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Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (K+)-channel dysfunction in hyperexcitability of CA3 pyramidal neurons in Fmrl knock-out (KO) mice. We observed a reduction of voltage-independent small conductance calcium (Ca2 1 j-activated K 1 (SK) currents in both male and female mice, leading to decreased action potential (AP) threshold and reduced medium afterhyperpolarization. These SK-channel-dependent deficits led to markedly increased AP firing and abnormal input-output signal transmission of CA3 pyramidal neurons. The SK-current defect was mediated, at least in part, by loss of FMRP interaction with the SK channels (specifically the SK2 isoform), without changes in channel expression. Intracellular application of selective SK-channel openers or a genetic reintroduction of an N-terminal FMRP fragment lacking the ability to associate with polyribosomes normalized all observed excitability defects in CA3 pyramidal neurons of Fmrl KO mice. These results suggest that dysfunction of voltage-independent SK channels is the primary cause of CA3 neuronal hyperexcitability in Fmrl KO mice and support the critical translation-independent role for the fragile X mental retardation protein as a regulator of neural excitability. Our findings may thus provide a new avenue to ameliorate hippocampal excitability defects in FXS. [ABSTRACT FROM AUTHOR]

Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitinlike containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved inDNAmethylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase andtensinhomolog(PTEN) andREST.Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration. [ABSTRACT FROM AUTHOR]

The present study was performed to evaluate the effect of medicinal plant extract on relieving hangovers in mice administered alcohol. The animals were divided into three groups. Each group was treated with fermented plant extract, non-fermented plant extract, or water 30 min after consuming ethanol (2 mL/kg). A locomotor activity test showed that all groups had decreased motor activity until 40 min after plant extract administration. The mice treated with water had lower motor activity until 100 min post-administration. However, the group treated with non-fermented plant extract showed increased motor activity 40 min post-administration, and the higher activity level was maintained until 120 min post-administration. The animals treated with fermented plant extract had a level of motor activity between those of the groups treated with water or non-fermented plant extract. Blood was collected from each mouse 120 min post-administration and aldehyde concentration was measured. The group treated with non-fermented plant extract had a significantly higher (p < 0.05) aldehyde concentration than the other groups. These results demonstrate that the non-fermented medicinal plant extract helped alleviate hangovers 40 min after administration by reducing aldehyde concentrations in the blood. [ABSTRACT FROM AUTHOR]

The Met receptor tyrosine kinase is an attractive target for cancer therapy as it promotes invasive tumor growth. SAIT301 is a novel anti-Met antibody, which induces LRIG1-mediated Met degradation and inhibits tumor growth. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1, which in turn promotes recruitment of Met and LRIG1 complex to the lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met.Wealso identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of RIG. In summary, SAIT301 employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a fully antagonistic antibody without Met activation. We found that USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and a Met inhibitor, such as SAIT301. [ABSTRACT FROM AUTHOR]

Chfr is a ubiquitin ligase that functions in the mitotic checkpoint by delaying entry into metaphase in response to mitotic stress. It has been suggested that Chfr is a tumour suppressor as Chfr is frequently silenced in human cancers. To better understand how Chfr activity relates to cell-cycle progression and tumorigenesis, we sought to identify Chfr-interacting proteins using affinity purification combined with mass spectrometry. Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Ectopic expression of Chfr in cancer cells that normally do not express it results in downregulation of HDAC1, leading to upregulation of the Cdk inhibitor p21CIP1/WAF1 and the metastasis suppressors KAI1 and E-cadherin. Coincident with these changes, cells arrest in the G1 phase of the cell cycle and become less invasive. Collectively, our data suggest that Chfr functions as a tumour suppressor by regulating HDAC1. [ABSTRACT FROM AUTHOR]

Objectives: We describe a case of multiple sclerosis presenting with sequential bilateral hearing loss. Methods: A 46-year-old woman underwent a series of audiological and neurologic evaluations for sequential bilateral hearing losses that occurred 6 months apart. Results: Initially, the patient suffered from sudden left hearing loss, and magnetic resonance imaging documented an enhancing lesion in the left middle cerebellar peduncle. Six months later, another episode of sudden vertigo, right hearing loss, and right facial palsy developed. Magnetic resonance imaging disclosed a new lesion in the right middle cerebellar peduncle. Conclusions: Sequential bilateral hearing loss may be a manifestation of multiple sclerosis. In younger patients with sudden hearing loss, multiple sclerosis should be included in the differential diagnosis. [ABSTRACT FROM AUTHOR]

Transgenic mice containing novel oncogene HCCR-2 were generated to analyse the phenotype and to characterize the role of HCCR-2 in cellular events. Mice transgenic for HCCR-2 developed breast cancers and metastasis. The level of p53 in HCCR-2 transgenic mice was elevated in most tissues including breast, brain, heart, lung, liver, stomach, kidney, spleen, and lymph node. We examined whether stabilized p53 is functional in HCCR-2 transgenic mice. Defective induction of p53 responsive genes including p21WAF1, MDM2, and bax indicates that stabilized p53 in HCCR-2 transgenic mice exists in an inactive form. These results suggest that HCCR-2 represents an oncoprotein that is related to breast cancer development and regulation of the p53 tumor suppressor.Oncogene (2004) 23, 1950-1953. doi:10.1038/sj.onc.1207356 Published online 22 December 2003 [ABSTRACT FROM AUTHOR]