism of its anti-cancer effects.
Antineoplastic Agents ; pharmacology ; Calcium ; metabolism ; Cell Line, Tumor ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Glioblastoma ; genetics ; metabolism ; pathology ; Humans ; Masoprocol ; analogs & derivatives ; pharmacology ; N-Formylmethionine Leucyl-Phenylalanine ; pharmacology ; RNA, Messenger ; biosynthesis ; genetics ; Receptors, Formyl Peptide ; agonists ; metabolism ; physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Spectrophotometry ; methods ; Vascular Endothelial Growth Factor A ; biosynthesis ; genetics

OBJECTIVETo emphasize early differential diagnosis from patients with hyperphenylalaninemia (HPA) and to evaluate the treatment and long-term outcome of patients with tetrahydrobiopterin synthase (BH4) deficiency in Northern Chinese population.

METHODSFrom 1992 to 2005, a total of 618 patients with HPA were diagnosed and/or cared for in our outpatient clinic. Urinary pterin analysis, detection of dihydropteridine reductase (DHPR) activity in blood, and then BH4 loading tests were carried out to differentiate BH4 deficiency in these patients from classical phenylketonuria. BH4 deficient patients were treated with BH4, levodopa and 5-hydroxytryptophane (5-HTP) immediately while the diagnosis was done to disease. Patientso blood phenylalanine levels, psychomotor and intelligence development were followed up.

RESULTSA total of 38 cases were diagnosed as BH4 deficiency, all of them were revealed as 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency from the extremely decreased urine biopterin, normal DHPR activities and drop down of blood phenylalanine level to normal range within 4 to 8 hours after BH4 loading. The most common manifestations were progressively psychomotor and mental retardation to patients even after taking early dietary treatment. The patients were diagnosed and treated with drugs at the ages of 2.1 months to 13 years. With 4 patients died of pneumonia, 7 patients refused to treatment, only 27 patients were under treatment and followed up. The average full scale development or intelligence quotient (DQ/IQ) of patients who were treated within and after 6 months were 86+/- 10 or 66+/- 7 respectively. Development was not even in different aspects. A significant negative correlation was observed between the level of the DQ and the age of treatment commenced (r was -0.714, P< 0.01). Eleven patients experienced the extrapyramidal movement disorders, 3 of them combined with epilepsy. The extrapyramidal disorders were controlled by administration of levodopa.

CONCLUSIONThe differential diagnosis for BH4 deficiency should be carried out in all patients with HPA. PTPS deficiency is the most common form of BH4 deficiency in Northern Chinese population. The long-term outcome of these patients benefits from diagnosis and treatment with BH4, levodopa and 5-HTP as early as possible.

5-Hydroxytryptophan ; therapeutic use ; Asian Continental Ancestry Group ; genetics ; Biopterin ; analogs & derivatives ; deficiency ; therapeutic use ; Child, Preschool ; China ; Dihydropteridine Reductase ; blood ; Humans ; Infant ; Levodopa ; therapeutic use ; Phenylalanine ; blood ; Phenylketonurias ; drug therapy ; genetics ; metabolism ; Phosphorus-Oxygen Lyases ; deficiency ; genetics