Novel compound heterozygous mutations of the NPC1 gene associated with Niemann-pick disease type C: a case report and review of the literature.

BACKGROUND: Niemann-Pick Disease type C is a fatal autosomal recessive lipid storage disorder caused by NPC1 or NPC2 gene mutations and characterized by progressive, disabling neurological deterioration and hepatosplenomegaly. Herein, we identified a novel compound heterozygous mutations of the NPC1 gene in a Chinese pedigree. CASE PRESENTATION: This paper describes an 11-year-old boy with aggravated walking instability and slurring of speech who presented as Niemann-Pick Disease type C. He had the maternally inherited c.3452 C > T (p. Ala1151Val) mutation and the paternally inherited c.3557G > A (p. Arg1186His) mutation using next-generation sequencing. The c.3452 C > T (p. Ala1151Val) mutation has not previously been reported. CONCLUSIONS: This study predicted that the c.3452 C > T (p. Ala1151Val) mutation is pathogenic. This data enriches the NPC1 gene variation spectrum and provides a basis for familial genetic counseling and prenatal diagnosis.

Sodium formononetin-3'-sulphonate alleviates cerebral ischemia-reperfusion injury in rats via suppressing endoplasmic reticulum stress-mediated apoptosis.

BACKGROUND: Sodium formononetin-3'-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia-reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis. RESULTS: The cerebral lesions of middle cerebral artery occlusion (MCAO) model in SD rats were aggravated after 24 h of reperfusion, including impaired neurological function, increased infarct volume, intensified inflammatory response and poor cell morphology. After intervention, the edaravone (EDA, 3 mg/kg) group and Sul-F high-dose (Sul-F-H, 80 mg/kg) group significantly alleviated I/R injury via decreasing neurological score, infarct volume and the serum levels of inflammatory factors (TNF-α, IL-1ß and IL-6), as well as alleviating pathological injury. Furthermore, the ER stress level and apoptosis rate were elevated in the ischemic penumbra of MCAO group, and were significantly blocked by EDA and Sul-F-H. In addition, EDA and Sul-F-H significantly down-regulated the ER stress related PERK/eIF2α/ATF4 and IRE1 signal pathways, which led to reduced cell apoptosis rate compared with the MCAO group. Furthermore, there was no difference between the EDA and Sul-F-H group in terms of therapeutic effect on cerebral I/R injury, indicating a therapeutic potential of Sul-F for ischemic stroke. CONCLUSIONS: Sul-F-H can significantly protects against cerebral I/R injury through inhibiting ER stress-mediated apoptosis in the ischemic penumbra, which might be a novel therapeutic target for ischemic stroke.

High expression of NF-κB inducing kinase in the bulge region of hair follicle induces tumor.

The bulge region, a reservoir of multipotent stem cells, is possibly responsible for tumorigenesis. NF-κB-inducing kinase (NIK) is a kinase involved in the activation of the noncanonical NF-κB pathway and exhibits positive staining in tumor cells. However, whether high expression of NIK can result in tumorigenesis has not been reported in published papers. By establishing Nik-coe (Nik-stopF/F crossed with Chat-cre) and Nik-soe (Nik-stopF/F crossed with Sox9-cre) mice, we found that overexpression of Nik in the bulge region of hair follicles induced hair follicle loss and tumorigenesis. Furthermore, RNA sequencing, proteomic and phosphopeptide analyses revealed that multiple cancer pathways are involved in tumor formation. Taken together, these findings indicate that constitutive activation of Nik in the bulge region induces tumorigenesis.

Myeloid TBK1 Deficiency Induces Motor Deficits and Axon Degeneration Through Inflammatory Cell Infiltration.

BACKGROUND: TANK-binding kinase1 (TBK1) haploinsufficiency has been shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the mechanism is unclear. METHODS: Myeloid Tbk1 knockout mice (Tbk1-LKO mice) were established and motor function and pathological analyses were also performed. The level of p-TBK1 was analyzed in the ALS animal model and in patient samples using flow cytometry. The expression of inflammatory proteins and mRNAs was analyzed via western blotting and RT-PCR, respectively. RESULTS: The latency to fall in seven-month-old Tbk1-LKO mice was significantly reduced in evaluations conducted on two consecutive days. Overall, 25.6% of Tbk1-LKO mice presented paralysis symptoms and signs, along with a loosened myelin sheath and axon degeneration at 14-16 months of age. Furthermore, the Tbk1 deficiency in myeloid cells induced inflammatory cell infiltration and dysbacteriosis in the digestive tract. Additionally, p-TBK1 levels were reduced by 29.5% and 14.8% in monocytes of patients with definite ALS and probable ALS and decreased by 27.6% and 45.5% in monocytes and microglia of ALS animals, respectively. The use of PEI-mannose-TBK1 or PEI-mannose-SaCas9-sgRNA to delete mutant SOD1 in macrophages significantly delayed disease onset and prolonged survival in the mouse model of ALS. CONCLUSIONS: Based on these data, inflammatory monocyte and macrophage infiltration and impaired innate immune defenses contribute to ALS and FTD.

[Study on absorption kinetics of astragaloside IV in rats intestines].

OBJECTIVE: To investigate the mechanisms of intestine absorption of astragaloside IV in rat. METHOD: The K(a) and P(app) of astragaloside IV was investigated using single-pass intestinal perfusion technique in rats. HPLC was used to determine the concentration of astragaloside IV. The effect of absorption site, drug concentration and the inhibitors of P-glycoproteon on the absorption had been studied. RESULT: By the testing of the statistics, the K(a) and the P(app) values of the duodenum, jejunum, ileum, colonic had significant differences (P < 0.05). The concentration from 20-80 mg x L(-1) had no distinctive effect on the K(a) and P(app) of small intestine. The inhibitors of P-glycoproteon had no distinctive effect on the absorption of small intestine. CONCLUSION: Astragaloside IV is absorbed by typical passive diffusion mechanism.

[Effects of Zhikeping on aortic oxyradical and the expression of ICAM-1 in a rat model of experimental early atherosclerosis].

OBJECTIVE: To investigate the effects of Zhikepingon the oxyradical andintercellular adhesion molecule-1 (ICAM-1) of experimental early atherosclerosis. METHOD: The model of SD rat early atherosclerosis was induced by cholesterol diet. The suspension of Zhikeping and simvastatin were administered intragastrically, respectively. After 10 weeks, the serum lipids, superoxide dismutase (SOD) and maleic dialdehyde (MDA) were detected by automatic biochemistry analyzer. ICAM-1 and its expression of mRNA in aortic wall were detected- by immunohistochemistry and RT-PCR, respectively. Aortic histomorphology was cbserved by HE stainning. RESULT: The results showed that the serum lipids, superoxide dismutase (SOD) and maleic dialdehyde (MDA) of treated groups were obviously improved as compared with those of the control group. The tissue pathological damage was improved indifferent degree, and ICAM-1 and its expression of mRNA was decreased obviously. CONCLUSION: It is suggested the mechanism of anti-atherosclerosis of Zhikeping have close relationship with the function of its anti-oxidizing and anti-adhesiveness that can protect aortic endothelial cell.