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Neurofibromatosis type 1（NF1）is one of the most common autosomal dominant disorders. The disease is caused by mutations in the NF1 gene，which can involve multiple systems and have a variety of clinical manifestations，including café au lait macules，lisch nodules，neuroglioma，autism spectrum disorder，learning difficulties，neurofibromas，and skeletal dysplasia，et al.In previous studies on the pathogenesis of NF1，most of them have focused on the regulation of the RAS signaling pathway by neurofibromin. In recent years，researchers start exploring pathways other than RAS signaling to explore the potential functions of neurofibromin. This article reviews the research progress on the pathogenesis of NF1 in recent years，aiming to provide new ideas for treatment.
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Hypoxic pulmonary hypertension(HPH)is a kind of chronic high-altitude sickness disease,which is also the initiation link of high-altitude sickness such as pneumocardial disease and high-altitude pulmonary edema.Its main features are persistent vasoconstriction and irreversible remodeling of blood vessels.HPH has greatly impacted the health of people in the plat-eau section.As a typical representative of ethnic medicine,Zang medicine embodies the wisdom of the Zang people in their long-term struggle against diseases.Adapting to local conditions for a long time,Zang medicine has unique advantages in the treatment of HPH.By reviewing the pathogenesis of HPH and the research of single Zang medicine and the complex prescription of Zang medicine in the treatment of HPH,this article aims to provide a theoretical basis for the physiological and pathological research of HPH and to provide a reference for the clinical application of Zang medicine.
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In the past decade, significant progress has been made in the study of epilepsy-causing genetic mutations and the molecular mechanisms of epilepsy clinical manifestations.A growing number of studies have shown that the mechanism of action of pathogenic genes related to clinical symptoms shows significant correlation.In the selection of antiepileptic drugs for patients with different gene mutation, early identification of pathogenic genes has guiding significance for the selection of antiepileptic drugs.This review summairzes common epilepsy pathogenic genes, including ion channels genes, cellular metabolism related genes and cell signaling pathway related genes, and research progress on therapeutic targets corresponding to pathogenic genes in recent years.As research deepens, specific gene defects and their machanisms of action provide a basis for studying new treatment methods.
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IL1RAPL1 gene is one of the genes related to X-linked nonspecific mental retardation(MRX), but its pathogenic mechanism has not been fully clarified.Interleukin-1 receptor accessory protein like 1(IL1RAPL1) is a synaptic adhesion molecule located on postsynaptic membrane.The mutation of IL1RAPL1 gene can lead to the deletion or dysfunction of this protein.Recent studies have shown that the IL1RAPL1 protein regulates dendritic formation and mediates the activity of IL-1β molecules on dendritic morphology.This review describes the latest advances in synaptic and neuronal functions of IL1RAPL1, and summarizes some gene mutations that have been found to be associated with mental retardation(MR)and autism spectrum disorder(ASD), to provide evidence for clinical diagnosis and treatment.
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SCN2A (sodium channel, voltage-gated, type Ⅱ, alpha) gene encodes neuronal voltage-gated sodium channel Na V1.2, one of the four sodium channel analogues expressed in the central nervous system, which participates in the initiation and conduction of a series of neuronal action potentials.The dysfunction of SCN2A gene is associated with a variety of neurodevelopmental disorders, and has been confirmed to be one of the main causes of epilepsy, autism spectrum disorder and mental retardation in infants.There is a strong correlation between the type of gene mutations and clinical phenotypes.The clinical symptoms of seizures can be improved by activating the function of sodium channels.This paper describes the related research on SCN2A gene-mediated epilepsy in recent years, and summarizes its clinical characteristics, which provides a new idea for treatment.
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Objective@#To summarize the clinical and genetic features of β-propeller protein-associated neurodegeneration (BPAN).@*Methods@#The clinical data of 17 patients with BPAN with WDR45 gene variants were retrospectively collected at Children’s Hospital of Fudan University, Peking University First Hospital, Capital Institute of Pediatrics, Shengjing Hospital of China Medical University and Shanghai Children's Hospital from June 2016 to December 2018, and their clinical manifestations, electroencephalogram, neuroimaging and genetics were analyzed.@*Results@#Seventeen cases (13 females, 4 males), aged 1.1-8.8 years, were included. The median age of seizure onset was 14.5 months, from 3 months to 24 months of age, manifested with epileptic spasm in 6 cases and focal seizures in 5 cases. Eight patients had only one seizure type and 8 patients had two or more seizure types. Nine patients had complete remission of seizures. All 16 patients with seizures had developmental delay before the seizure onset, of whom 13 patients had moderate to severe seizures. The brain magnetic resonance imaging (MRI) was abnormal in 13 patients, including cerebral atrophy (10 cases) and thinning of the corpus callosum (9 cases). The brain magnetic susceptibility weighted imaging (SWI) in preschool stage showed prominent T2 hypointense signals in bilateral globus pallidus and brainstem ventral in two cases. Five seizure types (spasm, focal, absence, myodonic and generalized tonic clonic seizures)were found on ictal electroencephalogram(EEG) recordings. Compared to female patients(17(6-24) months of ege), male cases had earlier seizure onset (3, 4, 5, 18 months of age) . All patients had de novo variations in WDR45(6 nonsense, 4 frameshift, 3 missense and 4 splicing variations), with hemizygous variants in 3 males, mosaic variants in a male and heterozygous variants in 13 females, within which 5 variations had not been reported (c.977-1C>T,c.976+1G>C,c.10C>T,c.806del and c.110T>C).@*Conclusions@#The patients with BPAN have profound developmental delay and are vulnerable to seizures. The male patients with BPAN tend to have more severer clinical phenotype than females. Early brain SWI could facilitate the timely diagnosis of this disease.
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Ataxia-telangiectasia (AT) is a rare autosomal recessive genetic disorder resulting from ataxia-telangiectasia mutated(ATM) gene mutation.ATM involved in DNA repair.ATM is made up of 66 exons.Its mutation forms are complex, including nonsense mutation, missense mutation, shear site mutation, insertion and deletion, etc.The patients are characterized by progressive cerebellar atrophy and ataxia, disturbance of eye movement, telangiectasia and dystonia, a high risk of cancer and immunodeficiency.These patients are also hypersensitive to radiotherapy.AT is often neglected at the early stage.As pediatricians, we should pay attention to early ataxia and conduct genetic testing as early as possible to avoid radiation exposure.
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The purpose of this study was to investigate the effects of salvianolic acid A (SAA) in systemic lupus erythematosus (SLE) induced by pristane in BALB/c mice. Lupus mice were established by confirming elevated levels of autoantibodies and IL-6 after intraperitoneal injection of pristane. Mice were then treated with daily oral doses of SAA for 5 months in parallel with mice treated with prednisone and aspirin as positive controls. The levels of autoantibodies were monitored at monthly intervals and nephritic symptoms observed by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. Western blot analysis of renal tissue was also employed. SAA treatment caused a significant reduction in the levels of anti-Sm autoantibodies and reduced renal histopathological changes and pathological effects. SAA treatment also significantly inhibited the phosphorylation of IKK, IB and NFB in renal tissues of lupus mice. In conclusion, the results suggest that SAA alleviates renal injury in pristane-induced SLE in BALB/c mice through inhibition of phosphorylation of IKK, IB and NFB.
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OBJECTIVE:To observe the clinical efficacy and safety of ambroxol hydrochloride in the treatment of neonatal re-spiratory distress syndrome. METHODS:108 cases of neonatal respiratory distress syndrome were randomly divided into control group and observation group,54 cases in each group. Control group were treated with conventional treatment,such as oxygen inha-lation,anti-infection and nutritional support,observation group was additionally treated with 30 mg/kg Ambroxol hydrochloride in-jection,ivgtt,qd,for continuous treatment of 4-6 d. Clinical efficacy,blood gas indexes [oxygen partial pressure(PaO2),carbon dioxide partial pressure (PaCO2)],12,24 and 48 h after treatment remission time of clinical symptoms,hospitalization time, changes of X-ray film value,tidal volume(VT)and dynamic lung compliance(Cdyn)in 2 groups were compared,and the inci-dence of adverse reactions was observed. RESULTS:The total effective rate in observation group was 94.44%,which was signifi-cantly higher than control group (51.58%),the difference was statistically significant (P0.05),PaO2 was significantly higher than control group and Pa-CO2 was significantly lower than control group 24 and 48 h after treatment,there was significant difference between 2 groups(P<0.05). Remission time of cyanosis,dyspnea,lung moist rales and hospitalization time in observation group were shorter than con-trol group,the difference was statistically significant(P<0.05). X-ray film value,Cdyn and VT levels in observation group were significantly higher than control group,the difference was statistically significant(P<0.05). The incidence of adverse reactions in observation group was 3.70%,which was significantly lower than control group(18.52%),the difference was statistically signifi-cant(P<0.05). CONCLUSIONS:Ambroxol hydrochloride shows obvious efficacy in the treatment of neonatal respiratory distress syndrome,it can improve blood gas indexes and accelerate the recovery from disease,with good safety.
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Aim To evaluate the vasorelaxant effect of two new chemical entities, J35242 and J35243, on iso-lated rat thoracic aorta rings as Rho-kinase inhibitors, and further to explore the underlying mechanisms of these two compounds. Methods Isolated rat thoracic aorta rings pre-contracted by KCl or norepinephrine ( NE) were used to evaluate the vasodilatory effect of J35242 and J35243 . Through the interventions of sev-eral tool drugs, the mechanisms of compounds concern-ing endothelium, K+ channels and Ca2+ were studied. Results J35242 and J35243 showed potent relaxant effect on both KCl and NE pre-contracted vessels, and exhibited partial endothelium dependency. L-NAME and Methylene Blue( MB) could influence the relaxant effect of these compounds. Meanwhile, the compounds could inhibit intracellular Ca2+ release and extracellu-lar Ca2+ influx, which indicated that the compounds might block the calcium channels to relax the vessels. In addition, the two compounds probably did not dilate the aorta rings through opening potassium channels. Conclusions J35242 and J35243 have vasorelaxant effects on vessels in vitro and the potency of J35242 is stronger than that of J35243 . The underlying mecha-nisms might be endothelium-dependent. Also the com-pounds might block Ca2+ channels, lowering intracel-lular Ca2+ concentration to relax the vessels.
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Salvia miltiorrhiza is dry root or rhizome of the labia-tae plant Salvia miltiorrhiza, whose water-soluble ingredients are recognized as its bioactive components in cardiovascular disea-ses. Based on researches at home and abroad in recent years, this article summarizes pharmacological effect resisting myocardi-al ischemia of Salvia miltiorrhiza ’ s water soluble compounds in multi-level from the prevention, treatment and anti-reperfusion damage, to provide theoretical basis for the research and devel-opment of the active monomers in Salvia miltiorrhiza and com-pound preparations.
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DNA polymerase γis the only known DNA polymerase in human mitochondria,and is essential for mitochondrial DNA replication and repair.DNA polymerase γ is encoded by POLG gene.POLG-related disorders resulted from mutations of POLG gene comprise a continuum of overlapping phenotypes including Alpers Huttenlocher syndrome and other five subtypes, with high prevalence rate at patients with intractable seizure.Genetic testing for POLG mutations in patients with intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations.
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Aim To investigate the effect of Salvianol-ic acid A (Sal A)on mice with isoproterenol (ISO)-induced myocardial infraction and its possible mecha-nisms.Methods The mice were subcutaneously in-jected with ISO (8 mg·kg-1 )to induce myocardial in-farction.The myocardial protective effect of Salvianolic acid A was evaluated from mortality rate,electrocardio-gram (ECG),heart function,myocardial infarction in-dex,serum myocardial enzymes and its action mecha-nisms were explored from inflammation,anti-oxidation and cells apoptosis.Results Salvianolic acid A dose-dependently enhanced the heart function of myocardial infarction mice,reduced the heart index,inhibited the myocardial enzyme leakage,showed obvious myocardi-al protection effects.ELISA results showed that Salvi- anolic acid A could reduce the expression of myocardial inflammatory cytokines such as IL-6(interleukin-6,IL-6),TNF-α(tumornecrosis factor-α,TNF-α).West-ern-blotting confirmed that Salvianolic acid A could in-crease the expression of anti-apoptotic proteins Bcl-2, reduce the expression of apoptosis protein Bax,and raise the phosphorylation level of PI3K and Akt.Con-clusion Salvianolic acid A displays a significant pro-tective effect against isoproterenol-induced myocardial infarction and its mechanism may be related to the in-crease of PI3K/Akt signal pathway and the inhibition of cell apoptosis and inflammatory reaction.
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This study is to investigate the effect of total flavonoids of Uygur medicine bugloss (BTF) on rats with myocardial ischemia/reperfusion injury, and to explore the mechanisms by which it acts. Left anterior descending (LAD) coronary artery in rats was occluded for 30 min followed by 4 h reperfusion. Meanwhile, BTF dissolved in saline was administered intraperitoneally at dosage of 10, 30 and 50 mg x kg(-1). Electrocardiograph, infarction index, serum myocardial enzymes and heart function were determined to evaluate the effect of BTF. Some other observations were carried out to explore whether inhibiting inflammation and apoptosis is involved in the mechanisms underlying BTF. Our results showed that in ischemia/reperfusion injured rats BTF could dose-dependently reduce myocardial infarction index and myocardial enzyme leakage, and enhance heart function, indicating that it possesses significant cardio protection. ELISA analysis showed that BTF could decrease the content of myocardial inflammatory cytokines such as IL-1beta, IL-6 and TNF-alpha. Western-blotting confirmed that BTF could increase the expression of anti-apoptotic protein Bcl-2 and reduce the expression of proapoptosis protein Bax. Further more, the phosphorylation level of PI3K and Akt was upregulated by BTF treatment. BTF can protect rat against myocardial ischemia/reperfusion injury. Anti-inflammation and inhibition of apoptosis through upregulating PI3K/Akt signal pathway may contribute to the protective effect of BTF.
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<p><b>OBJECTIVE</b>To investigate whether or not the gamma-aminobutyric acid (GABA) receptor subtype A genes GABRA5 and GABRB3 are associated with childhood absence epilepsy (CAE).</p><p><b>METHODS</b>Two microsatellite DNA, GABRA5 and GABRB3, adjoining to chromosome 15q11.2-q12 were used as genetic markers. Both case-control study and transmission/disequilibrium test (TDT) as well as fluorescence-based semi-automated genotyping technique were used in 90 trios with CAE and 100 controls to conduct association analysis.</p><p><b>RESULTS</b>The allele frequencies of the 2 microsatellite DNA in Chinese normal population are in good agreement with Hardy-Weinberg equilibrium. The polymorphism information content of microsatellite DNA GABRA5 and GABRB3, are 0.80 and 0.66 respectively. The allele 2 frequency of microsatellite DNA GABRA5 and the allele 5 frequency of microsatellite DNA GABRB3 are significantly higher in CAE patients than those in normal controls(P<0.001).</p><p><b>CONCLUSION</b>Both microsatellite DNA GABRA5 and GABRB3 are good genetic markers. The gamma-aminobutyric acid receptor subtype A genes GABRA5 and GABRB3 may be directly involved either in the etiology of CAE or in linkage disequilibrium with disease-predisposing sites.</p>