Beneficial metabolic effects of 2',3',5'-tri-acetyl-N6- (3-hydroxylaniline) adenosine in the liver and plasma of hyperlipidemic hamsters

Background

Pharmaceutical research of hyperlipidemia has been commonly pursued using traditional approaches. However, unbiased metabonomics attempts to explore the metabolic signature of hyperlipidemia in a high-throughput manner to understand pathophysiology of the disease process.

Methodology/Principal Findings

As a new way, we performed ¹H NMR-based metabonomics to evaluate the beneficial effects of 2′,3′,5′-tri-acetyl-N₆- (3-hydroxylaniline) adenosine (WS070117) on plasma and liver from hyperlipidemic Syrian golden hamsters. Both plasma and liver profiles provided a clearer distinction between the control and hyperlipidemic hamsters. Compared to control animals, hyperlipidemic hamsters showed a higher content of lipids (triglyceride and cholesterol), lactate and alanine together with a lower content of choline-containing compounds (e.g., phosphocholine, phosphatidylcholine, and glycerophosphocholine) and betaine. As a result, metabonomics-based findings such as the PCA and OPLS-DA plotting of metabolic state and analysis of potential biomarkers in plasma and liver correlated well to the assessment of biochemical assays, Oil Red O staining and in vivo ultrasonographic imaging suggesting that WS070117 was able to regulate lipid content and displayed more beneficial effects on plasma and liver than simvastatin.

Conclusions/Significance

This work demonstrates the promise of applying ¹H NMR metabonomics to evaluate the beneficial effects of WS070117 which may be a good drug candidate for hyperlipidemia.     

Leiomyosarcoma of the inferior vena cava level II involvement: curative resection and reconstruction of renal veins

ABSTRACT: Leiomyosarcoma of the inferior vena cava (IVCL) is a rare retroperitoneal tumor. We report two cases of level II (middle level, renal veins to hepatic veins) IVC Leiomyosarcoma, who underwent en bloc resection with reconstruction of bilateral or left renal venous return using prosthetic grafts. In our cases, IVC is documented to be occluded preoperatively, therefore, radical resection of tumor and/or right kidney was performed and the distal end of inferior vena cava was resected and without caval reconstruction. None of the patients developed edema or acute renal failure post-operatively. After surgical resection, adjuvant radiation therapy was administrated. The patients have been free of recurrence 2 years and 3 months, 9 months after surgery, respectively, indicating the complete surgical resection and radiatiotherapy contribute to the better survival. The reconstruction of inferior vena cava was not considered mandatory in level II IVC leiomyosarcoma, if the retroperitoneal venous collateral pathways have been established. In addition to the curative resection of IVC leiomyosarcoma, the renal vascular reconstruction minimized the risks of procedure-related acute renal failure, and was more physiologically preferable. This concept was reflected in the treatment of the two patients reported on.     

Dietary administration of zingerone to enhance growth, non-specific immune response, and resistance to Vibrio alginolyticus in Pacific white shrimp (Litopenaeus vannamei) juveniles

Zingerone, one of the active components of ginger, is a phenolic alkanone with antioxidant and anti-inflammatory properties. The effects of zingerone supplementation on the growth, immunity, and disease resistance of Pacific white shrimp (Litopenaeus vannamei) juveniles were studied. Four experimental diets, including a control diet (without zingerone enrichment) and 1, 2.5, and 5 mg zingerone (kg diet)⁻¹ were used. After 56 days of culture, shrimp fed diets supplemented with 1, 2.5, and 5 mg zingerone (kg diet)⁻¹ had significantly greater weight gain and feed efficiency than the controls. Furthermore, after 56 days of culture, shrimp fed all doses of the zingerone diet had higher survival rates compared to the controls after 24-72 h of challenge by the pathogen, Vibrio alginolyticus. Significantly increased phenoloxidase levels were found in shrimp fed the zingerone diets at all doses, and respiratory bursts, lysozyme and phagocytic activities of shrimp fed 2.5 and 5 mg zingerone (kg diet)⁻¹ also significantly increased. Neither the total hemocyte count nor superoxide dismutase activity of the experimental and control groups revealed significant differences at any dose. The results indicate that zingerone can be recommended as a supplement to shrimp feed to increase growth, immunity, and disease resistance against the pathogen, V. alginolyticus. Use of zingerone as appetizer and immunostimulant in shrimp is promising.     

Elicitation of neutralizing antibodies directed against CD4-induced epitope(s) using a CD4 mimetic cross-linked to a HIV-1 envelope glycoprotein

The identification of HIV-1 envelope glycoprotein (Env) structures that can generate broadly neutralizing antibodies (BNAbs) is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s) that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4) receptor-bound state, thereby exposing highly conserved "CD4 induced" (CD4i) epitope(s) known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH), was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140) using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1) complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-2(7312/V434M) and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s). These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s) here, and its potential role in vaccine application.     

NMR structure of hsp12, a protein induced by and required for dietary restriction-induced lifespan extension in yeast

Dietary restriction (DR) extends lifespan in yeast, worms, flies and mammals, suggesting that it may act via conserved processes. However, the downstream mechanisms by which DR increases lifespan remain unclear. We used a gel based proteomic strategy to identify proteins whose expression was induced by DR in yeast and thus may correlate with longevity. One protein up-regulated by DR was Hsp12, a small heat shock protein induced by various manipulations known to retard ageing. Lifespan extension by growth on 0.5% glucose (DR) was abolished in an hsp12Δ strain, indicating that Hsp12 is essential for the longevity effect of DR. In contrast, deletion of HSP12 had no effect on growth under DR conditions or a variety of environmental stresses, indicating that the effect of Hsp12 on lifespan is not due to increased general stress resistance. Unlike other small heat shock proteins, recombinant Hsp12 displayed negligible in vitro molecular chaperone activity, suggesting that its cellular function does not involve preventing protein aggregation. NMR analysis indicated that Hsp12 is monomeric and intrinsically unfolded in solution, but switches to a 4-helical conformation upon binding to membrane-mimetic SDS micelles. The structure of micelle-bound Hsp12 reported here is consistent with its recently proposed function as a membrane-stabilising 'lipid chaperone'. Taken together, our data suggest that DR-induced Hsp12 expression contributes to lifespan extension, possibly via membrane alterations.     

Dissection of human MiRNA regulatory influence to subpathway

The global insight into the relationships between miRNAs and their regulatory influences remains poorly understood. And most of complex diseases may be attributed to certain local areas of pathway (subpathway) instead of the entire pathway. Here, we reviewed the studies on miRNA regulations to pathways and constructed a bipartite miRNAs and subpathways network for systematic analyzing the miRNA regulatory influences to subpathways. We found that a small fraction of miRNAs were global regulators, environmental information processing pathways were preferentially regulated by miRNAs, and miRNAs had synergistic effect on regulating group of subpathways with similar function. Integrating the disease states of miRNAs, we also found that disease miRNAs regulated more subpathways than nondisease miRNAs, and for all miRNAs, the number of regulated subpathways was not in proportion to the number of the related diseases. Therefore, the study not only provided a global view on the relationships among disease, miRNA and subpathway, but also uncovered the function aspects of miRNA regulations and potential pathogenesis of complex diseases. A web server to query, visualize and download for all the data can be freely accessed at http://bioinfo.hrbmu.edu.cn/miR2Subpath.     

细胞外液酸碱度改变对自发性高血压大鼠脑动脉平滑肌细胞电生理特性的影响

目的:探讨细胞外液酸碱度(pHo)的改变对自发性高血压大鼠(SHR)脑动脉平滑肌细胞电生理特性的影响。方法:取200~250 g自发性高血压大鼠,应用全细胞膜片钳记录技术观察细胞外液酸碱度改变后对SHR脑动脉平滑肌细胞膜电流的作用,进一步揭示其离子机制。结果:①pHo酸化可电压依赖性的抑制SHR脑动脉平滑肌细胞的外向电流。其主要抑制SHR脑动脉平滑肌细胞0~+60 mV区间的电流幅度;②1 mmol/L TEA可以有效抑制pHo酸化对脑动脉平滑肌细胞外向电流的抑制作用。结论:pHo的改变引起SHR脑动脉平滑肌细胞外向电流变化,其可能与电压依赖性的抑制SHR脑动脉平滑肌细胞BKCa通道电流有关。     

双酚A对萼花臂尾轮虫毒性及生活史的影响

应用生态毒理学研究方法,研究了双酚A(BPA)对萼花臂尾轮虫毒性及生活史影响。结果表明:BPA对萼花臂尾轮虫24 h急性毒性LC₅₀为13.76 mg/L,95%置信限为10.97-17.10 mg/L。生活史研究显示:与对照组相比,0.25-4.0 mg/L的BPA对轮虫胚胎发育历时影响不显著;2.0-4.0 mg/L的BPA显著延迟了轮虫幼体发育时间;当BPA为0.5 mg/L时,轮虫净生殖率(R₀)显著上升,但BPA浓度为2.0和4.0 mg/L时R₀显著降低;4.0 mg/L的BPA显著缩短世代时间(T);BPA浓度为2.0、4.0 mg/L时,轮虫生命期望值(e₀)显著下降;BPA浓度为1.0、2.0、4.0 mg/L时,轮虫内禀增长率(r_m)显著下降;BPA浓度为0.5、1.0 mg/L时轮虫所产后代混交率(MR)显著增长。研究结果表明BPA对轮虫的生殖具有干扰作用,其中R₀和MR受BPA影响最为显著。     

河北阳原山神庙咀早更新世直隶狼(Canis chihliensis)新材料

于2006-2011期间的4次野外发掘中,在泥河湾盆地的山神庙咀遗址发现了大量犬科化石,材料包括残破颅骨、前颌骨、上颌骨、若干下颌骨及头后骨骼的主要部件,其中的头后骨骼是迄今在中国发现的早期犬属化石中最为完整的.依据有关形态特征和测量数据,将其归入直隶狼(Canis chihliensis).具体特征如下:体形较大,I3强大,P4窄长,原尖发育,M1前后向变扁并具宽阔的齿带状次尖,m1具下后尖和下内尖,相对其M1大小而言,上、下第二臼齿较大,m2下跟座宽阔等.其头部骨骼及牙齿测量数据与现代灰狼的较为接近,但头后骨骼数据较后者明显为小.该种的最大特征是其下臼齿舌侧齿尖的退化和P4窄长及M1前后方向变扁.但山神庙咀犬属材料的ml舌侧齿尖的发育程度变异较大,因此,仅仅依据ml的特征不足以区分直隶狼和拟豺(Xenocyon dubius (=Cuon dubius)),尽管后者的鉴定与分类问题尚存争议,但直隶狼与被归入拟豺的材料有更多相似之处,它们与非洲野犬(Lycaon pictus)差异很大.山神庙咀遗址化石层与邻近的小长梁遗址文化层时代相当或稍晚,大约为1.3 Ma.     

气候条件对典型草原牧草生长发育影响浅析

采用兴安盟扎赉特旗2004年～2011年气候生态环境监测站监测的典型草原牧草生长发育及地上生物量等基本资料。典型草原主要牧草种类有贝加尔针茅、野古草、羊草等禾草,伴生中旱生杂草、灌木及半灌木组成,草丛一般高30～50 cm。本文详细分析了当地气候条件对典型草原牧草生长发育及产量的影响。结果表明,典型草原牧草的高度、盖度及地上生物量受温度和降水量影响最明显,其中降水量的影响超过温度的影响。降水量多的年份地上生物量明显增加,而干旱年份地上生物量减少,其最大值一般出现在7月份,并滞后于降水量最大值。