Deletion of interleukin enhancer binding factor 2 (ILF2) resulted in defective biliary development and bile flow blockage.
白细胞介素增强子结合因子2 (ILF2) 的缺失导致胆道发育缺陷和胆汁流动阻塞。
- 作者列表："Cheung Y","Wu Z","Garcia-Barcelo MM","Tam PKH","Ma ACH","Lui VCH
PURPOSE:Biliary atresia (BA) is a devastating obstructive bile duct disease of newborns. BA has the highest incidence in Asians (1/5000), and its pathogenesis is unclear. We identified BA-private rare copy number variants (CNVs; 22 duplications and 6 deletions). ILF2 gene locates in the chromosome region (Chr1:153410347-153,634,058) which was deleted in a nonsyndromic BA patient. However, it is still not known whether ILF2 plays a role in hepatobiliary development and its deletion impacts on the bile duct development. METHODS:To investigate if ILF2 is required for biliary development, we knock-out the zebrafish homologs of ILF2 by CRISPR/Cas9 approach, and discover that deletion of ILF2 causes a defective biliary development and a lack of bile flow from the liver to the gall bladder in zebrafish, which is a resemblance of phenotypes of BA. RESULTS:Our data indicate that ILF2 gene is required for biliary development; deletion of ILF2 impairs bile duct development and could contribute to BA pathogenesis. This will be the first study to functionally evaluate the genes interfered by BA-private CNVs in hepatobiliary development and in BA pathogenesis. CONCLUSIONS:Such functional study may reveal the potential value of these BA-private CNVs in the disease pathogenesis for BA. LEVEL OF EVIDENCE:N/A (animal and laboratory study).
目的: 胆道闭锁 (BA) 是一种严重的新生儿胆道梗阻性疾病。BA在亚洲人中发病率最高 (1/5000)，其发病机制尚不清楚。我们鉴定了BA-私人罕见拷贝数变异 (CNVs; 22个重复和6个缺失)。ILF2基因位于染色体区域 (Chr1:153410347-153,634,058)，在非综合征型BA患者中缺失。然而，ILF2是否在肝胆发育中发挥作用以及其缺失对胆管发育的影响尚不清楚。 方法: 为了研究胆汁发育是否需要ILF2，我们通过CRISPR/Cas9方法敲除ILF2的斑马鱼同源物，并发现ILF2的缺失会导致胆汁发育缺陷和斑马鱼肝脏至胆囊的胆汁流不足，这是BA表型的相似之处。 结果: 我们的数据表明ILF2基因是胆道发育所必需的; ILF2的缺失会损害胆管发育，并可能导致BA发病。这将是第一项在功能上评估在肝胆发育和BA发病机制中受BA-私人cnv干扰的基因的研究。 结论: 此类功能研究可能揭示这些BA-私人cnv在BA的疾病发病机制中的潜在价值。 证据级别: N/A (动物和实验室研究)。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.