ABSTRACT
To investigate the incidence and gene mutation characteristics of fatty acid oxidative metabolism disorders in Jining area of Shandong province , and to evaluate the therapeutic effect. Blood samples of newborns were collected in Jining of Shandong province between July 14, 2014 and December 31, 2019. Tandem mass spectrometry was used to determine the levels of carnitine and acylcarnitine in the blood to screen for fatty acid oxidative metabolism disorder. For newborns with positive screening result, blood DNA was analyzed by MassARRAY and high-throughput sequencing, then verified by Sanger sequencing. The diagnosed children were given early intervention and treatment, and followed up. Forty-two children with fatty acid oxidative metabolism disorders were screened out of 608 818 newborns, with an incidence rate of 1/14 496. Primary carnitine deficiency (16 cases, 38.10%) and short-chain acyl-CoA dehydrogenase deficiency (16 cases, 38.10%) were the most common, followed by very long-chain acyl-CoA dehydrogenase deficiency (6 cases, 14.29%), medium-chain acyl-CoA dehydrogenase deficiency (4 cases, 9.53%). In children with primary carnitine deficiency, c.1400C>G (p.S467C) and c.51C>G were the most common in mutations; and c.278C>T (p.S93L), c.1049T >C (p.L350P), c.572A>G (p.K191R), c.431T>C (p.L144P) were newly discovered mutations. Ten children with carnitine replacement therapy showed normal development during the follow-up. In 6 children without carnitine replacement treatment, hypoglycemia developed during the neonatal period in 1 case, in whom the creatine kinase was increased, and the intellectual and language development delayed in the later period; the other 5 children developed normally during the follow-up period. The gene mutations c.1031A>G (p.E344G) and c.164C>T (p.P55L) were common in children with short-chain acyl-CoA dehydrogenase deficiency, and the children developed normally during the follow-up. In children with very long-chain acyl-CoA dehydrogenase deficiency, the c.1349G>A was common in gene mutations; and c.488T>A , c.1228G>T (p.D410Y), c.1276G>A (p.A426T), c.1522C>T (p.Q508*), c.1226C>T (p.T409M) were newly discovered mutations. Three children treated with milk powder rich in medium-chain fatty acids had normal development during the follow-up. The other 3 cases with combined carnitine reduction were treated with levocarnitine and milk powder enriched of medium-chain fatty acids, 1 case developed normally during the follow-up, 1 case died of acute illness at the age of and 1 case had acute illness and recovered after treatment, and developed normally during the follow-up. c.449_452del (p.T150Rfs*4) was the most common gene mutation in children with medium-chain acyl-CoA dehydrogenase deficiency, and c. 718A>G (p.M240V) was a newly discovered mutation. All children received low-fat diet, and hunger and fatigue were avoided; 1 child was supplemented with L-carnitine, and the other 3 children were not treated with drugs, and all of them developed normal during the follow-up. Primary carnitine deficiency and short-chain acyl-CoA dehydrogenase deficiency are the most common fatty acid oxidative metabolism disorders in Jining area. There are gene hotspot mutations and new discovered gene mutations in patients. Patients with early diagnosis and treatment through neonatal screening have a good prognosis.
Subject(s)
Lipid Metabolism, Inborn Errors , Acyl-CoA Dehydrogenase/genetics , Child , Fatty Acids , Follow-Up Studies , Humans , Infant, Newborn , Lipid Metabolism, Inborn Errors/genetics , Oxidative StressABSTRACT
YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions. We found that expression of YAPdeltaC during development, but not adulthood, rescued neurodegeneration phenotypes of mutant ataxin-1 knock-in (Atxn1-KI) mice. YAP/YAPdeltaC interacted with RORα via the second WW domain and served as co-activators of its transcriptional activity. YAP/YAPdeltaC formed a transcriptional complex with RORα on cis-elements of target genes and regulated their expression. Both normal and mutant Atxn1 interacted with YAP/YAPdeltaC, but only mutant Atxn1 depleted YAP/YAPdeltaC from the RORα complex to suppress transcription on short timescales. Over longer periods, mutant Atxn1 also decreased RORα in vivo. Genetic supplementation of YAPdeltaC restored the RORα and YAP/YAPdeltaC levels, recovered YAP/YAPdeltaC in the RORα complex and normalized target gene transcription in Atxn1-KI mice in vivo. Collectively, our data suggest that functional impairment of YAP/YAPdeltaC by mutant Atxn1 during development determines the adult pathology of SCA1 by suppressing RORα-mediated transcription.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Ataxin-1/genetics , Cerebellum/metabolism , Gene Expression Regulation, Developmental/genetics , Neurons/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism , Phosphoproteins/metabolism , Spinocerebellar Ataxias/genetics , Animals , Cell Cycle Proteins , Cerebellum/cytology , Disease Models, Animal , Gene Knock-In Techniques , Male , Mice , Phenotype , Protein Isoforms , Rotarod Performance Test , Spinocerebellar Ataxias/physiopathology , YAP-Signaling ProteinsABSTRACT
OBJECTIVE: To investigated the effect of Polygonum Bistorta L. n-butyl Alcohol (PBNA) extract on the NO content and NOS activity in ischemia/reperfusion (I/R) injury in the rat retina. METHODS: The model of retinal I/R injury in SD rats was made by reperfusion for 1 h after occlusion of common carotid artery (CCA) for 1 h. The rats were randomly divided into four groups: control group, retinal I/R injury group, low-dosage PBNA treated group and high-dosage treated PBNA group. The control group was injected with 1 ml/kg NS through sublingual vein after CCA was dissociated. Other groups were treated with normal saline or PBNA before occlusion of CCA. After occlusion of CCA for 1 h following reperfusion for 1 h, blood was collected and serum was separated to determine the contents of NO, the activity of T-NOS, iNOS and eNOS. RESULT: (1) The contents of NO in I/R group showed lower values than in control group (P<0.001) and low-dosage PBNA treated group (P<0.05). (2) The activities of T-NOS in both low-dosage PBNA group and high-dosage group increased, compared with I/R group (P<0.01). (3) The activity of serum iNOS in I/R group increased compared with control group (P<0.05) and low-dosage PBNA treated group evidently (P<0.05). (4) The activity of serum eNOS in I/R group decreased compared with control group (P<0.05), both low-dosage (P<0.05) and high-dosage PBNA (P<0.01) treated group markedly. CONCLUSION: The date suggest that PBNA have a therapeutic effect on retinal ischemia/reperfusion injury by increasing the activities of T-NOS and eNOS, decreasing the activity of iNOS, elevating the content of NO, enhancing the Anti-oxidation and expanding the blood vessel.
Subject(s)
Nitric Oxide Synthase/blood , Nitric Oxide/blood , Plant Extracts/therapeutic use , Polygonum/chemistry , Reperfusion Injury/blood , Reperfusion Injury/drug therapy , Animals , Male , Nitric Oxide Synthase Type II/blood , Nitric Oxide Synthase Type III/blood , Phytotherapy , Plant Extracts/pharmacology , Rats , Rats, Sprague-Dawley , Reperfusion Injury/enzymology , Retina/drug effects , Retina/enzymology , Retina/pathologyABSTRACT
Three new acetylated flavonoid glycosides, 5,6,4'-trihydroxyflavone 7-O-alpha-L-2,3-di-O-acetylrhamnopyranosyl-(1-->6)-beta-D-glucopyranoside (1), apigenin 7-O-alpha-L-3-O-acetylrhamnopyranosyl-(1-->6)-beta-D-glucopyranoside (2), and apigenin 7-O-alpha-L-2,3-di-O-acetylrhamnopyranosyl-(1-->6)-beta-D-glucopyranoside (3), were isolated from Scoparia dulcis together with the known compound eugenyl beta-D-glucopyranoside (4). Their structures were elucidated by spectroscopic analyses. Compounds 2 and 3 showed an enhancing activity of nerve growth factor-mediated neurite outgrowth in PC12D cells.
Subject(s)
Flavonoids/isolation & purification , Flavonoids/pharmacology , Glycosides/isolation & purification , Glycosides/pharmacology , Nerve Growth Factor/physiology , Neurites/drug effects , Plants, Medicinal/chemistry , Scoparia/chemistry , Acetylation , Animals , Flavonoids/chemistry , Glycosides/chemistry , Japan , Molecular Structure , Neurites/physiology , Nuclear Magnetic Resonance, Biomolecular , PC12 Cells , Rats , StereoisomerismABSTRACT
A new dihydrochalcone dimer, 2',4',3",2"',4"'-pentahydroxy-4-O-4"-tetrahydrobichalcone, given the name littorachalcone, was isolated from the aerial parts of Verbena littoralis H. B. K. along with two known flavonoids 4'-hydroxywogonin and 8,3'-dimethoxy-5,7,4'-trihydroxyflavone. Littorachalcone caused a significant enhancement of nerve growth factor-mediated neurite outgrowth from PC12D cells.
Subject(s)
Chalcone/analogs & derivatives , Chalcone/pharmacology , Nerve Growth Factor/pharmacology , Neurites/drug effects , Verbena , Animals , Chalcone/chemistry , Chalcone/isolation & purification , Chalcones , Drug Synergism , Neurites/physiology , PC12 Cells , Plant Components, Aerial , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , RatsABSTRACT
Two new sterols, stigmast-5-ene 3beta,4beta,7alpha,22alpha-tetraol (1) and stigmast-5-ene 3beta,7alpha,22alpha-triol (2), were isolated from the aerial parts of a Paraguayan medicinal plant, Verbena littoralis, together with the known compounds ursolic acid (3) and oleanolic acid (4). The structures of 1 and 2 were elucidated by spectroscopic analyses. Compounds 2-4 showed an enhancing activity of nerve growth factor (NGF)-mediated neurite outgrowth in PC12D cells.