Mechanism of RNA-binding protein Lin28 in neuronal ferroptosis after intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is a highly risky cerebrovascular disease with poor prognosis. Lin-28 homolog A (Lin28) has been identified as a crucial regulator in ICH. This study aims to analyse the mechanism of Lin28 in neuronal ferroptosis after ICH and provide theoretical basis for ICH treatment. An ICH mouse model was established via injection of collagenase VII, followed by neurological impairment assessment, and haematoxylin-eosin staining. An in vitro ICH model was established using hemin treatment. Next, cell viability and ferroptosis parameters were detected via cell counting kit-8, assay kits, enzyme-linked immunosorbent assay and western blot. Lin28 expression and tripartite motif-containing 37 (Trim37) mRNA level were detected via western blot and quantitative real-time polymerase chain reaction (qRT-PCR). The binding relationship of Lin28 and Trim37 was verified. ICH mice exhibited neuronal ferroptosis and upregulation of Lin28. Lin28 inhibition alleviated neurological impairment, manifested by decreased hematoma, oedema, neuronal necrosis, glial cell swelling, intracellular vacuoles and inflammatory cell infiltration, reduced Fe2+ concentration and reactive oxygen species content, and increased glutathione and glutathione peroxidase 4 activity. In the hemin-induced HT-22 cells, Lin28 inhibition promoted cell viability and alleviated neuronal ferroptosis. Lin28 bound to Trim37 mRNA to stabilize the mRNA level of Trim37. Overexpression of Trim37 reversed the alleviating role of silencing Lin28 in neuronal ferroptosis after ICH. Overall, Lin28 stabilized the mRNA level of Trim37 to aggravate neuronal ferroptosis after ICH.

Whole-Exome Sequencing Reveals Novel Variations in Patients with Familial Von Hippel-Lindau Syndrome.

OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare disease that occurs in an autosomal-dominant genetic pattern. Due to the high genetic variability of VHL diseases, current studies have limited clinical value. Moreover, casual genetic variations in patients with VHL syndrome are still unclear. METHODS: Here, we performed whole-exome sequencing of 25 individuals to identify reliable disease-related variations. Systemic computational analysis was performed for variant detection, and Sanger sequencing was used to validate detected mutations. RESULTS: Most of the known mutations in the VHL gene were observed in the studied population. In addition, a large fragment deletion in VHL exon 2 in the immediate family members of the last family was detected. This had not been reported earlier. Moreover, we identified 3 novel mutation sites in the MAP2K3 gene that may be involved in the occurrence and development of the VHL disease. CONCLUSIONS: These results demonstrated that the heterogeneous nature of VHL syndrome and novel mutational signatures may help to improve the diagnostic ability of VHL syndrome.

The Coexistence of Gliosarcoma and Arteriovenous Malformation with the BRAF V600E Mutation.

BACKGROUND: The authors report a case of a woman aged 33 years who suffered from the combination of primary gliosarcoma and arteriovenous malformation as the first clinical presentation of intracranial hemorrhage. CASE DESCRIPTION: Subsequently, gene examination rarely finds BRAF V600E mutation in the surgical specimen. The lesion was not completely identified with magnetic resonance imaging and digital subtraction angiography. CONCLUSIONS: This case illustrates the occult and unusual feature of gliosarcoma. The pathogenesis of such coexistence might be related to underlying genetic alterations.

MicroRNA­451 relieves inflammation in cerebral ischemia­reperfusion via the Toll­like receptor 4/MyD88/NF­κB signaling pathway.

The present study was designed to investigate the role of microRNA­451 (miRNA­451) on cerebral ischemia­reperfusion and to explore its possible mechanism. The expression of miRNA­451 was downregulated in rats with cerebral ischemia­reperfusion. In an in vitro model of cerebral ischemia­reperfusion, the downregulation of miRNA­451 increased inflammation, demonstrated by increased levels of tumor necrosis factor α, interleukin (IL)­1b, IL­6 and IL­18. However, the upregulation of miRNA­451 expression decreased inflammation in the same in vitro model of cerebral ischemia­reperfusion. In addition, it was found that the downregulation of miRNA­451 induced the expression of Toll­like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88 (MyD88) and nuclear factor­κB (NF­κB)/p65. Moreover, the administration of a MyD88 inhibitor, ST 2825, reduced the expression of MyD88 and NF­κB/p65 in the in vitro model of cerebral ischemia­reperfusion, inhibiting the effects of miRNA­451 upregulation on inflammation. A TLR4 inhibitor, TAK­242, was used to reduce the expression of TLR4 in the in vitro model of cerebral ischemia­reperfusion. TAK­242 suppressed the effects of miRNA­451 downregulation on inflammation. The present study suggested that miRNA­451 regulated cerebral ischemia­reperfusion­induced inflammation, which is mediated through the TLR4/MyD88/NF­κB signaling pathway.