KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース)

Collagen and elastin networks make up the majority of the extracellular matrix in many organs, such as the skin. The mechanisms which are involved in the maintenance of homeostatic equilibrium of these networks are numerous, involving the regulation of genetic expression, growth factor secretion, signalling pathways, secondary messaging systems, and ion channel activity. However, many factors are capable of disrupting these pathways, which leads to an imbalance of homeostatic equilibrium. Ultimately, this leads to changes in the physical nature of skin, both functionally and cosmetically. Although various factors have been identified, including carcinogenesis, ultraviolet exposure, and mechanical stretching of skin, it was discovered that many of them affect similar components of regulatory pathways, such as fibroblasts, lysyl oxidase, and fibronectin. Additionally, it was discovered that the various regulatory pathways intersect with each other at various stages instead of working independently of each other. This review paper proposes a model which elucidates how these molecular pathways intersect with one another, and how various internal and external factors can disrupt these pathways, ultimately leading to a disruption in collagen and elastin networks.

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Molecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of octadecadienoic acid [linoleic acid (LA), 18:2n-6] commonly found in beef, lamb and dairy products. The most abundant isomer of CLA in nature is the cis-9, trans-11 (c9t11) isomer. Commercially available CLA is usually a 1:1 mixture of c9t11 and trans-10, cis-12 (t10c12) isomers with other isomers as minor components. Conjugated LA isomer mixture and c9t11 and t10c12 isomers alone have been attributed to provide several health benefits that are largely based on animal and in vitro studies. Conjugated LA has been attributed many beneficial effects in prevention of atherosclerosis, different types of cancer, hypertension and also known to improve immune function. More recent literature with availability of purified c9t11 and t10c12 isomers suggests that t10c12 is the sole isomer involved in antiadipogenic role of CLA. Other studies in animals and cell lines suggest that the two isomers may act similarly or antagonistically to alter cellular function and metabolism, and may also act through different signaling pathways. The effect of CLA and individual isomers shows considerable variation between different strains (BALB/C mice vs. C57BL/6 mice) and species (e.g., rats vs. mice). The dramatic effects seen in animal studies have not been reflected in some clinical studies. This review comprehensively discusses the recent studies on the effects of CLA and individual isomers on body composition, cardiovascular disease, bone health, insulin resistance, mediators of inflammatory response and different types of cancer, obtained from both in vitro and animal studies. This review also discusses the latest available information from clinical studies in these areas of research.

Biological effects of conjugated linoleic acids in health and disease.

Aloe barbadensis (Miller), Aloe vera, has a long history of use as a topical and oral therapeutic. The plant is the source of two products, gel and latex, which are obtained from its fleshy leaves. Aloe vera products contain multiple constituents with potential biological and toxicological activities, yet the active components elude definition. Ingestion of Aloe vera is associated with diarrhea, electrolyte imbalance, kidney dysfunction, and conventional drug interactions; episodes of contact dermatitis, erythema, and phototoxicity have been reported from topical applications. This review examines the botany, physical and chemical properties, and biological activities of the Aloe vera plant.

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An evaluation of the biological and toxicological properties of Aloe barbadensis (miller), Aloe vera.

Conjugated linoleic acids: are they beneficial or detrimental to health?

Aloe vera gel has a beneficial effect on wound healing. Because angiogenesis is an essential process in wound healing, we hypothesized that Aloe vera gel might contain potent angiogenic compounds. Here we demonstrate that Aloe vera gel and its extracts are angiogenic on the chorioallantoic membrane (CAM) of chick embryo. Out of the three compounds purified from the final fraction of Aloe vera gel, beta-sitosterol showed a potent angiogenic activity in the CAM assay. In the presence of heparin, beta-sitosterol stimulated neovascularization in the mouse Matrigel plug assay and the motility of human umbilical vein endothelial cells in an in vitro wound migration assay. Thus beta-sitosterol is a novel plant-derived angiogenic factor which may have potential pharmaceutical applications for the management of chronic wounds.

A novel angiogenic factor derived from Aloe vera gel: beta-sitosterol, a plant sterol.

Conjugated linoleic acid (CLA) is a potent inhibitor of mammary carcinogenesis. Cancer cells produce various angiogenic factors which stimulate host vascular endothelial cell mitogenesis and chemotaxis for their growth and metastasis. Basic fibroblast growth factor (bFGF) is a potent angiogenic factor that is expressed in many tumors. In this study, we found that CLA decreased bFGF-induced endothelial cell proliferation and DNA synthesis in a dose-dependent manner. However, CLA did not inhibit endothelial cell migration. Furthermore, CLA showed a potent inhibitory effect on embryonic vasculogenesis and bFGF-induced angiogenesis in vivo. Collectively, these results suggest that CLA selectively inhibits the active proliferating endothelial cells induced by bFGF, which may explain its anti-carcinogenic properties in vivo.

Anti-angiogenic activity of conjugated linoleic acid on basic fibroblast growth factor-induced angiogenesis.

Although a coarse-grained description of proteins is a simple and convenient way to attack the protein folding problem, the construction of a global pairwise energy function which can simultaneously recognize the native folds of many proteins has resulted in partial success. We have sought the possibility of a systematic improvement of this pairwise-contact energy function as we extended the parameter space of amino acids, incorporating local environments of amino acids, beyond a $20\ifmmode\times\else\texttimes\fi{}20$ matrix. We have studied the pairwise contact energy functions of $20\ifmmode\times\else\texttimes\fi{}20$, $60\ifmmode\times\else\texttimes\fi{}60$, and $180\ifmmode\times\else\texttimes\fi{}180$ matrices depending on the extent of parameter space, and compared their effect on the learnability of energy parameters in the context of a gapless threading, bearing in mind that a $20\ifmmode\times\else\texttimes\fi{}20$ pairwise contact matrix has been shown to be too simple to recognize the native folds of many proteins. In this paper, we show that the construction of a global pairwise energy function was achieved using 1006 training proteins of a homology of less than 30%, which include all representatives of different protein classes. After parametrizing the local environments of the amino acids into nine categories depending on three secondary structures and three kinds of hydrophobicity (desolvation), the 16290 pairwise contact energies (scores) of the amino acids could be determined by perceptron learning and protein threading. These could simultaneously recognize all the native folds of the 1006 training proteins. When these energy parameters were tested on the 382 test proteins of a homology of less than 90%, 370 (96.9%) proteins could recognize their native folds. We set up a simple thermodynamic framework in the conformational space of decoys to calculate the unfolded fraction and the specific heat of real proteins. The different thermodynamic stabilities of E.coli ribonuclease H (RNase H) and its mutants were well described in our calculation, agreeing with the experiment.

Perceptron learning of pairwise contact energies for proteins incorporating the amino acid environment.

Several computational methods have been developed to solve the problem of protein thermostabilization. One common drawback of them is that they must have the information of a backbone structure of a protein for the generation of a proper amino acid sequence. In this paper, we propose a new method called TargetStar by incorporating computational biology and statistical physics, in which an approximate partition function and a specific heat are used to calculate the folding transition temperature of a protein and then to predict the relative thermal stabilities for given proteins based only on their amino acid sequences. To evaluate the prediction accuracy of TargetStar, we calculated folding transition temperatures of 289 orthologous protein pairs using the proposed method, where each protein pair contains one hyperthermophilic protein and one mesophilic protein. According to our evaluation, hyperthermophilic and mesophilic proteins are distinguished from each other in terms of relative thermal stabilities with 77% prediction accuracy. Thus, TargetStar may serve as an efficient method to design an amino acid sequence of a target protein with the desired thermal stability prior to the expensive and time-consuming mutagenesis experiment.

Eun-Joung Moon

Papers

A novel angiogenic factor derived from Aloe vera gel: beta-sitosterol, a plant sterol.

Anti-angiogenic activity of conjugated linoleic acid on basic fibroblast growth factor-induced angiogenesis.

Perceptron learning of pairwise contact energies for proteins incorporating the amino acid environment.

New method of evaluating relative thermal stabilities of proteins based on their amino acid sequences: targetstar

Environment-dependent one-body score function for proteins by perceptron learning and protein threading