Japanese eel retinol dehydrogenases 11/12-like are 17-ketosteroid reductases involved in sex steroid synthesis.
- 作者列表："Suzuki H","Ozaki Y","Gen K","Kazeto Y
:The synthesis of 11-ketotestosterone (11KT) and estradiol-17β (E2), which play important roles in the regulation of gametogenesis in teleost fishes, is catalyzed by several steroidogenic enzymes. In particular, 17β-hydroxysteroid dehydrogenases (Hsd17bs) with 17-ketosteroid reducing activity (17KSR activity) are essential enzymes in the formation of these sex steroid hormones in the gonads and other tissues. Retinol dehydrogenase 11 (RDH11) has been suggested to be a novel tentative HSD17B (HSD17B15) in humans for a decade, however no definitive proof has been provided yet. In this study, three cDNAs related to human RDH11 were isolated from Japanese eel testis and characterized. Sequence similarity and phylogenetic analyses revealed their close relationship to human rdh11 and rdh12 gene products and they were designated as rdh11/12-like 1, rdh11/12-like 2, and rdh11/12-like 3. Three recombinant Rdh11/12-like proteins expressed in HEK293T cells catalyzed the transformation of estrone into E2 and androstenedione into testosterone. Only Rdh11/12-like 1 catalyzed the conversion of 11-ketoandrostenedione into 11KT. Tissue-distribution analysis by quantitative real-time polymerase chain reaction revealed, in immature male Japanese eel, that rdh11/12-like 1 and rdh11/12-like 2 are predominantly expressed in testis and brain, while rdh11/12-like 3 is expressed ubiquitously. Moreover, we analyzed the effects of gonadotropins and 11KT on the expression of the three rdh11/12-like mRNAs in the immature testis. In vitro incubation of immature testes with various doses of recombinant Japanese eel follicle stimulating hormone, luteinizing hormone, and 11KT indicated that the expression of rdh11/12-like 1 mRNA, rdh11/12-like 2, and rdh11/12-like 3 did not change. These findings suggest that the three Rdh11/12-like proteins metabolize sex steroids. Rdh11/12-like 1 may be one of the enzymes with 17KSR activity involved in the production of 11KT in the testis.
: 11-酮睾酮 (11KT) 和雌二醇-17 β (E2) 的合成是由几种类固醇生成酶催化的，它们在硬骨鱼的配子发生调节中起重要作用。特别地，具有17-酮类固醇还原活性 (17KSR活性) 的17β-羟基类固醇脱氢酶 (Hsd17bs) 是在性腺和其它组织中形成这些性类固醇激素的必需酶。近十年来，视黄醇脱氢酶11 (RDH11) 一直被认为是人类中一种新的暂定HSD17B (HSD17B15)，但尚未提供确切的证据。本研究从日本鳗鱼睾丸中分离得到3个与人RDH11相关的cdna，并对其进行了表征。序列相似性和系统发育分析揭示了它们与人rdh11和rdh12基因产物的密切关系，它们被命名为rdh11/12样1、rdh11/12样2和rdh11/12样3。HEK293T细胞中表达的三种重组Rdh11/12样蛋白催化雌酮转化为E2和雄烯二酮转化为睾酮。只有Rdh11/12样1催化11-酮雄烯二酮转化为11KT。通过定量实时聚合酶链反应的组织分布分析发现，在未成熟的雄性日本鳗鱼中，rdh11/12-样1和rdh11/12-样2主要在睾丸和脑中表达，而rdh11/12-样3广泛表达。此外，我们分析了促性腺激素和11KT对未成熟睾丸中三种rdh11/12样mrna表达的影响。将未成熟睾丸与不同剂量的重组日本鳗鱼促卵泡激素、促黄体生成素和11KT体外孵育表明rdh11/12样1 mRNA、rdh11/12样2和rdh11/12样3的表达没有变化。这些发现表明三种Rdh11/12样蛋白代谢性类固醇。Rdh11/12样1可能是参与睾丸中11KT产生的具有17KSR活性的酶之一。
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.