Growth inhibitory,insecticidal and antifeedant effects of some antileukemic and cytotoxic quassinoids on two species of agricultural pests

Summary Several quassinoids, obtained by isolation and derivatization fromSimaba multiflora andSoulamea soulameoides, were evaluated for growth inhibitory and insecticidal effects against the tobacco budworm (Heliothis virescens) and for antifeedant effects againstH. virescens and the fall armyworm (Spodoptera frugiperda). The relative activity of the quassinoids as insect growth inhibitors generally paralleled their known relative potency as antileukemic and cytotoxic agents.Phytochemical aspects of this work were supported by Contract CM-97295 with the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Md. Insects were kindly supplied by the agency of the United States Department of Agriculture at Brownsville, TX.     

The isolation and structure of 13,18-dehydroglaucarubinone,a new antineoplastic quassinoid fromSimarouba amara

Summary An investigation of the Guyana plantSimarouba amara Aubl. (Simaroubaceae) for antineoplastic quassinoids led to isolation and structural determination of the new quassinoids 2-acetylglaucarubine (1a) and 13,18-dehydroglaucarubinone (2). The previously known 2-acetylglaucarubinone (3a) and glaucarubinone (3b) were also obtained. The new quassinoid2 was found significantly to inhibit growth of the murine lymphocytic leukemia P388.Antineoplastic agents 59. For part 58 refer to M. T. Edgar, G.R. Pettit and T.H. Smith, J. org. Chem., in preparation.Acknowledgments. We wish to thank Mr B. Septe for providing the¹³C-NMR-data. Dr Jean H. Schmidt and Miss Linda M. Lange for assistance with biological studies.—G.R. Pettit is grateful to the National Cancer Institute (performed pursuant to contract No. N01-67048 with the Division of Cancer Treatment, NCI, National Institutes of Health, Dept. of Health, Education and Welfare), Public Health Services Research grant No. CA 16049-03 from the National Cancer Institute, the Fannie E. Rippel Foundation, Talley Industries, and the Phoenix Coca-Cola Bottling Co., for partial support of this investigation.     

Aberrant, canavanyl protein formation and the ability to tolerate or utilize L-canavanine

L-Canavanine, 2-amino-4-(guanidinooxy)butyric acid, and L-arginine incorporation into de novo synthesized proteins was compared in six organisms. Utilizing L-[guanidinooxy14C]canavanine and L-[guanidino14C]arginine at substrate saturation, the canavanine to arginine incorporation ratio was determined in de novo synthesized proteins. Caryedes brasiliensis and Sternechus tuberculatus, canavanine utilizing insects; Canavalia ensiformis, a canavanine storing plant; and to a lesser extent Heliothis virescens, a canavanine resistant insect, failed to accumulate significant canavanyl proteins. By contrast, Manduca sexta, a canavanine-sensitive insect, and Glycine max, a canavanine free plant, readily incorporated canavanine into newly synthesized proteins. This study supports the contention that the incorporation of canavanine into proteins in place of arginine contributes significantly to canavanine's antimetabolic properties.     

Leaf-blade crimping in grasses: A new measure of growth

In grasses, ligules compress and permanently crimp emerging leaf-blades (primary crimping). Ligule compression may also mark the abaxial surface of older leaves in some species (secondary crimping). Secondary crimping appears directly related to leaf daily growth rate. Leaf-blade crimping can be used for determination of relative tissue age and as a natural record of growth rate in grasses.     

De-synthesizing the relative a priori

This paper considers the question whether the notion of the relative apriori, central to Michael Friedman’s transcendentalist programme for philosophy of science, is available also to philosophers who reject appeals to a synthetic a priori. After tracing the rediscovery of the relative a priori and delineating its potential, the question is considered whether Friedman’s arguments against Quinean naturalism and Carnap’s attenuated logicism tell against a conception of philosophy as scientific metatheory that combines logical and empirical inquiries. Finding an opening here it is argued that this conception can also help itself to the notion of a relative a priori which, it is agreed, is central to historically informed theorising about science.     

The role of estrogen receptor α in the regulation of bone and growth plate cartilage

Estrogens are important endocrine regulators of skeletal growth and maintenance in both females and males. Studies have demonstrated that the estrogen receptor (ER)-α is the main mediator of these estrogenic effects in bone. Therefore, estrogen signaling via ERα is a target both for affecting longitudinal bone growth and bone remodeling. However, treatment with estradiol (E2) leads to an increased risk of side effects such as venous thromboembolism and breast cancer. Thus, an improved understanding of the signaling pathways of ERα will be essential in order to find better bone specific treatments with minimal adverse effects for different estrogen-related bone disorders. This review summarizes the recent data regarding the intracellular signaling mechanisms, in vivo, mediated by the ERα activation functions (AFs), AF-1 and AF-2, and the effect on bone, growth plate and other estrogen responsive tissues. In addition, we review the recent cell-specific ERα-deleted mouse models lacking ERα specifically in neuronal cells or growth plate cartilage. The newly characterized signaling pathways of estrogen, described in this review, provide a better understanding of the ERα signaling pathways, which may facilitate the design of new, bone-specific treatment strategies with minimal adverse effects.     

用于细胞培养的聚乙烯醇水凝胶力学性能模拟及定量控制

采用化学交联法制备聚乙烯醇（PVA）水凝胶,以此作为细胞体外培养基底。通过改进的拉伸法测量材料的杨氏模量（E）,并讨论交联剂与羟基单体的摩尔比（d）、PVA的初始浓度（C0）对E的影响。利用回归分析建立E与C0、d关系的数学模型,实现对E的定量控制,模拟细胞在体内生长的生物物理环境。结果表明：该数学模型模拟的相对误差不超过0．08,可实现对PVA力学性能的定量控制。此外,研究了基底硬度对L02细胞铺展及形态学特征的影响,细胞更倾向于在硬基底上铺展,在软的基底上,细胞的形态更趋近于圆形。     

Measuring downside risk and severity for global output

This paper attempts to provide a critical measure of downside risk and severity for global output by applying the Value at Risk approach to four country groups in the world as a ‘portfolio’. Global output downside risk, measured by global Growth at Risk (GaR), estimates the worst possible growth decline, relative to the baseline projection, with a specified probability over a given time horizon. This measure serves as a practical summary for predicting the risk for output downturn given a one‐year time horizon, based on the past growth distribution of individual countries and correlation among their growth rates. Our empirical estimates show that the downside risk that the world economy faced in 2002 was not as severe as the last global downturn in 1992–1993. In particular, the global GaR estimates that the worst outcome of the global economy in 2002, at 95% confidence level, was a growth rate of 0.34%. Copyright © 2007 John Wiley & Sons, Ltd.     

Regulation of B and T cell development by anterior pituitary hormones

Hormones produced by the anterior pituitary gland have been implicated in the regulation of primary lymphocyte development. In order to identify endocrine factors involved in that process, several strains of mice with genetic defects resulting in a selective impairment in the production of one or more anterior pituitary-derived hormones have been analysed. This study has resulted in the classification of endocrine hormones into the following four categories (i) hormones such as prolactin with no apparent effects on primary lymphopoiesis; (ii) anabolic hormones such as growth hormone and insulin-like growth factor-I whose stimulatory effects on primary lymphopoiesis are non-lineage-specific and related to their actions as systemic mediators of growth and/or differentiation; (iii) hormones such as thyroid hormones that have an obligate role in primary B lymphopoiesis; and (iv) hormones such as oestrogens that act as negative regulators of lymphopoiesis.     

Increased relative growth rate of normal rat cells in vitro with crocetin

Summary The carotenoid crocetin (earlier found to increase relative growth of Walker 256 tumor cells and their radiosensitivity), is shown to increase the relative growth of normal Sprague-Dawley rat muscle derived cells in vitro, presumably by increasing oxygen transport.     

New approaches to therapy of cancers of the stomach,colon and pancreas based on peptide analogs

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.Received 20 November 2003; accepted 6 January 2004     

Ureido-ethyl-imidazolines active against autochthonous diethylnitrosamine-induced epidermoid,papillary and adenocarcinomatous tumors of the respiratory tract of Syrian hamsters and against human bronchogenic carcinomas in nu/nu mice

Summary The detection of a new class of tumor inhibiting substances is described. Employing a chemical reaction discovered several years ago, a series of imidazolinylureas were prepared. It was found that some compounds of this group were active against diethylnitrosamine (DENA)-induced tumours in hamsters. CGP 15 720 A (1-{2-[2-(4-pyridyl)-2-imidazoline-l-yl]-ethyl}-3-(4-carboxy-phenyl)urea,Xb), the most active compound at present, was developed through a series of structural variations. CGP 15 720 A inhibits significantly in oral or parenteral treatment with well tolerated doses (10–30 mg/kg) the progressive growth of autochthonous, DENA-induced papillary, epidermoid and adenocarcinomatous tumors of the respiratory system in Syrian hamsters and prolongs significantly the survival. The substance also inhibits significantly the growth of 2 poorly differentiated human epidermoid or anaplastic bronchogenic carcinomas in nu/nu Balb/c mice and prolongs the mean survival time. In these mice, the substance is also active against the rodent ascites tumors Ehrlich carcinoma, CrSa 180 and Yoshida Sa AH 66, although it is only marginally active or inactive against these tumors in normal mice or rats. — In the therapeutic trials, hamsters tolerated the highest dose administered for 4 weeks, 1000 mg/kg p.o., without signs or symptoms of toxicity.Editorial remarks. There is still an urgent medical need for effective and welltolerated drugs for the treatment of the most common forms of cancer, such as bronchial carcinoma, or for post-operative prophylaxis against relapse and metastasis. — The old-established screening method based on rapidly proliferating acute transplantable lymphatic leukemias in the mouse that is applied in the major cancer research centers has certainly achieved some measure of clinical success, inasmuch as the mean duration of survival of patients with acute lymphatic leukemia has increased from 3 months to about 6 years and similar activity has been found in some rapidly proliferating lymphomas, sarcomas and teratomas.The authors were convinced, however, that chemotherapeutic agents effective against lung cancer could only be found with the help of new specific animal models. They developed a model of an autochthonous tumor in the hamster, applied it in extensive series of experiments, and succeeded in synthesizing and identifying a group of compounds that were both effective and well tolerated. They describe the synthesis and biological activity of CGP 15 720, the compound with the highest therapeutic index and an apparently non-cytotoxic mode of action.     

Supraphysiological dosages of vitamins and their implications in man

Some recent evidence on the benefits and hazards of elevated dosages of vitamins is summarized. Special emphasis is given on the safety of vitamins A, D, K1 and B6. Furthermore, the possibly beneficial effects of vitamins for athletic performance as well as the preventive potential of antioxidative vitamins and of carotenoids against cancer are discussed.     

Selenium and selenoproteins in mammals: extraordinary,essential, enigmatic

Selenium (Se), once known only for its potential toxicity, is now well established as an essential trace element for mammals. Insufficient Se intake predisposes to and manifests in a variety of diseases. Recent studies have proven that it is the synthesis of selenocysteine (Sec)-containing proteins, designated selenoproteins, which represents an essential prerequisite for regular development and a long and healthy life. New transgenic mouse models analysing those selenoproteins with proven enzymatic functions displayed particular phenotypes and highlighted essential Se-dependent processes in development, growth or against specific challenges. While there is a growing molecular understanding of and general agreement on the importance of sufficiently high Se intake and undisturbed selenoprotein biosynthesis, many of the recently identified selenoproteins are still uncharacterised, and the effects and consequences of supra-physiological Se dosages are not biochemically understood. With the recent definition of the human and mouse selenoproteomes and a growing number of available tools, the Se field is now geared for a great leap forward. Se biology has already broadened our knowledge about the genetic code and about protein translation. It now holds great promises also for a better understanding of some key aspects of cancer, inflammation, fertility and prevention of age-associated diseases.Received 17 March 2004; received after revision 29 April 2004; accepted 27 May 2004     

A morphological study of the expression of the small G protein RhoA in resting and activated MDCK cells

The small G protein Rho subfamily controls several cellular events such as growth, movement, proliferation and differentiation by rearranging actin and cytoskeleton proteins. Most of these effects are mediated by the activation of growth factor and extracellular matrix molecule receptors, suggesting a role for Rho molecules in the transduction pathway of these receptors. Despite the importance of Rho peptides in fundamental cellular events, data on their subcellular immunolocalisation are sparse: here we investigated the expression and subcellular localisation of RhoA in resting (cultured on plastic) and activated (Matri-cell or hepatocyte growth factor) MDCK cells by immunoperoxidase and immunogold techniques. Resting MDCK cells contain detectable amounts of RhoA mainly localised in the cytoplasm; RhoA expression is significantly enhanced by Matri-cell substrates that promote translocation of RhoA at the membrane level. This enhancing effect is reduced after exposure to hepatocyte growth factor.     

土壤与箭竹群落的互动关系研究进展

由于箭竹独特的生物学特性及其对亚高山森林生态系统功能的影响和作为大熊猫主食竹的保护生物学意义，大熊猫主食竹生态学的研究受到了国内外学者的广泛关注。但迄今为止，有关箭竹生态学的研究主要集中在箭竹群落地上部分的研究，而有关土壤生态条件对箭竹群落的生长、演替和开花影响的研究报道还相当少见。因此，建议在未来的箭竹生态学研究中加强以下几方面的研究：(1)土壤养分库及其有效性与箭竹群落生长和演替之间的互动过程；(2)通过控制实验检验“箭竹开花机理的养分假说”；(3)箭竹群落土壤生态过程。     

Vascular endothelial growth factors (VEGFs) and stroke

Vascular endothelial growth factors (VEGFs) have been shown to participate in atherosclerosis, arteriogenesis, cerebral edema, neuroprotection, neurogenesis, angiogenesis, postischemic brain and vessel repair, and the effects of transplanted stem cells in experimental stroke. Most of these actions involve VEGF-A and the VEGFR-2 receptor, but VEGF-B, placental growth factor, and VEGFR-1 have been implicated in some cases as well. VEGF signaling pathways represent important potential targets for the acute and chronic treatment of stroke.     

Supraphysiological dosages of vitamins and their implications in man

Summary Some recent evidence on the benefits and hazards of elevated dosages of vitamins is summarized. Special emphasis is given on the safety of vitamins A, D, K₁ and B₆. Furthermore, the possibly beneficial effects of vitamins for athletic performance as well as the preventive potential of antioxidative vitamins and of carotenoids against cancer are discussed.     

Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA

Celiac disease is characterized by the presence of specific autoantibodies targeted against transglutaminase 2 (TG2) in untreated patients’ serum and at their production site in the small-bowel mucosa below the basement membrane and around the blood vessels. As these autoantibodies have biological activity in vitro, such as inhibition of angiogenesis, we studied if they might also modulate the endothelial barrier function. Our results show that celiac disease patient autoantibodies increase endothelial permeability for macromolecules, and enhance the binding of lymphocytes to the endothelium and their transendothelial migration when compared to control antibodies in an endothelial cell-based in vitro model. We also demonstrate that these effects are mediated by increased activities of TG2 and RhoA. Since the small bowel mucosal endothelium serves as a “gatekeeper” in inflammatory processes, the disease-specific autoantibodies targeted against TG2 could thus contribute to the pathogenic cascade of celiac disease by increasing blood vessel permeability.