Patterns of associations of clinical features in neurofibromatosis 1 (NF1)

Neurofibromatosis 1 (NF1) is a common, fully penetrant autosomal dominant disease. The clinical course is generally progressive but highly variable, and the pathogenesis is poorly understood. We studied statistical associations among 13 of the most common or important clinical features in data from four separate sets of NF1 patients: a "developmental sample" of 1,413 probands from the NNFF International Database, an independent "validation sample" of 1,384 probands from the same database, 511 affected relatives of these probands, and 441 patients from a population-based registry in northwest England. We developed logistic regressive models for each of the 13 features using the developmental sample and attempted to validate these models in the other three samples. Age and gender were included as covariates in all models. Models were successfully developed and validated for ten of the 13 features analysed. The results are consistent with grouping nine of the clinical features into three sets: (1) café-au-lait spots, intertriginous freckling and Lisch nodules; (2) cutaneous, subcutaneous and plexiform neurofibromas; (3) macrocephaly, optic glioma and other neoplasms. In addition, three-way interactions among café-au-lait spots, intertriginous freckling and subcutaneous neurofibromas indicate that the first two groups are not independent. Our studies show that some individuals with NF1 are more likely than others to develop certain clinical features of the disease. Some NF1 features appear to share pathogenic mechanisms that are not common to all features.     

Inhibition of Cytidine Deaminase by Derivatives of 1-(β-D-Ribofuranosyl)-Dihydropyrimidin-2-One (Zebularine)

Abstract

The 2′-deoxy and ara derivatives of 1-β-(D-ribofuranosyl)-1,2-dihydropyrimidin-2-one (zebularine) were synthesized by improved routes and tested for their inhibitory properties against cytidine deaminase. It was shown that the K_i′s of both compounds were comparable to that of the parent zebularine in inhibition studies with purified enzyme. In contrast to zebularine, 2′-deoxy and ara zebularine showed only nominal cytotoxicity against MOLT-4 and L1210 cells in vitro. A model compound for the inhibition of deoxycytidylate deaminase, 2′-deoxyzebularine 5′-monophosphate (6), was also prepared.     

Pathogenic involvement of heregulin-β(1) in anti-atherogenesis

Human heregulins are neuregulin-1 type I polypeptides that act as ligands of the ErbB family of receptor tyrosine kinases. These peptides play an essential role in the development of the cardiovascular system, including angiogenesis and compensation of cardiac function. Both heregulins and ErbB receptors are expressed at high levels in various types of vascular cells. The results of cell culture, animal, and clinical experiments have shown heregulin-β(1) to be a promising drug candidate for prevention of atherosclerosis. Various mechanisms have been suggested to be involved in this process, such as suppression of macrophage foam cell formation and vascular smooth muscle cell proliferation. Heregulin-β(1) retards pro-inflammatory responses by attenuating the expression of interleukin-1β, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase-9, and cyclooxygenase-2 in monocytes. The peptide also has anti-oxidant and anti-apoptotic properties, and activates endothelial nitric oxide synthase in cardiomyocytes. Chronic infusion of heregulin-β(1) into apolipoprotein E-knockout mice suppresses the development of atherosclerotic lesions. In rat balloon injury models, heregulin-β(1) injection attenuates neointimal formation in the carotid artery. Clinical studies have shown that markedly reduced levels of heregulin-β(1) in the arterial wall and blood are closely associated with the progression of human coronary atherosclerotic lesions in patients with coronary artery disease. Therefore, these findings provide insight into the potential use of heregulin-β(1) as an extended therapeutic window for combating atherosclerosis and restenosis after coronary angioplasty.     

β-Secretase (BACE-1) inhibitory effect of biflavonoids

Here, we describe amentoflavone-type biflavonoids, which were isolated from natural sources and were found to inhibit β-secretase (BACE-1). The structure–activity relationship was studied, and compounds 1–8, 10, 17, and 18 showed BACE-1 inhibitory activity. Among these compounds, 2,3-dihydroamentoflavone 17 and 2,3-dihydro-6-methylginkgetin 18 exhibited potent inhibitory effects with IC₅₀ values of 0.75 and 0.35 μM, respectively.     

Expression of Bioactive Thymosin Alpha 1 (Tα1) in Marker-free Transgenic Lettuce (Lactuca sativa)

Thymosin α1 (Tα1) was widely used for the treatment of hepatitis (B and C) and several cancers. However, current production of Tα1 is difficultly meeting clinical needs. To develop a novel and safety approach for Tα1 production, we synthesized a Tα1 gene (124 bp) based on the plant codon usage bias and constructed a four-copy Tα1 gene concatemer (408 bp) by using isocaudamer technique. This 4 × Tα1 structure was cloned into plant binary expression vector pCAMBIA2300 with twin transfer deoxyribonucleic acids (T-DNAs) and integrated into lettuce genome via Agrobacterium-mediated transformation. Thirteen positive plants were identified by polymerase chain reaction and confirmed by Southern blot analysis, and 11 marker-free lettuce plants were obtained in T2 generation. The content of recombined Tα1 (rTα1) protein reached 1798.317 ± 87.312 ng/g in fresh leaves of transgenic lettuce. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay demonstrated that rTα1 protein stimulated mouse splenic lymphocyte proliferation in vitro. These data suggest that biologically active rTα1 was successfully expressed in marker-free transgenic lettuce, and this method could provide an alternative choice for large-scale production of Tα1 in the future.     

Synergistic Suppression of Early Phase of Adipogenesis by Microsomal PGE Synthase-1 (PTGES1)-Produced PGE(2) and Aldo-Keto Reductase 1B3-Produced PGF(2α)

We recently reported that aldo-keto reductase 1B3-produced prostaglandin (PG) F(2α) suppressed the early phase of adipogenesis. PGE(2) is also known to suppress adipogenesis. In this study, we found that microsomal PGE(2) synthase (PGES)-1 (mPGES-1; PTGES1) acted as the PGES in adipocytes and that PGE(2) and PGF(2α) synergistically suppressed the early phase of adipogenesis. PGE(2) production was detected in preadipocytes and transiently enhanced at 3 h after the initiation of adipogenesis of mouse adipocytic 3T3-L1 cells, followed by a quick decrease; and its production profile was similar to the expression of the cyclooxygenase-2 (PTGS2) gene. When 3T3-L1 cells were transfected with siRNAs for any one of the three major PTGESs, i.e., PTGES1, PTGES2 (mPGES-2), and PTGES3 (cytosolic PGES), only PTGES1 siRNA suppressed PGE(2) production and enhanced the expression of adipogenic genes. AE1-329, a PTGER4 (EP4) receptor agonist, increased the expression of the Ptgs2 gene with a peak at 1 h after the initiation of adipogenesis. PGE(2)-mediated enhancement of the PTGS2 expression was suppressed by the co-treatment with L-161982, a PTGER4 receptor antagonist. Moreover, AE1-329 enhanced the expression of the Ptgs2 gene by binding of the cyclic AMP response element (CRE)-binding protein to the CRE of the Ptgs2 promoter; and its binding was suppressed by co-treatment with L-161982, which was demonstrated by promoter luciferase and chromatin immunoprecipitation assays. Furthermore, when 3T3-L1 cells were caused to differentiate into adipocytes in medium containing both PGE(2) and PGF(2α), the expression of the adipogenic genes and the intracellular triglyceride level were decreased to a greater extent than in medium containing either of them, revealing that PGE(2) and PGF(2α) independently suppressed adipogenesis. These results indicate that PGE(2) was synthesized by PTGES1 in adipocytes and synergistically suppressed the early phase of adipogenesis of 3T3-L1 cells in cooperation with PGF(2α) through receptor-mediated activation of PTGS2 expression.     

Inhibitors of human 20α-hydroxysteroid dehydrogenase (AKR1C1)

Human 20α-hydroxysteroid dehydrogenase (AKR1C1), a member of the aldo-keto reductase (AKR) superfamily, is one of four isoforms (with >84% amino acid sequence identity) existing in human tissues. AKR1C1 most efficiently reduces biologically active progesterone and 5α-pregnan-3α-ol-20-one into their corresponding 20α-hydroxysteroids among the isoforms. The enzyme also accepts endogenous and xenobiotic non-steroidal carbonyl compounds as the substrates. In addition to the up-regulation of the AKR1C1 gene in cancer cells, the enzyme's over-expression in the cells of lung, ovary, uterine cervix, skin and colon carcinomas was reported to be associated with resistance against several anticancer agents. Thus, AKR1C1 may be a marker of the above cancers and a target of poor prognosis in cancer therapy. The recently determined X-ray crystal structures of AKR1C1/NADP(+)/20α-hydroxyprogesterone and AKR1C1/NADP(+)/3,5-dichlorosalicylic acid ternary complexes have provided a strong foundation for structure-based design methods to improve inhibitor selectivity and potency. In this review we provide an overview of the different types of AKR1C1 inhibitors and an update on the design of potent and selective inhibitors based on the crystal structure of the enzyme-inhibitor complex. Article from the Special issue on Targeted Inhibitors.     

(1→2) and (1→6)-linked β-d-galactofuranan of microalga Myrmecia biatorellae, symbiotic partner of Lobaria linita

A structural study of the cell wall polysaccharides of Myrmecia biatorellae, the symbiotic algal partner of the lichenized fungus Lobaria linita was carried out. It produced a rhamnogalactofuranan, with a (1→6)-β-d-galactofuranose in the main-chain, substituted at O-2 by single units of β-d-Galf, α-l-Rhap or by side chains of 2-O-linked β-d-Galf units. The structure of the polysaccharide was established by chemical and NMR spectroscopic analysis, and is new among natural polysaccharides. Moreover, in a preliminary study, this polysaccharide increased the lethality of mice submitted to polymicrobial sepsis induced by cecal ligation and puncture, probably due to the presence of galactofuranose, which have been shown to be highy immunogenic in mammals.     

Structure-activity relationship (SAR) of the α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists

This letter describes the structure-activity relationship (SAR) of the ‘right-wing’ α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing α-amino acids have been identified as replacements of the ‘right-wing’ (S)-2,3-diaminopropanoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human serum has also been achieved.     

问题解答(1)

问:绿色植物在有阳光时行光合作用吸二氧化碳放出氧气,在晚上没阳光时只有呼吸作用吸氧气放二氧化碳,为什么总说早晨到树林中散步空气好呢? 答:因为空气流动得很厉害,所以在一般树林中白天夜晚O_2及CO_2含量的改变是极小的.说早晨空气好,并不是植物起了什么作用,而是因为夜间人们的活动停止了,车马不在路上奔驰了,工厂的烟囱不冒烟了.加上树林中的湿度较大,尘土都降落在地上,空气就更为清洁了.我们夜间睡在屋中,屋中温度较高,不好气味的有机物(器物中发出或人呼出)空气中也很多,所以一到树林中,凉爽而清洁的空气,眼界的开朗就使我们心神为之一振.(吴相钰、董愚得答)     

Effect of inter-renal aortic coarctation-induced hypertension on function and expression of vascular α(1A)- and α(1D)-adrenoceptors

We investigated the effect of inter-renal aortic coarctation on the function and expression of vascular α(1A)- and α(1D)-adrenoceptors and plasma angiotensin II (ATII) in rats. Male Wistar rats, either sham operated (SO), or with aortic coarctation for 7 (AC7) and 14?days (AC14) were used for agonist-induced pressor responses in vehicle (physiological saline)- and antagonist-treated anesthetized animals, immunoblot analysis (α(1A)- and α(1D)-adrenoceptor in aorta and caudal arteries), and immunoassay (plasma ATII). The α(1D)-adrenoceptor antagonist, BMY-7378 (BMY) blocked noradrenaline-induced responses in the order SO?> AC7?? AC14; in contrast, the α(1A)-adrenoceptor antagonist RS-100329 (RS), produced a marginal shift to the right of the dose-response curve to noradrenaline, along with a strong decrease of the maximum pressor effect in the order SO?> AC7?= AC14. The potency of the α(1A)-adrenoceptor agonist A-61603 increased in rats with AC14, and responses were inhibited by RS in the order AC14?> AC7?> SO. In aorta, α(1D)-adrenoceptor protein increased in AC7 and decreased in AC14; α(1A)-adrenoreceptor protein increased in the caudal artery of AC7 and returned to control values in AC14. Plasma ATII increased in AC7 and AC14, compared with SO rats. These results suggest an early and direct relationship between ATII and α(1D)-adrenoreceptors in the development of hypertension in this experimental model.