RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains / 神经科学通报·英文版

The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.

Protective effects of ghrelin against alcoholic induced liver injury in mice via anti-inflammation and anti-oxidative stress / 中国药理学通报

Aim To investigate the effects of ghrelin on alcohol-induced liver injury. Methods The alcoholic liver injury mouse model was induced by chronic etha-nol feeding ( 4-week ad libitum oral feeding with the ethanol liquid diet) plus a single binge ethanol (5 g· kg-1 ) feeding. The level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in serum, malondiadehyde ( MDA ) content, superoxide dis-mutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver homogenate were assayed by spectro-photometer. Hepatic pathological examination was ob-served by HE staining. The mRNA expression of proin-flammatory cytokines including TNF-α, IL-1β, IFN-γ, IL-6 and MCP-1 in the liver was measured by real-time PCR method. Results This chronic-plus-single-binge high dose ethanol feeding synergistically induced liver injury, inflammation and fatty liver change. Treatment with Ghrelin ( 5 , 10 , 20 μg · kg-1 ) significantly de-creased the enhanced level of transaminase ( ALT, AST) in serum, improved the pathologic change in liv-er, and reduced the infiltration of inflammatory cells induced by alcohol administration. Ghrelin also de-creased MDA content and increased the reduced SOD and GSH-Px level in liver homogenate. Furthermore, ghrelin decreased inflammatory cytokines mRNA ex-pression including TNF-α, IL-1β, IFN-γ, IL-6 and MCP-1 in the liver. Conclusion Ghrelin has protec-tive effects against alcoholic liver injury in mice via in-hibiting inflammation and suppressing oxidative stress.

Establishment and evaluation of mild cognitive dysfunction models in elderly rats and roles of G proteincoupled receptor kinase 2 / 中华老年医学杂志

Objective To establish mild cognitive dysfunction (MCI) models in elderly rats,and to investigate the pathophysiological features.Methods Totally 40 SD rats (14 to 18-month-old) were randomly divided into 2 groups:the model group (n=20) and the sham operation group (n=20).Bilateral carotid artery stenosis was prepared in the model group while bilateral carotid artery was seperated with no bilateral narrowing in the sham operation group.30 days after the operation,Morris water maze test was performed,pathomorphological and electron microscopic observations of the cerebral tissue were examined and the expression of G protein-coupled receptor kinase 2(GRK2) in hippocampus tissue w detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blottin.Results The mortality in model group was only 10％.Pathological morphology and ultrastructure showed that hippocampal tissue structure was almost normal in sham operated group,but in model group group,hippocampal CA1 pyramidal cells were in ischemic demyelination,arranged loose,and part of the cells showed nucleus pyknosis,deeply stained; there was no obvious infarct in white matter,part of the white matter fiher hecame thinner and disorder,nucleolus became smaller and steped aside,cytoplasmic electron density increased,lipofuscin appeared occasionally.Rough endoplasmic reticulum and Golgi were expanded,cytosolic free ribosomes increased,part of mitochondria became swelled,vacuolated.Morris water maze test results showed that the average escape latency in model group was longer than in sham group (P＜0.05).In spatial probe test,the average time of crossing the first original platform in model rats was significantly longer than the sham operated group [(36.80±7.68) s vs.(20.87±6.16)s,P＜0.05].The average number of crossing the original platform in 60 seconds in model group was significantly less than in sham group(1.43±0.51 vs.3.10±1.45,P＜0.05).The expressiones of GRK2 mRNA and protein in the hippocampus were significantly increased in model group rats than in sham group (P＜0.05).Conclusions The model of severe CCA stenosis in elderly rats can be applied for MCI animal models with good stability and repeatability.Compared with sham group,the cells morphology and ultrastructure in model group appeare more obvious pathological changes and mild impairments in cognitive function.GRK2 may play an important role in the development of MCI.

Relationship between osteoporosis and carotid artery disease in the elderly / 中华老年医学杂志

ObjectiveTo study the relationship between osteoporosis and carotid artery disease in the elderly. Methods102 elderly patients were registered for this study and the extraeranial carotid was detected by ultrasound scan. The carotid intima-media thickness (IMT) and the plaque index (PI) were measured and calculated respectively. Meanwhile the patients were divided into two groups according to the results of bone mineral density (BMI) measurement: the osteoporosis group and the non-osteoporosis group. The IMT, PI, carotid stenotic rate and some biochemical parameters were recorded and compared between the two groups. Relationship between these parameters and osteoporosis were evaluated by logistic regression model and partial correlation analysis. ResultsThe differences in serum calcium and the levels of TC,TG,HDL and LDL between osteoporosis group and non-osteoporosis group were statistically significant (all P＜0.05), while the level differences in serum phosphorus, fasting blood glucose and uric acid had no statistical significance between the two groups (P＞0.05). Moreover, the IMT and PI in osteoporosis group were significantly higher than those in non-osteoporosis group (P＜0.05). Among the 102 patients, 48 cases showed the carotid stenotic rate ＞ 50%, including 41 patients in osteoporosis group as well as 7 patients in non-osteoporosis group(P＜0.05). Logistic regression showed that age, HDL-C, IMT, PI and carotid stenotic rate＞50 % were the correlated factors of osteoporosis and among them, IMT, PI and carotid stenotic rate＞50% had higher risks (OR = 17.13,99.33,289.13). There was positive correlation between the carotid artery disease and osteoporosis. ConclusionsThere is a relationship between osteoporosis and carotid artery disease in the elderly. Emphasis should be paid on comprehensive prevention for osteoporosis and carotid artery disease in the elderly.