http://www.mdpi.com/journal/biomolecules Latest open access articles published in Biomolecules at http://www.mdpi.com/journal/biomolecules http://www.mdpi.com/2218-273X/2/2/269 The secretion of insulin by pancreatic islet β-cells plays a pivotal role in glucose homeostasis and diabetes. Recent work suggests an important role for SUMOylation in the control of insulin secretion from β-cells. In this paper we discuss mechanisms whereby (de)SUMOylation may control insulin release by modulating β-cell function at one or more key points; and particularly through the acute and reversible regulation of the exocytotic machinery. Furthermore, we postulate that the SUMO-specific protease SENP1 is an important mediator of insulin exocytosis in response to NADPH, a metabolic secretory signal and major determinant of β-cell redox state. Dialysis of mouse β-cells with NADPH efficiently amplifies β-cell exocytosis even when extracellular glucose is low; an effect that is lost upon knockdown of SENP1. Conversely, over-expression of SENP1 itself augments β-cell exocytosis in a redox-dependent manner. Taken together, we suggest that (de)SUMOylation represents an important mechanism that acutely regulates insulin secretion and that SENP1 can act as an amplifier of insulin exocytosis. http://www.mdpi.com/2218-273X/2/2/269 Thu, 24 May 2012 00:00:00 CEST Biomolecules 2012-05-24 2 2 Article 269 281 2218-273X DeSUMOylation Controls Insulin Exocytosis in Response to Metabolic Signals 2012-05-24 doi: 10.3390/biom2020269 Elisa Vergari Gregory Plummer Xiaoqing Dai Patrick E. MacDonald http://www.mdpi.com/2218-273X/2/2/256 Post-translational modifications of proteins are essential for cell function. Covalent modification by SUMO (small ubiquitin-like modifier) plays a role in multiple cell processes, including transcriptional regulation, DNA damage repair, protein localization and trafficking. Factors affecting protein localization and trafficking are particularly crucial in neurons because of their polarization, morphological complexity and functional specialization. SUMOylation has emerged as a major mediator of intranuclear and nucleo-cytoplasmic translocations of proteins involved in critical pathways such as circadian rhythm, apoptosis and protein degradation. In addition, SUMO-regulated re-localization of extranuclear proteins is required to sustain neuronal excitability and synaptic transmission. Thus, SUMOylation is a key arbiter of neuronal viability and function. Here, we provide an overview of recent advances in our understanding of regulation of neuronal protein localization and translocation by SUMO and highlight exciting areas of ongoing research. http://www.mdpi.com/2218-273X/2/2/256 Mon, 14 May 2012 00:00:00 CEST Biomolecules 2012-05-14 2 2 Review 256 268 2218-273X Regulation of Neuronal Protein Trafficking and Translocation by SUMOylation 2012-05-14 doi: 10.3390/biom2020256 Anja Berndt Kevin A. Wilkinson Jeremy M. Henley http://www.mdpi.com/2218-273X/2/2/240 SUMO (small ubiquitin-related modifier) conjugation is a reversible three-step process of protein post-translational modifications mediating protein-protein interactions, subcellular compartmentalization and regulation of transcriptional events. Among divergent transcription factors regulated by SUMOylation and deSUMOylation, the androgen receptor (AR) is of exceptional significance, given its established role in prostate carcinogenesis. The enzymes of the SUMO pathway can have diverse effects on AR transcriptional activity, either via direct modification of the AR or through modification of AR co-regulators. Accumulating in vitro and in vivo evidence implicates the SUMO pathway in AR-dependent signaling. Prostate cancer cell proliferation and hypoxia-induced angiogenesis are also regulated by the SUMO pathway, through an AR-independent mechanism. Thus, an important role has been revealed for members of the SUMO pathway in prostate cancer (PCa) development and progression, offering new therapeutic targets. http://www.mdpi.com/2218-273X/2/2/240 Mon, 23 Apr 2012 00:00:00 CEST Biomolecules 2012-04-23 2 2 Review 240 255 2218-273X The Role of the Small Ubiquitin-Related Modifier (SUMO) Pathway in Prostate Cancer 2012-04-23 doi: 10.3390/biom2020240 Panagiotis J. Vlachostergios Christos N. Papandreou http://www.mdpi.com/2218-273X/2/2/228 orf256 is a wheat mitochondrial gene associated with cytoplasmic male sterility (CMS) that has different organization in various species. This study exploited the orf256 gene as a mitochondrial DNA marker to study the genetic fingerprint of Triticum and Aegilops species. PCR followed by sequencing of common parts of the orf256 gene were employed to determine the fingerprint and molecular evolution of Triticum and Aegilops species. Although many primer pairs were used, two pairs of orf256 specific primers (5:-94/C: 482, 5:253/C: 482), amplified DNA fragments of 576 bp and 230 bp respectively in all species were tested. A common 500 bp of nine species of Triticum and Aegilops were aligned and showed consistent results with that obtained from other similar chloroplast or nuclear genes. Base alignment showed that there were various numbers of base substitutions in all species compared to S. cereal (Sc) (the outgroup species). Phylogenetic relationship revealed similar locations and proximity on phylogenetic trees established using plastid and nuclear genes. The results of this study open a good route to use unknown function genes of mitochondria in studying the molecular relationships and evolution of wheat and complex plant genomes. http://www.mdpi.com/2218-273X/2/2/228 Fri, 13 Apr 2012 00:00:00 CEST Biomolecules 2012-04-13 2 2 Article 228 239 2218-273X Genetic Fingerprinting of Wheat and Its Progenitors by Mitochondrial Gene orf256 2012-04-13 doi: 10.3390/biom2020228 Ahmed M. El-Shehawi Abdelmeguid I. Fahmi Samy M. Sayed Mona M. Elseehy http://www.mdpi.com/2218-273X/2/2/203 Many viral proteins have been shown to be sumoylated with corresponding regulatory effects on their protein function, indicating that this host cell modification process is widely exploited by viral pathogens to control viral activity. In addition to using sumoylation to regulate their own proteins, several viral pathogens have been shown to modulate overall host sumoylation levels. Given the large number of cellular targets for SUMO addition and the breadth of critical cellular processes that are regulated via sumoylation, viral modulation of overall sumoylation presumably alters the cellular environment to ensure that it is favorable for viral reproduction and/or persistence. Like some viruses, certain bacterial plant pathogens also target the sumoylation system, usually decreasing sumoylation to disrupt host anti-pathogen responses. The recent demonstration that Listeria monocytogenes also disrupts host sumoylation, and that this is required for efficient infection, extends the plant pathogen observations to a human pathogen and suggests that pathogen modulation of host sumoylation may be more widespread than previously appreciated. This review will focus on recent aspects of how pathogens modulate the host sumoylation system and how this benefits the pathogen. http://www.mdpi.com/2218-273X/2/2/203 Thu, 05 Apr 2012 00:00:00 CEST Biomolecules 2012-04-05 2 2 Review 203 227 2218-273X Sumoylation at the Host-Pathogen Interface 2012-04-05 doi: 10.3390/biom2020203 Van G. Wilson http://www.mdpi.com/2218-273X/2/2/187 The cell membrane is a highly selective barrier. This limits the cellular uptake of molecules including DNA, oligonucleotides, peptides and proteins used as therapeutic agents. Different approaches have been employed to increase the membrane permeability and intracellular delivery of these therapeutic molecules. One such approach is the use of Cell Penetrating Peptides (CPPs). CPPs represent a new and innovative concept, which bypasses the problem of bioavailability of drugs. The success of CPPs lies in their ability to unlock intracellular and even intranuclear targets for the delivery of agents ranging from peptides to antibodies and drug-loaded nanoparticles. This review highlights the development of cell penetrating peptides for cell-specific delivery strategies involving biomolecules that can be triggered spatially and temporally within a cell transport pathway by change in physiological conditions. The review also discusses conjugations of therapeutic agents to CPPs for enhanced intracellular delivery and bioavailability that are at the clinical stage of development. http://www.mdpi.com/2218-273X/2/2/187 Fri, 30 Mar 2012 00:00:00 CEST Biomolecules 2012-03-30 2 2 Review 187 202 2218-273X Cell Penetrating Peptides in the Delivery of Biopharmaceuticals 2012-03-30 doi: 10.3390/biom2020187 Were LL Munyendo Huixia Lv Habiba Benza-Ingoula Lilechi D. Baraza Jianping Zhou http://www.mdpi.com/2218-273X/2/1/165 The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms. Calcium is accumulated in the ER by Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA)-type calcium pumps. SERCA activity can determine ER calcium content available for intra-ER functions and for calcium release into the cytosol, and can shape the spatiotemporal characteristics of calcium signals. SERCA function therefore constitutes an important nodal point in the regulation of cellular calcium homeostasis and signaling, and can exert important effects on cell growth, differentiation and survival. In several cell types such as cells of hematopoietic origin, mammary, gastric and colonic epithelium, SERCA2 and SERCA3-type calcium pumps are simultaneously expressed, and SERCA3 expression levels undergo significant changes during cell differentiation, activation or immortalization. In addition, SERCA3 expression is decreased or lost in several tumor types when compared to the corresponding normal tissue. These observations indicate that ER calcium homeostasis is remodeled during cell differentiation, and may present defects due to decreased SERCA3 expression in tumors. Modulation of the state of differentiation of the ER reflected by SERCA3 expression constitutes an interesting new aspect of cell differentiation and tumor biology. http://www.mdpi.com/2218-273X/2/1/165 Mon, 05 Mar 2012 00:00:00 CET Biomolecules 2012-03-05 2 1 Review 165 186 2218-273X Endoplasmic Reticulum Calcium Pumps and Cancer Cell Differentiation 2012-03-05 doi: 10.3390/biom2010165 Béla Papp Jean-Philippe Brouland Atousa Arbabian Pascal Gélébart Tünde Kovács Régis Bobe Jocelyne Enouf Nadine Varin-Blank Ágota Apáti http://www.mdpi.com/2218-273X/2/1/143 Mortalin is a highly conserved heat-shock chaperone usually found in multiple subcellular locations. It has several binding partners and has been implicated in various functions ranging from stress response, control of cell proliferation, and inhibition/prevention of apoptosis. The activity of this protein involves different structural and functional mechanisms, and minor alterations in its expression level may lead to serious biological consequences, including neurodegeneration. In this article we review the most current data associated with mortalin’s binding partners and how these protein-protein interactions may be implicated in apoptosis and neurodegeneration. A complete understanding of the molecular pathways in which mortalin is involved is important for the development of therapeutic strategies for cancer and neurodegenerative diseases. http://www.mdpi.com/2218-273X/2/1/143 Thu, 01 Mar 2012 00:00:00 CET Biomolecules 2012-03-01 2 1 Review 143 164 2218-273X Mortalin, Apoptosis, and Neurodegeneration 2012-03-01 doi: 10.3390/biom2010143 Carolina Londono Cristina Osorio Vivian Gama Oscar Alzate http://www.mdpi.com/2218-273X/2/1/122 Protein tyrosine phosphatase interacting protein 51 (PTPIP51), also known as regulator of microtubule dynamics protein 3, was identified as an in vitro and in vivo interaction partner of CGI-99 and Nuf-2. PTPIP51 mRNA is expressed in all stages of the cell cycle; it is highly expressed six hours post-nocodazole treatment and minimally expressed one hour post-nocodazole treatment. Recent investigations located PTPIP51 protein at the equatorial plate. This study reports the localization of the PTPIP51/CGI-99 and the PTPIP51/Nuf-2 complex at the equatorial region during mitosis. Moreover, Duolink proximity ligation assays revealed an association of PTPIP51 with the microtubular cytoskeleton and the spindle apparatus. High amounts of phosphorylated PTPIP51 associated with the spindle poles was seen by confocal microscopy. In parallel a strong interaction of PTPIP51 with the epidermal growth factor receptor phosphorylating PTPIP51 at the tyrosine 176 residue was seen. In the M/G1 transition a high level of interaction between PTPIP51 and PTP1B was registered, thus restoring the interaction of PTPIP51 and Raf-1, depleted in mitotic cells. Summarizing these new facts, we conclude that PTPIP51 is necessary for normal mitotic processes, impacting on chromosomal division and control of the MAPK pathway activity. http://www.mdpi.com/2218-273X/2/1/122 Thu, 23 Feb 2012 00:00:00 CET Biomolecules 2012-02-23 2 1 Article 122 142 2218-273X Interaction of PTPIP51 with Tubulin, CGI-99 and Nuf2 During Cell Cycle Progression 2012-02-23 doi: 10.3390/biom2010122 Alexander Brobeil Michaela Graf Moritz Eiber Monika Wimmer http://www.mdpi.com/2218-273X/2/1/104 The phosphorylated kinase-inducible activation domain (pKID) adopts a helix–loop–helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and αB. We performed all-atom multicanonical molecular dynamics simulations of pKID with and without KIX in explicit solvents to generate conformational ensembles. Although the unbound pKID was disordered overall, αA and αB exhibited a nascent helix propensity; the propensity of αA was stronger than that of αB, which agrees with experimental results. In the bound state, the free-energy landscape of αB involved two low free-energy fractions: native-like and non-native fractions. This result suggests that αB folds according to the induced-fit mechanism. The αB-helix direction was well aligned as in the NMR complex structure, although the αA helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the αB helix can bind to another site of KIX, to which another protein MLL also binds with the adopting helix. Consequently, MLL can facilitate pKID binding to the pKID-binding site by blocking the MLL-binding site. This also supports experimentally obtained results. http://www.mdpi.com/2218-273X/2/1/104 Wed, 22 Feb 2012 00:00:00 CET Biomolecules 2012-02-22 2 1 Article 104 121 2218-273X Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics 2012-02-22 doi: 10.3390/biom2010104 Koji Umezawa Jinzen Ikebe Mitsunori Takano Haruki Nakamura Junichi Higo http://www.mdpi.com/2218-273X/2/1/76 Oxysterols are oxidized 27-carbon cholesterol derivatives or by-products of cholesterol biosynthesis, with a spectrum of biologic activities. Several oxysterols have cytotoxic and pro-apoptotic activities, the ability to interfere with the lateral domain organization, and packing of membrane lipids. These properties may account for their suggested roles in the pathology of diseases such as atherosclerosis, age-onset macular degeneration and Alzheimer’s disease. Oxysterols also have the capacity to induce inflammatory responses and play roles in cell differentiation processes. The functions of oxysterols as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol, are well established. Furthermore, their actions as endogenous regulators of gene expression in lipid metabolism via liver X receptors and the Insig (insulin-induced gene) proteins have been investigated in detail. The cytoplasmic oxysterol-binding protein (OSBP) homologues form a group of oxysterol/cholesterol sensors that has recently attracted a lot of attention. However, their mode of action is, as yet, poorly understood. Retinoic acid receptor-related orphan receptors (ROR) α and γ, and Epstein-Barr virus induced gene 2 (EBI2) have been identified as novel oxysterol receptors, revealing new physiologic oxysterol effector mechanisms in development, metabolism, and immunity, and evoking enhanced interest in these compounds in the field of biomedicine. http://www.mdpi.com/2218-273X/2/1/76 Wed, 15 Feb 2012 00:00:00 CET Biomolecules 2012-02-15 2 1 Review 76 103 2218-273X Oxysterols and Their Cellular Effectors 2012-02-15 doi: 10.3390/biom2010076 Vesa M. Olkkonen Olivier Béaslas Eija Nissilä http://www.mdpi.com/2218-273X/2/1/46 Complement is an essential part of innate immunity as it participates in host defense against infections, disposal of cellular debris and apoptotic cells, inflammatory processes and modulation of adaptive immune responses. Several soluble and membrane-bound regulators protect the host from the potentially deleterious effects of uncontrolled and misdirected complement activation. Factor H is a major soluble regulator of the alternative complement pathway, but it can also bind to host cells and tissues, protecting them from complement attack. Interactions of factor H with various endogenous ligands, such as pentraxins, extracellular matrix proteins and DNA are important in limiting local complement-mediated inflammation. Impaired regulatory as well as ligand and cell recognition functions of factor H, caused by mutations or autoantibodies, are associated with the kidney diseases: atypical hemolytic uremic syndrome and dense deposit disease and the eye disorder: age-related macular degeneration. In addition, factor H binds to receptors on host cells and is involved in adhesion, phagocytosis and modulation of cell activation. In this review we discuss current concepts on the physiological and pathophysiological roles of factor H in light of new data and recent developments in our understanding of the versatile roles of factor H as an inhibitor of complement activation and inflammation, as well as a mediator of cellular interactions. A detailed knowledge of the functions of factor H in health and disease is expected to unravel novel therapeutic intervention possibilities and to facilitate the development or improvement of therapies. http://www.mdpi.com/2218-273X/2/1/46 Tue, 07 Feb 2012 00:00:00 CET Biomolecules 2012-02-07 2 1 Review 46 75 2218-273X Factor H: A Complement Regulator in Health and Disease, and a Mediator of Cellular Interactions 2012-02-07 doi: 10.3390/biom2010046 Anne Kopp Mario Hebecker Eliška Svobodová Mihály Józsi http://www.mdpi.com/2218-273X/2/1/34 Oligosaccharides, sequences of carbohydrates conjugated to proteins and lipids, are arguably the most abundant and structurally diverse class of molecules. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. Recent advances in glycomics have identified several types of glyco-biomarkers containing fucosylation that are linked to certain types of cancer. Fucosylated alpha-fetoprotein (AFP) is widely used in the diagnosis of hepatocellular carcinoma because it is more specific than alpha-fetoprotein. High levels of fucosylated haptoglobin have also been found in sera of patients with various carcinomas. We have recently established a simple lectin-antibody ELISA to measure fucosylated haptoglobin and to investigate its clinical use. Cellular fucosylation is dependent upon fucosyltransferase activity and the level of its donor substrate, guanosine diphosphate (GDP)-fucose. GDP-mannose-4,6-dehydratase (GMDS) is a key enzyme involved in the synthesis of GDP-fucose. Mutations of GMDS found in colon cancer cells induced a malignant phenotype, leading to rapid growth in athymic mice resistant to natural killer cells. This review describes the role of fucosylated haptoglobin as a cancer biomarker, and discusses the possible biological role of fucosylation in cancer development. http://www.mdpi.com/2218-273X/2/1/34 Mon, 30 Jan 2012 00:00:00 CET Biomolecules 2012-01-30 2 1 Review 34 45 2218-273X Fucosylation Is a Promising Target for Cancer Diagnosis and Therapy 2012-01-30 doi: 10.3390/biom2010034 Eiji Miyoshi Kenta Moriwaki Naoko Terao Cheng-Cheng Tan Mika Terao Tsutomu Nakagawa Hitoshi Matsumoto Shinichiro Shinzaki Yoshihiro Kamada http://www.mdpi.com/2218-273X/2/1/23 Hydrodynamic tail vein (HTV) delivery is a simple and rapid tail vein injection method of a high volume of naked plasmid DNA resulting in high levels of foreign gene expression in organs, especially the liver. Compared to other organs, HTV delivery results in more than a 1000-fold higher transgene expression in liver. After being bitten by malaria-infected mosquitoes, malaria parasites transiently infect the host liver and form the liver stages. The liver stages are known to be the key target for CD8+ T cells that mediate protective anti-malaria immunity in an animal model. Therefore, in this study, we utilized the HTV delivery technique as a tool to determine the in vivo cytotoxic effect of malaria antigen-specific CD8+ T cells. Two weeks after mice were immunized with recombinant adenoviruses expressing malarial antigens, the immunized mice as well as naïve mice were challenged by HTV delivery of naked plasmid DNA co-encoding respective antigen together with luciferase using dual promoters. Three days after the HTV challenge, non-invasive whole-body bioluminescent imaging was performed. The images demonstrate in vivo activity of CD8+ T cells against malaria antigen-expressing cells in liver. http://www.mdpi.com/2218-273X/2/1/23 Thu, 05 Jan 2012 00:00:00 CET Biomolecules 2012-01-05 2 1 Article 23 33 2218-273X A New Method to Determine Antigen-Specific CD8+ T Cell Activity in Vivo by Hydrodynamic Injection 2012-01-05 doi: 10.3390/biom2010023 Urvashi Rai Jing Huang Satish Mishra Xiangming Li Takayuki Shiratsuchi Moriya Tsuji http://www.mdpi.com/2218-273X/2/1/1 Accurately predicting essential genes is important in many aspects of biology, medicine and bioengineering. In previous research, we have developed a machine learning based integrative algorithm to predict essential genes in bacterial species. This algorithm lends itself to two approaches for predicting essential genes: learning the traits from known essential genes in the target organism, or transferring essential gene annotations from a closely related model organism. However, for an understudied microbe, each approach has its potential limitations. The first is constricted by the often small number of known essential genes. The second is limited by the availability of model organisms and by evolutionary distance. In this study, we aim to determine the optimal strategy for predicting essential genes by examining four microbes with well-characterized essential genes. Our results suggest that, unless the known essential genes are few, learning from the known essential genes in the target organism usually outperforms transferring essential gene annotations from a related model organism. In fact, the required number of known essential genes is surprisingly small to make accurate predictions. In prokaryotes, when the number of known essential genes is greater than 2% of total genes, this approach already comes close to its optimal performance. In eukaryotes, achieving the same best performance requires over 4% of total genes, reflecting the increased complexity of eukaryotic organisms. Combining the two approaches resulted in an increased performance when the known essential genes are few. Our investigation thus provides key information on accurately predicting essential genes and will greatly facilitate annotations of microbial genomes. http://www.mdpi.com/2218-273X/2/1/1 Tue, 27 Dec 2011 00:00:00 CET Biomolecules 2011-12-27 2 1 Article 1 22 2218-273X Exploring the Optimal Strategy to Predict Essential Genes in Microbes 2011-12-27 doi: 10.3390/biom2010001 Jingyuan Deng Lirong Tan Xiaodong Lin Yao Lu Long J. Lu http://www.mdpi.com/2218-273X/1/1/48 Glycosylation improves the solubility and stability of proteins, contributes to the structural integrity of protein functional sites, and mediates biomolecular recognition events involved in cell-cell communications and viral infections. The first step toward understanding the molecular mechanisms underlying these carbohydrate functionalities is a detailed characterization of glycan structures. Recently developed glycomic approaches have enabled comprehensive analyses of N-glycosylation profiles in a quantitative manner. However, there are only a few reports describing detailed O-glycosylation profiles primarily because of the lack of a widespread standard method to identify O-glycan structures. Here, we developed an HPLC mapping method for detailed identification of O-glycans including neutral, sialylated, and sulfated oligosaccharides. Furthermore, using this method, we were able to quantitatively identify isomeric products from an in vitro reaction catalyzed by N-acetylglucosamine-6O-sulfotransferases and obtain O-glycosylation profiles of serum IgA as a model glycoprotein. http://www.mdpi.com/2218-273X/1/1/48 Wed, 14 Dec 2011 00:00:00 CET Biomolecules 2011-12-14 1 1 Article 48 62 2218-273X Development and Application of Multidimensional HPLC Mapping Method for O-linked Oligosaccharides 2011-12-14 doi: 10.3390/biom1010048 Hirokazu Yagi Erina Ohno Sachiko Kondo Atsuhiro Yoshida Koichi Kato http://www.mdpi.com/2218-273X/1/1/32 Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, induce the expression of a wide variety of genes, including intercellular adhesion molecule-1 (ICAM-1). Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) was identified to inhibit the cell-surface ICAM-1 expression induced by pro-inflammatory cytokines in human lung carcinoma A549 cells. Ursolic acid was found to inhibit the TNF-α-induced ICAM-1 protein expression almost completely, whereas the TNF-α-induced ICAM-1 mRNA expression and NF-κB signaling pathway were decreased only partially by ursolic acid. In line with these findings, ursolic acid prevented cellular protein synthesis as well as amino acid uptake, but did not obviously affect nucleoside uptake and the subsequent DNA/RNA syntheses. This inhibitory profile of ursolic acid was similar to that of the Na+/K+-ATPase inhibitor, ouabain, but not the translation inhibitor, cycloheximide. Consistent with this notion, ursolic acid was found to inhibit the catalytic activity of Na+/K+-ATPase. Thus, our present study reveals a novel molecular mechanism in which ursolic acid inhibits Na+/K+-ATPase activity and prevents the TNF-α-induced gene expression by blocking amino acid transport and cellular protein synthesis. http://www.mdpi.com/2218-273X/1/1/32 Mon, 07 Nov 2011 00:00:00 CET Biomolecules 2011-11-07 1 1 Article 32 47 2218-273X Ursolic Acid Inhibits Na+/K+-ATPase Activity and Prevents TNF-α-Induced Gene Expression by Blocking Amino Acid Transport and Cellular Protein Synthesis 2011-11-07 doi: 10.3390/biom1010032 Tomonobu Yokomichi Kyoko Morimoto Nana Oshima Yuriko Yamada Liwei Fu Shigeru Taketani Masayoshi Ando Takao Kataoka http://www.mdpi.com/2218-273X/1/1/3 Intregins are heterodimeric α- and β-subunit containing membrane receptor proteins which serve various cell adhesion roles in tissue repair, hemostasis, immune response, embryogenesis and metastasis. At least 18 α- (ITA or ITGA) and 8 β-integrin subunits (ITB or ITGB) are encoded on mammalian genomes. Comparative ITB amino acid sequences and protein structures and ITB gene locations were examined using data from several vertebrate genome projects. Vertebrate ITB genes usually contained 13–16 coding exons and encoded protein subunits with ~800 amino acids, whereas vertebrate ITB4 genes contained 36-39 coding exons and encoded larger proteins with ~1800 amino acids. The ITB sequences exhibited several conserved domains including signal peptide, extracellular β-integrin, β-tail domain and integrin β-cytoplasmic domains. Sequence alignments of the integrin β-cytoplasmic domains revealed highly conserved regions possibly for performing essential functions and its maintenance during vertebrate evolution. With the exception of the human ITB8 sequence, the other ITB sequences shared a predicted 19 residue α-helix for this region. Potential sites for regulating human ITB gene expression were identified which included CpG islands, transcription factor binding sites and microRNA binding sites within the 3’-UTR of human ITB genes. Phylogenetic analyses examined the relationships of vertebrate beta-integrin genes which were consistent with four major groups: 1: ITB1, ITB2, ITB7; 2: ITB3, ITB5, ITB6; 3: ITB4; and 4: ITB8 and a common evolutionary origin from an ancestral gene, prior to the appearance of fish during vertebrate evolution. The phylogenetic analyses revealed that ITB4 is the most likely primordial form of the vertebrate β integrin subunit encoding genes, that is the only β subunit expressed as a constituent of the sole integrin receptor ‘α6β4’ in the hemidesmosomes of unicellular organisms. http://www.mdpi.com/2218-273X/1/1/3 Tue, 23 Aug 2011 00:00:00 CEST Biomolecules 2011-08-23 1 1 Review 3 31 2218-273X Comparative Studies of Vertebrate Beta Integrin Genes and Proteins: Ancient Genes in Vertebrate Evolution 2011-08-23 doi: 10.3390/biom1010003 Roger S. Holmes Ujjwal K. Rout http://www.mdpi.com/2218-273X/1/1/1 I am pleased to introduce Biomolecules, a new journal to report on all aspects of science that focuses on biologically derived substances, from small molecules to complex polymers. Some examples are lipids, carbohydrates, vitamins, hormones, amino acids, nucleotides, peptides, RNA and polysaccharides, but this list is far from exhaustive. Research on biomolecules encompasses multiple fascinating questions. How are biomolecules synthesized and modified? What are their structures and interactions with other biomolecules? How do biomolecules function in biological processes, at the level of organelles, cells, organs, organisms, or even ecosystems? How do biomolecules affect either the organism that produces them or other organisms of the same or different species? How are biomolecules shaped by evolution, and how in turn do they affect cellular phenotypes? What is the systems-level contribution of biomolecules to biological function? http://www.mdpi.com/2218-273X/1/1/1 Mon, 22 Aug 2011 00:00:00 CEST Biomolecules 2011-08-22 1 1 Editorial 1 2 2218-273X A Multidisciplinary, Open Access Platform for Research on Biomolecules 2011-08-22 doi: 10.3390/biom1010001 Jürg Bähler