Antineoplastic Agents/therapeutic use* ; Gastrointestinal Stromal Tumors/drug therapy* ; Humans ; Liver ; Liver Neoplasms/drug therapy* ; Lung ; Naphthyridines/therapeutic use* ; Urea/analogs & derivatives*

OBJECTIVE: To investigate the genetic characterization of 3-hydroxyisovalerylcarnitine (C5-OH) metabolic abnormality in neonates. METHODS: Fifty two newborns with increased C5-OH, C5-OH/C3 and C5-OH/C8 detected by tandem mass spectrometry during neonatal screening were enrolled in the study. Genomic DNA was extracted from the whole blood samples of 52 cases and their parents. Seventy-nine genes associated with genetic and metabolic diseases including , were targeted by liquid capture technique. Variation information of these genes was examined by high-throughput sequencing and bioinformatic analysis, and then was classified based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. The genetic types were classified as wild-type, -maternal-mutation, -paternal-mutation and -mutation. Wilcoxon rank-sum test was performed for the increased multiples of C5-OH calculated in neonatal screening. RESULTS: Twenty one variants (14 novel) were identified in 37 cases, 6 variants (5 novel) in 4 cases. The increased multiple of C5-OH calculated in -maternal-mutation and -mutation groups were significantly higher than that in wild-type group (all <0.05), while there was no significant difference between MCCC1-paternal-mutation group and wild-type group (>0.05). CONCLUSIONS Mutations on and genes are the major genetic causes for the increased C5-OH in neonates, and maternal single heterozygous mutation can contribute to the moderately to severely increased C5-OH.
Carbon-Carbon Ligases ; genetics ; Carnitine ; analogs & derivatives ; metabolism ; Female ; Genetic Testing ; Genetic Variation ; Humans ; Infant, Newborn ; Male ; Mutation ; Neonatal Screening ; Urea Cycle Disorders, Inborn ; genetics

Medium- and short-chain acyl-CoA dehydrogenase deficiency is a disorder of fatty acid β-oxidation. Gene mutation prevents medium- and short-chain fatty acids from entry into mitochondria for oxidation, which leads to multiple organ dysfunction. In this study, serum acylcarnitines and the organic acid profile in urea were analyzed in two children whose clinical symptoms were hypoglycemia and metabolic acidosis. Moreover, gene mutations in the two children and their parents were evaluated. One of the patients was a 3-day-old male who was admitted to the hospital due to neonatal asphyxia, sucking weakness, and sleepiness. The serum acylcarnitine profile showed increases in medium-chain acylcarnitines (C6-C10), particularly in C8, which showed a concentration of 3.52 μmol/L (reference value: 0.02-0.2 μmol/L). The analysis of organic acids in urea gave a normal result. Sanger sequencing revealed a reported c.580A>G (p.Asn194Asp) homozygous mutation at exon 7 of the ACADM gene. The other patient was a 3-month-old female who was admitted to the hospital due to cough and recurrent fever for around 10 days. The serum acylcarnitine profile showed an increase in serum C4 level, which was 1.66 μmol/L (reference value: 0.06-0.6 μmol/L). The analysis of organic acids in urea showed an increase in the level of ethyl malonic acid, which was 55.9 (reference value: 0-6.2). Sanger sequencing revealed a reported c.625G>A (p.Gly209Ser) homozygous mutation in the ACADS gene. This study indicates that screening tests for genetic metabolic diseases are recommended for children who have unexplained metabolic acidosis and hypoglycemia. Genetic analyses of the ACADM and ACADS genes are helpful for the diagnosis of medium- and short-chain acyl-CoA dehydrogenase deficiency.
Acyl-CoA Dehydrogenase ; deficiency ; genetics ; Carnitine ; analogs & derivatives ; blood ; Female ; Humans ; Infant ; Infant, Newborn ; Lipid Metabolism, Inborn Errors ; genetics ; Male ; Mutation ; Urea ; analysis

In the study, the inhibitory effect of epigallocatechin gallate (EGCG) on Calcium oxalate nephrolithiasis and its possible mechanism were investigated. The rat Calcium oxalate nephrolithiasis model was induced through the combined oral administration of ethylene glycol and ammonium chloride, which was intervened with EGCG. Rat blood samples were collected to detect blood creatinine (Cr), blood urea nitrogen (BUN) and blood calcium. Rat urine samples were collected to observe and compare 24-hour urine volume, oxalic acid (Ox) and calcium in urine. Renal samples were collected to prepare tissue slices and observe the pathological changes in Calcium oxalate nephrolithiasis. The expression of osteopontin (OPN) in renal tissues was evaluated by Real-time PCR and Western blot. According to the results, compared with normal rats, rats in the nephrolithiasis model showed significant increases in Cr, BUN, urine Calcium, urine Ox and renal OPN expression (P < 0.05), but obvious decrease in 24-hour urine volume (P < 0.05); Compared with rats with nephrolithiasis, those processed with EGCG revealed remarkable declines in Cr, BUN, urine Calcium and urine Ox (P < 0.05), with significant rise in 24-hour urine volume (P < 0.05) in a concentration-dependent manner. Additionally, compared with the control group, nephrolithiasis rats showed significant pathological changes in Calcium oxalate calculus. After ECCG treatment, the renal pathological changes and OPN expression attenuated significantly in a concentration-dependent manner. The results showed that EGCG inhibits the formation of calcium oxalate nephrolithiasis in rats and shows a notable protective effect on renal functions.
Animals ; Blood Urea Nitrogen ; Calcium ; blood ; Calcium Oxalate ; metabolism ; Catechin ; administration & dosage ; analogs & derivatives ; Creatinine ; blood ; Disease Models, Animal ; Humans ; Kidney ; drug effects ; metabolism ; Male ; Nephrolithiasis ; blood ; drug therapy ; genetics ; Osteopontin ; genetics ; metabolism ; Rats ; Rats, Wistar

OBJECTIVETo investigate the effects of epigallocatechin gallate (EGCG)against exercise-induced fatigue in mice.

METHODSTotal 120 mice were randomly divided into three groups and tested separately. For each test, there were 30 mice subdivided into high dose (50 mg/kg . d EGCG) and low dose (10 mg/kg . d EGCG) groups as well as saline control group(1 ml/kg . d) with 10 in each. Burden swimming, running wheel endurance, stick climbing and hypoxia tolerance exercise were used to establish fatigue mice training model in three groups. And intraperitoneal injection with different doses of EGCG per day for consecutively 28 days and the mice in the control group were treated with normal saline. After the last each test, the blood lactic acid (BLA), blood urea nitrogen (BUN), blood lactate dehydrogenase (LDH), muscle glycogen (MG) and liver glycogen (LG) of each group of mice were determined.

RESULTSEGCG treatment groups(B and C)revealed a prolonged the mice survival time of burden swimming test, hypoxia tolerance, running wheel time and the ability of stick climbing(P < 0.05 or P <0.01), and increased LDH activity and MG and LG contents, reduced contents of BLA and BUN. High dose group had an obviously increase effect than lower dose group(P <0.05).

CONCLUSIONEGCG has significant effects against exercise-induced fatigue in mice.

Animals ; Blood Urea Nitrogen ; Catechin ; analogs & derivatives ; pharmacology ; Exercise Tolerance ; Fatigue ; drug therapy ; Glycogen ; metabolism ; L-Lactate Dehydrogenase ; blood ; Mice ; Physical Conditioning, Animal

The present study was aimed to investigate the effects of orexin-A and orexin-1 receptor (OX1R) antagonist injected into the fourth ventricle of rats on food-intake and spontaneous physical activity (SPA). Obese rat model was induced by high fat diet. Different doses of orexin-A or SB334867, an OX1R antagonist, were injected into the fourth ventricle of obese and normal rats respectively. SPA and food intake were monitored for 4 h after injection in both light and dark environment. In the light measurement cycle, different doses of orexin-A significantly stimulated feeding and SPA in all injected rats, and the animals' responses showed a dose-dependent manner (P < 0.05-0.01), and compared with those of normal rats, the orexin-A induced food intake and SPA were more pronounced in obese rats. In the dark measurement cycle, different doses of orexin-A had no obvious effect on food intake and SPA in both normal and obese rats (P > 0.05). In the light cycle, different doses of SB334867 significantly decreased food intake and SPA in all rats during 0-2 h and 2-4 h after injection (P < 0.05), but the food intake and SPA in obese rats were significantly greater than those of normal rats. In the dark cycle, different doses of SB334867 showed no obvious effect on food intake and SPA of normal and obese rats (P > 0.05). These results suggest that fourth cerebral ventricle nuclei may be one target for orexin-A and light condition may play an important role in orexin-A and OX1R physiological functional processes.
Animals ; Benzoxazoles ; pharmacology ; Diet, High-Fat ; Eating ; drug effects ; Fourth Ventricle ; Motor Activity ; drug effects ; Obesity ; Orexin Receptor Antagonists ; pharmacology ; Orexin Receptors ; Orexins ; pharmacology ; Rats ; Urea ; analogs & derivatives ; pharmacology

OBJECTIVE3-Methylcrotonyl-coenzyme A carboxylase deficiency (MCCD) is an autosomal recessive inborn error of leucine catabolism. The cases suspected as MCCD detected by neonatal screening are not rare. The aim of the study was to investigate the clinical outcomes in cases suspected as MCCD by neonatal screening. The second aim was to investigate the mutation spectrum of MCC gene in Chinese population and hotspot mutation.

METHODForty-two cases (male 33, female 9) , who had higher blood 3-hydroxy-isovalerylcarnitine (C5-OH) levels(cut-off <0.6 µmol/L) detected by neonatal screening using MS/MS, were recruited to this study during Sept.2011 to Mar.2013. The C5-OH concentrations were [0.84 (0.61-20.15) µmol/L] in 42 cases at the screening recall. Five cases were firstly diagnosed as maternal MCCD, 6 cases as benign MCCD and 31 cases were suspected as MCCD. To follow up the height, weight, mental development, blood C5-OH concentrations and urinary 3-methylcrotonyl-glycine (3-MCG) and 3-hydroxy isovalerate (3-HIVA) in order to investigate the clinical outcome. The MCCC1 and MCCC2 gene mutation were analyzed for some cases. The novel gene variants were evaluated, and the influence of novel missense variants on the protein structure and function were predicted by PolyPhen-2, SIFT, UniProt and PDB software.

RESULT(1) Forty-two cases had no symptoms, their physical and mental development were normal in the last visit at the median ages of 29 months, the oldest age of follow up was nearly 9 years. (2) Gene mutation analysis was performed for 29 cases with informed consent signed by parents.Fourteen different mutations were identified in 19 cases. The mutations in MCCC1 gene accounted for 86%, the most common mutation was c.ins1680A, (accounted for 40%). Nine kinds of novel variant were detected including 211AG>CC/p.Q74P, c.295G>A/p.G99S, c.764A>C/p.H255P, c.964G>A/p. E322K, c.1331G>A/p.R444H, c.1124delT, c.39_58del20, c.1518delG, c.639+2T>A.Other 3 kinds of mutation in MCCC1 gene and 2 kinds of mutation in MCCC2 gene have been reported previously; the amino acid of mutant positions of five kinds of novel missense variant are almost highly conserved. These missense variants were predicted to cause change of human MCC protein side chain structure by changing hydrogen bonding, size of amino acid residue and electric charge, and predicted to damage the protein function possibly according to PolyPhen-2 and PDB analysis. So these novel variants may be disease-causing mutations. No mutation were detected in 10 cases. (3) Blood concentrations of C5-OH when screening, recall and end of follow-up in maternal MCCD was 3.50 (1.63-11.43), 1.84 (1.00-9.30), 0.27 (0.26-5.81) µmol/L. There was a significant downward trend.In contrast, benign MCCD group was 8.20 (3.60-9.60), 9.67 (3.88-20.15), 23.0 (5.87-49.10) µmol/L.It showed a rising trend. Children's urinary 3-MCG of benign MCCD group was found abnormally elevated in 4 cases (100%) when they were recalled.

CONCLUSIONA certain number of cases with MCCD or suspected as MCCD in this study had no symptoms and normal physical and mental development after follow-up to oldest age of nearly 9 years. The mutation in MCCC1 gene is common, nine novel mutations were found, c.ins1680A may be a hotspot mutation in Chinese population. The urinary GC/MS analysis and blood MS/MS analysis for mother should be routinely performed for all cases with high blood C5-OH level detected by neonatal screening.

Amino Acid Sequence ; Asian Continental Ancestry Group ; genetics ; Carbon-Carbon Ligases ; blood ; deficiency ; genetics ; Carnitine ; analogs & derivatives ; blood ; Child ; Child, Preschool ; DNA Mutational Analysis ; Female ; Follow-Up Studies ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation ; Neonatal Screening ; Tandem Mass Spectrometry ; Urea Cycle Disorders, Inborn ; blood ; diagnosis ; enzymology ; genetics

BACKGROUND/AIMS: Gemcitabine-based chemotherapy has been used as a standard treatment in patients with unresectable pancreatic cancer. However, the clinical outcomes of this regimen are still unsatisfactory in prolonging survival. We retrospectively analyzed clinical characteristics of patients with advanced pancreatic cancers who received gemcitabine-based chemotherapy and showed long-term survival. METHODS: We enrolled 49 patients who underwent treatment with more than three cycles of gemcitabine-based chemotherapy. Long-term survivor was defined as patient who has survived more than 12 months after diagnosis. The clinical characteristics were analyzed to compare the differences between long-term and short-term survivors. Univariate or multivariate analyses were performed to identify prognostic factors associated with chemo-responses. RESULTS: Twenty patients (41%) survived more than 12 months. Long-term survivors had smaller tumor size (OR 2.190, p=0.049, 95% CI 1.005-4.773) and higher serum BUN level (OR 0.833, p=0.039, 95% CI 0.701-0.990) compared to short-term survivors. Overall median and progression-free survivals were 11 and 4 months, respectively. Presence of distant metastasis (hazard ratio 1.441, p=0.035, 95% CI 1.002-2.908) was a significant independent predictor of progression-free survival. Tumor size (hazard ratio 1.534, p=0.004, 95% CI 1.150-2.045) was associated with overall survival. CONCLUSIONS: Gemcitabine chemotherapy may be more effective and allow longer survivals in patients with clinical characters of smaller tumor size and normal serum BUN level at diagnosis. We suggest a well-designed large controlled study to evaluate the prognostic factors such as clinical characteristics and molecular biological features in patients with advanced pancreatic cancers who receive gemcitabine-based chemotherapy.
Age Factors ; Aged ; Antimetabolites, Antineoplastic/*therapeutic use ; Blood Urea Nitrogen ; CA-19-9 Antigen/blood ; Deoxycytidine/*analogs & derivatives/therapeutic use ; Female ; Humans ; Logistic Models ; Male ; Middle Aged ; Neoplasm Staging ; Odds Ratio ; Pancreatic Neoplasms/*drug therapy/mortality/pathology ; Prognosis ; Proportional Hazards Models ; Retrospective Studies ; Sex Factors ; Survival Rate

OBJECTIVETo evaluate the clinical efficacy and safety of sequential treatment with alprostadil and beraprost sodium for chronic renal failure caused by chronic glomerulonephritis.

METHODSSixty-three patients with chronic renal failure due to chronic glomerulonephritis, after receiving a 2-week-long conventional treatment, were randomly divided into alprostadil group (n=20, with alprostadil injection at 10 µg/d for 2 weeks), sequential treatment group (n=21, with alprostadil injection at 10 µg/d for 2 weeks and oral beraprost sodium at 20 µg three times a day for 12 weeks), and strengthened sequential treatment group (n=22, with alprostadil injection at 20 µg/d for 2 weeks and a double dose of oral beraprost sodium for 12 weeks). Urinary albumin excretion rate (UAER), cystatin C (Cys C), blood urea nitrogen, creatinine, fibrinogen, D-dimer, prothrombin time (PT), and platelets were tested before and after the treatment, and the changes in urinary albumin discharge rate, serum creatinine, and glomerular filtration rate were determined.

RESULTSThe patients in strengthened sequential treatment group showed a significantly decreased change rate of urinary albumin discharge rate (P<0.01) than those in the other two groups. In the two sequential treatment groups, especially the strengthened treatment group, the change rate of glomerular filtration rate increased significantly compared with that in alprostadil group (P<0.01). Strengthened sequential treatment resulted also in significantly decreased increment of serum creatinine compared that in the other 2 groups (P<0.01). After 14 weeks of treatment, fibrinogen and D-dimer were decreased in all the 3 groups (P<0.05) to a comparable level between the 3 groups (P>0.05), and prothrombin time (PT) or platelet showed no significant changes (P>0.05).

CONCLUSIONSequential treatment with alprostadil and beraprost sodium can improve the glomerular filtration rate and decrease urine albumin excretion rate, serum creatinine increase rate, and lower blood fibrinogen and D-dimer levels, thus delaying the progression of chronic renal failure caused by chronic glomerulonephritis. This therapy shows a dose-related effect with good clinical safety.

Adolescent ; Adult ; Aged ; Alprostadil ; therapeutic use ; Blood Urea Nitrogen ; Chronic Disease ; Creatinine ; blood ; Drug Therapy, Combination ; Epoprostenol ; analogs & derivatives ; therapeutic use ; Female ; Fibrin Fibrinogen Degradation Products ; metabolism ; Fibrinogen ; metabolism ; Glomerular Filtration Rate ; Glomerulonephritis ; complications ; Humans ; Kidney Failure, Chronic ; blood ; drug therapy ; etiology ; Male ; Middle Aged ; Platelet Aggregation Inhibitors ; therapeutic use ; Platelet Count ; Prothrombin Time ; Urological Agents ; therapeutic use ; Young Adult

A novel series of benzyl urea analogues based on the structural modification of sorafenib were synthesized. Their in vitro antitumor activities against MX-1, HepG2, Ketr3 and HT-29 were evaluated using the standard MTT assay. While several target compounds showed inhibitory activity against multiple cancer cell lines, compound 9 was of particular interest, demonstrating IC50 values (5.69-13.6 micromol x L(-1)) comparable to those of sorafenib. Furthermore, compounds 20 and 23 showed more potent inhibitory activity against HT-29 and MX-1 when compared to sorafenib. In particular, compound 20 bearing the N-3-pyridyl moiety not only exhibited greater inhibitory activity against HT-29 cell line (IC50 3.82 micromol x L(-1)), but also had improved solubility at pH 7.2, is worthy of further investigation as a lead to identify novel antitumor agents.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Screening Assays, Antitumor ; HT29 Cells ; Humans ; Inhibitory Concentration 50 ; Molecular Structure ; Niacinamide ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Phenylurea Compounds ; chemical synthesis ; chemistry ; pharmacology ; Solubility ; Structure-Activity Relationship ; Urea ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology