Cdc20 mutation promotes development of colon cancer in APCmin/+ mice / 肿瘤研究与临床

Objective To demonstrate the relationship between Cdc20 mutation and the promotion of colon cancer via Cdc20loxp/+ APCmin/+ villin-cre+/-compound mutant mice.Methods Cdc20loxp/+ APCmin/+ villin-cre+/-compound mutant mice and APCmin/+ mutant mice were generated by mice mating strategy.The colon tumors of two group mice were compared by phenotypic analysis and histology analysis.Results Phenotypic analysis showed that the number of tumors in Cdc20loxp/+ APCmin/+ villin-cre+/-compound mutant mice group and APCmin/+ mutant mice group was 1.2±0.5 and 1.6±0.5, respectively (t =0.215, P =0.588), and the maximum diameter of tumors was (2.7±0.3) cm and (2.5±0.2) cm, respectively (t =0.568, P =0.575).Pathologic type of Cdc20loxp/+ APCmin/+ villin-cre+/-compound mutant mice was adenocarcinoma, while that of APCmin/+ mice was tubular adenoma.Conclusion Cdc20 carrying a null allele can accelerate the promotion of colon cancer in APCmin/+ mice without influence on the tumor number and size.

Current research in animal models of dry age-related macular degeneration / 中华实验眼科杂志

Age-related macular degeneration (AMD) is the leading cause of the irreversible vision loss in population over 55 years of age.With the increasingly serious problem of aging,the prevalence of AMD is rising year by year.However,as the pathogenesis of dry AMD is largely unknown,the effective therapy still is lack.Given that there was a lack of proper animal models,it brought about obstacles to researches about molecular mechanism underlying dry AMD.Nowadays,lots of murine models of dry AMD have been established and developed,which provide suitable tools for relevant researches.But,different dry AM D models show varied pathogenesis features,and a reasonable choice of models is very important for different studies.The characteristics of different dry models were reviewed in this article.

Processamento intracelular da fibrilina-1 mutada na síndrome de Marfan: escape do controle de qualidade pela dissulfeto isomerase proteica / Mutated fibrillin-1 intracellular processing in Marfan syndrome: bypass of a protein disulfide isomerase-mediated quality control

A Síndrome de Marfan (SMF) é a enfermidade hereditária mais comum dentre as que afetam o sistema conjuntivo, causada por mutações da glicoproteína fibrilina-1, o principal componente estrutural das microfibrilas elásticas da matriz extracelular. As manifestações fenotípicas da SMF são sistêmicas e acometem tipicamente os sistemas ocular, esquelético e cardiovascular, este uma importante causa de morbi-mortalidade. Entretanto, não está claro como a mutação induz a doença. Estudos anteriores sugerem anomalias morfológicas do retículo endoplasmático (RE) ou retenção intracelular da fibrilina-1 nos estágios avançados da SMF. Entretanto, a contribuição do enovelamento da fibrilina-1 mutada e do estresse do RE na fisiopatologia celular da SMF não é conhecida. Proteínas mal-enoveladas podem levar à retenção intracelular e/ou aumento da degradação através da via de degradação associada ao RE (ERAD), além da indução da resposta a proteínas mal-enoveladas (UPR), ambas com potencial contribuição à fisiopatologia de doenças, incluindo a SMF. Assim, estudamos em fibroblastos embrionários isolados de camundongos (MEFs) com SMF se a fibrilina-1 mutada é reconhecida pelo controle de qualidade do RE pelo seu mal- enovelamento e induz estresse do RE por sua retenção intracelular. Demonstramos que a mutação na fibrilina-1 per se não promoveu chaperonas marcadoras de UPR ou geração de oxidantes. Além disso, não levou a uma maior sensibilização das células à indução exógena de estresse do RE, nem promoveu maior morte celular após inibição do proteassoma. Além disso, não foi observada retenção intracelular da fibrilina-1 nas células SMF, e mesmo após inibição da via secretora ou indução de estresse do RE, a inibição da secreção da fibrilina-1 foi similar nos MEFs SMF e wild-type (WT). A dissulfeto isomerase proteica (PDI), uma importante chaperona redox do RE, interage com fibrilina-1, e seu silenciamento levou a um aumento na secreção da fibrilina-1 pelos MEFs WT...

Marfan syndrome (MFS) is the most common connective tissue hereditary disease, caused by mutations in the glycoprotein fibrillin-1, the main structural component of extracellular matrix elastic microfibrils. MFS phenotypic manifestations are systemic and typically involve the ocular, skeletal and cardiovascular systems, the latter a major cause of morbidity/mortality. However, how gene mutation induxes disease is yet unclear. Previous studies suggest endoplasmic reticulum (ER) morphological abnormalities or fibrillin-1 intracellular retention in advanced MFS stages. However, the contribution of mutated fibrillin-1 folding and ER stress to MFS cellular pathophysiology is unknown. Un/misfolded proteins may associate with their intracellular retention and/or increased degradation through ER-associated degradation (ERAD), in addition to inducing the unfolded protein response (UPR), both sharing potential contributions to disease pathophysiology, including MFS. Thus, we studied in embryonic fibroblasts (MEFs) isolated from WT and MFS mice, if mutated fibrillin-1 can be recognized by ER quality control as a misfolded protein, able to induce ER stress due to its intracellular retention. We showed that fibrillin-1 mutation by itself did not promote UPR chaperone markers or oxidant generation. Moreover, it did not sensitize cells to exogenous ER stress nor affected cell survival curves after proteasome inhibition. Furthermore, no intracellular retention of fibrillin-1 was observed in MFS cells, and even after secretory pathway inhibition or ER stress induction, fibrillin-1 secretion inhibition was similar in MFS and wild-type (WT) MEFs. Protein disulfide isomerase (PDI), an important ER redox chaperone, interacts with fibrillin-1 and its silencing induced an increased fibrillin-1 secretion in WT...

Alzheimer disease associated phenotypes in PDAP_(SW) transgenic mice / 中华神经科杂志

Objective In order to study the role of APP SW mutation in the aetiology of Alzheimer′s disease(AD), the phenotypes of the PDAP SW transgenic mice were investigated. Methods Body weight, coat color and reproducibility of transgenic mice were observed;The pathological changes in the brain of the transgenic mice were examined using immunohistochemistry; Behavioral changes of transgenic mice were examined by Y-maze. Result At 3 month′s age, the mean body weight of the transgenic mice was (31.0?3.7) g, that of non-transgenic was (34.0?2.9) g;while the mean body weight of F1 transgenic mice was (32.0?3.3) g, of negative mice was (31.0?4.2) g. There were no significant difference between these two groups. There were three transgenic mice with abnormal coat and one male was infertile. The transgenic mice had amyloid deposit in their brains. In the Y-maze test, transgenic mice showed an increased number of arm entered (53?7 versus 37?4) and an impaired spontaneous alternation. The frequency of alternation was 48.2% in the transgenic mice and 76.4% in the non-transgenic mice,respectively.Conclusion The PDAP SW transgenic mice had typical pathological and behavioral changes similar to that of AD and could be used as an animal model for studying AD.