Objective To explore the possible mechanism by which thioredoxin-interacting protein (TXNIP) par?ticipated in early brain injury (EBI) of subarachnoid hemorrhage (SAH) via examination of the expression of TXNIP and its downstream apoptotic factors before and after intervention. Methods Subarachnoid Hemorrhage (SAH) was performed by endovascular perforation. Total 97 adult male SD rats were randomly divided into 6 groups:sham-operation (17), SAH (32), control siRNA (12), TXNIP siRNA (12), resveratrol control (12) and resveratrol injection (12). Western blot was used to examine the expression of TXNIP, p-ASK-1, Caspase-3 before and after intervention. Laser scanning confocal microscopy (LSCM) was used to detect the expression of TXNIP in neurons. The co-localization of TXNIP with apoptotic cells was examined by using fluorescent TUNEL. Mortality, behavior score and cerebral edema were also evaluated. Re?sults Mortality, behavior scores and brain edema were improved after TXNIP siRNA and resveratrol injection(P<0.05). LSCM showed that TXNIP was widely expressed in brain and mainly located in cytoplasm of neurons in SAH rats. Fluo?rescent TUNEL revealed the co-localization of TXNIP with apoptotic cells. The expression level of TXNIP was signifi?cantly higher in SAH group than in sham operation (P<0.05, n=3). The expression level of TXNIP gradually increased at 12h and still remained at high level at 72h (P<0.05). This increase was simultaneously accompanied by the increase in downstream apoptosis factors, p-ASK-1 and Caspase-3. Inhibition of TXNIP by siRNA or resveratrol significantly re?duced the expression of TXNIP, p-ASK-1 and Caspase-3 (P<0.05, n=3). Conclusion TXNIP gradually increases in ear?ly period after SAH and aggravates brain damage through activation of ASK-1 apoptosis signaling pathway, whereas inhi?bition of TXNIP may attenuate EBI through reduction of p-ASK-1 and Caspase-3 after SAH.

OBJECTIVE: To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. METHODS: Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. RESULTS: The proband of pedigree 1 was a fetus at 23⁺⁵ weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. CONCLUSION The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.
Female ; Humans ; Pregnancy ; Pedigree ; Cerebellum/abnormalities* ; Abnormalities, Multiple/diagnosis* ; Eye Abnormalities/diagnosis* ; Kidney Diseases, Cystic/diagnosis* ; Phosphoric Monoester Hydrolases/genetics* ; Retina/abnormalities* ; East Asian People ; Mutation