14-3-3γ Haploinsufficient Mice Display Hyperactive and Stress-sensitive Behaviors

14-3-3γ plays diverse roles in different aspects of cellular processes. Especially in the brain where 14-3-3γ is enriched, it has been reported to be involved in neurological and psychiatric diseases (e.g. Williams-Beuren syndrome and Creutzfeldt-Jakob disease). However, behavioral abnormalities related to 14-3-3γ deficiency are largely unknown. Here, by using 14-3-3γ deficient mice, we found that homozygous knockout mice were prenatally lethal, and heterozygous mice showed developmental delay relative to wild-type littermate mice. In addition, in behavioral analyses, we found that 14-3-3γ heterozygote mice display hyperactive and depressive-like behavior along with more sensitive responses to acute stress than littermate control mice. These results suggest that 14-3-3γ levels may be involved in the developmental manifestation of related neuropsychiatric diseases. In addition, 14-3-3γ heterozygote mice may be a potential model to study the molecular pathophysiology of neuropsychiatric symptoms.

Gadd45b Acts as Neuroprotective Effector in Global Ischemia-Induced Neuronal Death / 대한배뇨장애요실금학회지

PURPOSE@#Transient global ischemia arising in human due to cardiac arrest causes selective, delayed neuronal death in hippocampal CA1 and cognitive impairment. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) is a wellknown molecule in both DNA damage-related pathogenesis and therapies. Emerging evidence suggests that Gadd45b is an anti-apoptotic factor in nonneuronal cells and is an intrinsic neuroprotective molecule in neurons. However, the mechanism of Gadd45b pathway is not fully examined in neurodegeneration associated with global ischemia.@*METHODS@#Rats were subjected to transient global ischemia by the 4-vessel occlusion or sham operation. The animals were sacrificed at 24 hours, 48 hours, and 7 days after ischemia. The hippocampal CA1 was microdissected and processed to examine mRNA and protein level. To assess neuronal death, tissue sections were cut and processed for Fluoro-Jade and Nissl staining.@*RESULTS@#Here we show that ischemic insults increase abundance of Gadd45b and brain-derived neurotrophic factor, a known target of Gadd45 mediated demethylation, in selectively-vulnerable hippocampal CA1 neurons. We further show that knockdown of Gadd45b increases abundance of a pro-apoptotic Bcl-2 family member Bax while decreasing the antiapoptotic protein Bcl-2, which together promote neuronal death.@*CONCLUSIONS@#These findings document a protective role of Gadd45b against neuronal insults associated with global ischemia and identify Gadd45b as a potential therapeutic target for the amelioration of hippocampal neurodegeneration.

BubR1 Insufficiency Impairs Affective Behavior and Memory Function in Mice / 대한배뇨장애요실금학회지

PURPOSE: Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function. METHODS: To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1 H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function. RESULTS: We found that BubR1 H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1 H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function. CONCLUSIONS: Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction.

Frontier of Epilepsy Research - mTOR signaling pathway

Studies of epilepsy have mainly focused on the membrane proteins that control neuronal excitability. Recently, attention has been shifting to intracellular proteins and their interactions, signaling cascades and feedback regulation as they relate to epilepsy. The mTOR (mammalian target of rapamycin) signal transduction pathway, especially, has been suggested to play an important role in this regard. These pathways are involved in major physiological processes as well as in numerous pathological conditions. Here, involvement of the mTOR pathway in epilepsy will be reviewed by presenting; an overview of the pathway, a brief description of key signaling molecules, a summary of independent reports and possible implications of abnormalities of those molecules in epilepsy, a discussion of the lack of experimental data, and questions raised for the understanding its epileptogenic mechanism.

Plaque Rupture is a Determinant of Vascular Events in Carotid Artery Atherosclerotic Disease: Involvement of Matrix Metalloproteinases 2 and 9

BACKGROUND AND PURPOSE: Unstable carotid atherosclerotic plaques are characterized by cap rupture, leading to thromboembolism and stroke. Matrix metalloproteinases (MMPs) have been implicated in the progression of atherosclerosis and plaque rupture. The aim of this study was to assess the relationship between the expressions of MMP-2 and MMP-9 and carotid plaque instability. METHODS: Eighty atherosclerotic plaques were collected from 74 patients undergoing carotid endarterectomy. Clinical information was obtained from each patient, and plaque morphology was examined at the macroscopic and microscopic levels. The immunohistochemical expressions of MMPs were graded using semiquantitative scales. RESULTS: Macroscopic ulceration (84.6% versus 63.4%, p=0.042) and microscopic cap rupture (79.5% versus 51.2%, p=0.010) were more common in symptomatic than in asymptomatic patients. Immunoreactivities of MMP-2 and MMP-9 were increased in 40 and 36 atheromatous plaques, respectively. Macroscopic ulceration was strongly correlated with the expressions of MMP-2 (p<0.001) and MMP-9 (p=0.001). There were significant correlations between increased MMP-2 expression and cap rupture (p=0.002), intraplaque hemorrhage (p=0.039), and a thin fibrous cap (p=0.002), and between increased MMP-9 expression and cap rupture (p=0.010) and a large lipid core (p=0.013). CONCLUSIONS: Plaque rupture was significantly associated with the development of vascular events in carotid atherosclerotic disease. MMP-2 and MMP-9 are strongly correlated with plaque instability.

Telomerase is strongly activated in hepatocellular carcinoma but not in chronic hepatitis and cirrhosis

Telomerase is highly activated in human immortal cell lines and tumor tissues, whereas it is not activated in primary cell strains and many tumor-adjacent tissues. It is suggested that telomerase activation is one of the critical steps in malignant transformation. In the present study, the telomerase activity was investigated in hepatocellular carcinoma tissues and non-tumor liver tissues from Korean patients with chronic hepatitis and cirrhosis. Eighty two liver tissues (24 chronic hepatitis specimens, 34 cirrhosis specimens, and 24 hepatocellular carcinomas) were obtained from 23 chronic viral hepatitis patients, 19 cirrhosis patients (including 7 liver transplants), and 24 patients with hepatocellular carcinoma, of which the surrounding non-tumor liver tissues were available in 16 patients (1 chronic hepatitis and 15 cirrhosis). As negative controls, 3 normal liver tissues were included. Protein from liver specimens was purified by a detergent lysis method as described elsewhere, and telomerase activity was measured in 2 diluents of each sample (1:1 and 1:100) by a telomeric repeat amplification protocol (TRAP). Telomerase was strongly activated in 79% (19/24) of the hepatocellular carcinomas, while weakly in 8% (2/24) of the chronic hepatitis tissues and in 24% (8/34) of the cirrhosis tissues. All of 3 normal control livers showed no telomerase activation. No relationship could be observed between the enhancement of telomerase activity and tumor nature. None of the chronic heaptitis or cirrhosis patients with mild telomerase activation in the liver have developed hepatocellular carcinoma for at least 2 years of follow-up period. These results suggest that the strong enhancement of telomerase activity may be a critical part of hepatocarcinogenesis, although the exact mechanism of such high activation in hepatocellular carcinoma is not clear. In addition, further study will be necessary to clarify the reason why no telomerase activity detectable by a conventional TRAP can be seen in some hepatocellular carcinoma.

Clinical experience of multiple valve replacement / 대한흉부외과학회지

No abstract available.