Early-onset progressive encephalopathy is a lethal encephalopathy caused by NAXE gene mutations. This paper reports the clinical and genetic features of a patient with early-onset progressive encephalopathy. A 4-year-old boy admitted to the hospital had repeated walking instability and limb weakness for 2 years. The patient and his elder brother (already dead) had clinical onset at 2 years of age. Both of them showed symptoms such as strabismus, ataxia, reduced muscle tone, delayed development, and repeated respiratory failure after infection. The NAXE gene of the patient showed new compound heterozygous mutations, i.e., c.255 (exon 2) A>T from his mother and c.361 (exon 3) G>A from his father. The NAXE gene encodes an epimerase that is essential for the repair of cellular metabolites of NADHX and NADPHX. This disease is associated with a deficiency of the mitochondrial NAD(P)HX repair system. Patients usually have rapid disease progression. They are also quite likely to have respiratory failure immediately after infection.
Adult ; Age of Onset ; Base Sequence ; Brain Diseases ; enzymology ; genetics ; Child, Preschool ; Disease Progression ; Female ; Heterozygote ; Humans ; Male ; Mutation ; Racemases and Epimerases ; genetics

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.
Animals ; Anti-Inflammatory Agents ; administration & dosage ; Blood-Brain Barrier ; drug effects ; enzymology ; immunology ; Brain ; Brain Ischemia ; drug therapy ; enzymology ; genetics ; Caffeic Acids ; administration & dosage ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Lactates ; administration & dosage ; Male ; Matrix Metalloproteinase 9 ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; enzymology ; genetics ; immunology ; prevention & control ; Salvia miltiorrhiza ; chemistry ; Tissue Inhibitor of Metalloproteinase-1 ; genetics ; metabolism ; Transcription Factor RelA ; genetics ; immunology

Phenylalanine hydroxylase (PAH) is a member of aromatic amino acid hydroxylase (AAAHs) family, and catalyze phenylalanine (Phe) into tyrosine (Tyr). Using immunological and RT-PCR methods to prove the existence of phenylalanine hydroxylase (PAH) gene in the brain of Neanthes japonica in protein and nucleic acid level. Using Western blotting to detect the pah immunogenicity of Neanthes japonica. Making paraffin sections and using immunohistochemical technique to identify the presence and distribution of the phenylalanine hydroxylase gene in the brain of Neanthes japonica. Clone pah gene from the brain of Neanthes japonica by RT-PCR, constructing plasmid and transferring into E. coli to amplification, picking a single homogeneous colony, double digesting then making sequence and comparing homology. Western blotting results showed that the expression of the protein is present in Neanthes japonica brain, immunohistochemistry technique results showed that phenylalanine hydroxylase mainly expressed in abdominal of forebrain, dorsal and sides of midbrain. RT-PCR technique results showed that the phenylalanine hydroxylase exist in the brain of Neanthes japonica and has a high homology with others animals. PAH is present in the lower organisms Neanthes japonica, in protein and nucleic acid level. Which provide the foundation for further study the evolution of aromatic amino acid hydroxylase genes in invertebrate.
Animals ; Blotting, Western ; Brain ; enzymology ; Escherichia coli ; metabolism ; Phenylalanine Hydroxylase ; genetics ; metabolism ; Polychaeta ; enzymology ; genetics

OBJECTIVETo explore pathogenic mutation in a family affected with 2-hydroxyglutaric aciduria.

METHODSExons of 3 candidate genes, including L2HGDH, D2HGDH and SLC25A1, were amplified with polymerase chain reaction and subjected to direct sequencing.

RESULTSDNA sequencing has found that the proband and his affected younger brother have both carried a heterozygous mutation c.845G>A (p.R282Q) in the exon 7 of the L2HGDH gene. The same mutation was not detected in the his sister who was healthy. Pedigree analysis has confirmed that the above mutation was inherited from the mother. No mutation was detected in exons and flanking sequences of the D2HGDH and SLC25A1 genes.

CONCLUSIONMutation of the L2HGDH gene probably underlies the 2-hydroxyglutaric aciduria in this family.

Alcohol Oxidoreductases ; genetics ; Base Sequence ; Brain ; diagnostic imaging ; Brain Diseases, Metabolic, Inborn ; diagnostic imaging ; enzymology ; genetics ; Child ; Female ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Pedigree ; Radiography ; Young Adult

BACKGROUNDGinsenoside Rd (GSRd), one of the main active ingredients in traditional Chinese herbal Panax ginseng, has been found to have therapeutic effects on ischemic stroke. However, the molecular mechanisms of GSRd's neuroprotective function remain unclear. Ischemic stroke-induced oxidative stress results in DNA damage, which triggers cell death and contributes to poor prognosis. Oxidative DNA damage is primarily processed by the base excision repair (BER) pathway. Three of the five major DNA glycosylases that initiate the BER pathway in the event of DNA damage from oxidation are the endonuclease VIII-like (NEIL) proteins. This study aimed to investigate the effect of GSRd on the expression of DNA glycosylases NEILs in a rat model of focal cerebral ischemia.

METHODSNEIL expression patterns were evaluated by quantitative real-time polymerase chain reaction in both normal and middle cerebral artery occlusion (MCAO) rat models. Survival rate and Zea-Longa neurological scores were used to assess the effect of GSRd administration on MCAO rats. Mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damages were evaluated by the way of real-time analysis of mutation frequency. NEIL expressions were measured in both messenger RNA (mRNA) and protein levels by quantitative polymerase chain reaction and Western blotting analysis. Apoptosis level was quantitated by the expression of cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay.

RESULTSWe found that GSRd administration reduced mtDNA and nDNA damages, which contributed to an improvement in survival rate and neurological function; significantly up-regulated NEIL1 and NEIL3 expressions in both mRNA and protein levels of MCAO rats; and reduced cell apoptosis and the expression of cleaved caspase-3 in rats at 7 days after MCAO.

CONCLUSIONSOur results indicated that the neuroprotective function of GSRd for acute ischemic stroke might be partially explained by the up-regulation of NEIL1 and NEIL3 expressions.

Animals ; Blotting, Western ; Brain Ischemia ; drug therapy ; enzymology ; DNA Damage ; drug effects ; DNA Glycosylases ; genetics ; metabolism ; Ginsenosides ; therapeutic use ; Infarction, Middle Cerebral Artery ; drug therapy ; enzymology ; Male ; N-Glycosyl Hydrolases ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo assess the association of impairment of surface area of first-episode schizophrenia(SZ) with polymorphisms of COMT gene, and the difference in the impaired patterns between familial patients with schizophrenia(FPS) and sporadic patients with schizophrenia(SPS).

METHODSNinety-eight patients with first-episode SZ(FPS=40, SPS=58) and 78 healthy controls were recruited. COMT gene was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Participants were scanned for 3.0T magnetic resonance images. Freesurfer software was used to analyze the difference in brain surface area between SZ and controls, its association with COMT genotypes, and the difference between SPS, FPS and control groups. Multiple tests were corrected using a Monte Carlo simulation at P<0.05.

RESULTSCompared with controls, SZ showed decreased surface area in right occipital cortex and left prefrontal cortex. No association was found between COMT polymorphisms and whole brain area difference. Among the three subgroups, SPS showed smaller left prefrontal area compared with both FPS and control groups. Patients with SPS also showed significant area reduction in right occipital lobe compared with controls.

CONCLUSIONSurface area impairment can be found in those with first-episode SZ, but without association with COMT gene polymorphisms. The SPS have more severe area impairment than FPS, indicating that SPS and FPS may be attributed to different etiological mechanisms.

Adult ; Brain ; diagnostic imaging ; Catechol O-Methyltransferase ; genetics ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Polymorphism, Restriction Fragment Length ; Radiography ; Schizophrenia ; diagnostic imaging ; enzymology ; genetics ; Young Adult

OBJECTIVETo report on clinical features of four patients with glutaric academia type Ⅰ (GA-1) and mutations identified in the glutaryl-CoA dehydrogenase (GCDH) gene.

METHODSAll of the patients underwent magnetic resonance imaging (MRI) analysis. Blood acylcarnitine and urine organic acid were analyzed with tandem mass spectrometry and gas chromatographic mass spectrometry. Genomic DNA was extracted from peripheral blood samples. The 11 exons and flanking sequences of the GCDH gene were amplified with PCR and subjected to direct DNA sequencing.

RESULTSMutations of the GCDH gene were identified in all of the patients. Three had homozygous mutations. A recurrent mutation, IVS10-2A>C, was found in the four unrelated families, while the mutation of c.245G>C (p.Arg82Pro) was novel.

CONCLUSIONIVS10-2A>C is likely a founder mutation for Chinese population in Wenzhou.

Amino Acid Metabolism, Inborn Errors ; diagnostic imaging ; enzymology ; genetics ; Amino Acid Sequence ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Brain Diseases, Metabolic ; diagnostic imaging ; enzymology ; genetics ; DNA Mutational Analysis ; Exons ; Female ; Glutaryl-CoA Dehydrogenase ; chemistry ; deficiency ; genetics ; metabolism ; Humans ; Infant ; Magnetic Resonance Imaging ; Male ; Molecular Sequence Data ; Point Mutation ; Radiography ; Sequence Alignment

OBJECTIVETo explore the value of serum neuron-specific enolase (NSE) before treatment in predicting brain metastases and prognosis of advanced non-small cell lung cancer (NSCLC).

METHODSA total of 128 hospitalized patients with advanced NSCLC from Jan 2012 to Mar 2012 were followed up, and their clinicopathological data, serum NSE, carcinoembryonic antigen, cytokeratin 21-1 (cyfra21-1) levels, albumin (ALB), white blood cell (WBC) before treatment were analyzed retrospectively to determine the factors affecting brain metastasis and prognosis of advanced NSCLC.

RESULTSAmong the 128 NSCLC patients, 90 cases were of adenocarcinoma, 30 cases were of squamous cell carcinoma, and 8 cases were of large cell carcinoma. The median levels of pre-treatment NSE, CEA and cyfra21-1 were 13.6 ng/ml, 7.8 ng/ml and 6.1 ng/ml, respectively. The average levels of ALB and WBC were (35.41 ± 5.60) g/L and (8.16 ± 2.53) × 10⁹/ml, respectively. Multi-variate logistic regression analysis showed that serum NSE before treatment was associated with brain metastasis of advanced NSCLC (P = 0.030). Pre-treatment NSE levels were (34.18 ± 28.48) ng/ml in 28 patients with brain metastasis and (13.87 ± 4.49) ng/ml in 98 patients without brain metastasis (P < 0.05). The median survival time were 3.5 months in patients with normal levels of NSE, and 10.7 months in patients with elevated levels of NSE pre-treatment (P < 0.05).

CONCLUSIONSA higher pre-treatment level of NSE is closely correlated with brain metastasis of advanced NSCLC, and can be used as a predictor of brain metastases in advanced NSCLC. High pre-treatment levels of NSE indicate a poor prognosis in advanced NSCLC patients.

Adenocarcinoma ; blood ; enzymology ; secondary ; Antigens, Neoplasm ; blood ; Brain Neoplasms ; secondary ; Carcinoembryonic Antigen ; blood ; Carcinoma, Large Cell ; blood ; enzymology ; secondary ; Carcinoma, Non-Small-Cell Lung ; blood ; enzymology ; secondary ; Carcinoma, Squamous Cell ; blood ; enzymology ; secondary ; Humans ; Keratin-19 ; blood ; Leukocyte Count ; Lung Neoplasms ; blood ; enzymology ; pathology ; Phosphopyruvate Hydratase ; blood ; Prognosis ; Retrospective Studies ; Serum Albumin ; analysis

Transglutaminase (TG) is a kind of calcium-dependent enzymes. The TGase family found in rodents and human contains 9 types, including TG1-7, blood coagulation factor XIIIa and erythrocyte membrane protein 4.2, with the former 8 types possessing catalytic activity. TG catalyzes various conversion reactions of glutamine, including transamination, deamination and esterification, and participates in post-transcriptional modification of proteins such as cross-linking peptides glutamine residue and lysyl-residue, stabilizing protein structure and catalyzing formation of protein aggregates. TGase has been found to contribute to a variety of important physiological and pathological processes and play a role in the pathogenesis of multiple diseases. Notably, neurodegenerative diseases such as Huntington's disease, spinocerebellar ataxia, Alzheimer's disease and Parkinson's disease, have a close connection with TGase's role in the human body.
Animals ; Brain ; enzymology ; Humans ; Neurodegenerative Diseases ; enzymology ; genetics ; Transglutaminases ; genetics ; metabolism

Borneol is a traditional Chinese medicine. In the past few years, many studies showed that borneol can improve the bioavailability of other drugs, promoting drugs to cross the blood-brain barrier, so the potential drug interactions between borneol and other medicines have attracted great attention, but the influence of borneol to CYP450 and its isoforms are rarely reported. In this research, male Wistar rats were orally administered by borneol for 7 days, then the mRNA and protein expression and the activities of CYP2D were detected, we also compared the pharmacokinetic parameters of CYP2D's specific substrate between control group and borneol group. The results show that borneol (33, 100 and 300 mg x kg(-1) x d(-1)) have no significant effect on CYP2D, while the activites of CYP2D increased 1.71, 1.97 and 2.89 times comparing to the control group. At the same time, borneol (300 mg x kg(-1) x d(-1)) caused the C(max) decreased 10.6% (P > 0.05), AUC(0-∞) decreased 27.5% (P < 0.01), CL/F increased 41.1% (P < 0.01), V(z)/F increased 23.1% (P > 0.05) of dextromethorphan. Our data provided that borneol speed up dextromethorphan's elimination in vivo. Since the activity of CYP2D can be induced by borneol, the metabolic interactions might happen when borneol and the substrate drug CYP2D are used together.
Animals ; Aryl Hydrocarbon Hydroxylases ; metabolism ; Blood-Brain Barrier ; Bornanes ; pharmacology ; Cytochrome P-450 Enzyme Inducers ; pharmacology ; Dextromethorphan ; Drug Interactions ; Liver ; drug effects ; enzymology ; Male ; Medicine, Chinese Traditional ; RNA, Messenger ; Rats ; Rats, Wistar