Understanding the importance of selenium and selenoproteins in muscle function

Selenium is an essential trace element. In cattle, selenium deficiency causes dysfunction of various organs, including skeletal and cardiac muscles. In humans as well, lack of selenium is associated with many disorders, but despite accumulation of clinical reports, muscle diseases are not generally considered on the list. The goal of this review is to establish the connection between clinical observations and the most recent advances obtained in selenium biology. Recent results about a possible role of selenium-containing proteins in muscle formation and repair have been collected. Selenoprotein N is the first selenoprotein linked to genetic disorders consisting of different forms of congenital muscular dystrophies. Understanding the muscle disorders associated with selenium deficiency or selenoprotein N dysfunction is an essential step in defining the causes of the disease and obtaining a better comprehension of the mechanisms involved in muscle formation and maintenance. Received 13 July 2005; received after revision 9 September 2005; accepted 4 October 2005     

Human selenoproteins at a glance

The public perception of selenium has changed significantly over the last decades. Originally mainly known for its high toxicity, it was later recognized as an essential trace element and is now (despite its narrow therapeutic window) almost being marketed as a lifestyle drug. Indeed, some clinical and preclinical studies suggest that selenium supplementation may be beneficial in a large number of clinical conditions. However, its mode of action is unresolved in most of these cases. Selenocysteine – identified as the 21^st amino acid used in ribosome-mediated protein synthesis – is incorporated in at least 25 specific, genetically determined human selenoproteins, many of which have only recently been discovered. Restoration of normal selenoprotein levels may be – apart from direct supranutritional effects – one possible explanation for the effects of selenium supplements. In this review we provide a brief but up-to-date overview of what is currently known about these 25 acknowledged human selenoproteins and their synthesis. Received 30 March 2005; received after revision 4 July 2005; accepted 13 July 2005     

Physiological and nutritional importance of selenium

Summary The essential trace element selenium has recently attracted attention because of its potentialities in the maintenance of human health. Selenium forms part of the active site of the peroxide-destroying enzyme glutathione peroxidase, and it also has other functions, for example in biotransformation, detoxification and the immune response. Functional and clinical consequences of selenium deficiency states have been described, and the selenium requirement, which is influenced by the usual selenium exposure, has been discussed. Wide variations have been found in selenium status in different parts of the world, and populations or groups of patients exposed to marginal deficiency are more numerous than was previously thought.Current research activities in the field of human medicine and nutrition are devoted to the possibilities of using selenium for the prevention or treatment of degenerative or free radical diseases such as neurological disorders, inflammatory diseases or cancer. Pharmacological selenium doses are also recommended as an adjuvant in some treatments.     

Ca2+/Calmodulin-dependent Protein Kinases

In this article the calcium/calmodulin-dependent protein kinases are reviewed. The primary focus is on the structure and function of this diverse family of enzymes, and the elegant regulation of their activity. Structures are compared in order to highlight the conserved architecture of their catalytic domains with respect to each other as well as protein kinase A, a prototype for kinase structure. In addition to reviewing structure and function in these enzymes, the variety of biological processes for which they play a mediating role are also examined. Finally, how the enzymes become activated in the intracellular setting is considered by exploring the reciprocal interactions that exist between calcium binding to calmodulin when interacting with the CaM-kinases.     

Regulation of insulin receptor function

Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human disease, is reviewed in this article. Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007     

Lytic transglycosylases in macromolecular transport systems of Gram-negative bacteria

The cell wall of Gram-negative bacteria is essential for the integrity of the bacterial cell but also imposes a physical barrier to trans-envelope transport processes in which DNA and/or proteins are taken up or secreted by complex protein assemblies. The presence of genes encoding lytic transglycosylases in macromolecular transport systems (bacteriophage entry, type II secretion and type IV pilus synthesis, type III secretion, type IV secretion) suggests an important role for these specialised cell-wall-degrading enzymes. Such enzymes are capable of locally enlarging gaps in the peptidoglycan meshwork to allow the efficient assembly and anchoring of supramolecular transport complexes in the cell envelope. In this review, current knowledge on the role and distribution of these specialised murein-degrading enzymes in diverse macromolecular transport systems is summarised and discussed.Received 13 February 2003; received after revision 25 April 2003; accepted 12 May 2003     

Angiotensin-converting enzyme 2 in acute respiratory distress syndrome

Angiotensin-converting enzyme (ACE) and ACE2 are highly homologous metalloproteases that provide essential catalytic functions in the renin-angiotensin system (RAS). Angiotensin II is one key effector peptide of the RAS, inducing vasoconstriction and exerting multiple biological functions. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 reduces angiotensin II levels. Accumulating evidence has demonstrated a physiological and pathological role of ACE2 in the cardiovascular systems. Intriguingly, the SARS coronavirus, the cause of severe acute respiratory syndrome (SARS), utilizes ACE2 as an essential receptor for cell fusion and in vivo infections. Moreover, recent studies have demonstrated that ACE2 protects murine lungs from acute lung injury as well as SARS-Spike protein-mediated lung injury, suggesting a dual role of ACE2 in SARS infections and protection from ARDS. Received 18 May 2006; received after revision 12 March 2007; accepted 24 April 2007     

硼的生物效应及健康影响研究进展

硼是动物所必需的一种微量元素，硼缺乏和硼过量都会产生不利的影响。通过动物试验，硼污染问题已经开始引起人们的重视。美国已将硼列入环境雌激素重点研究化学品之一。已有的三项针对硼作业人群的生殖健康影响研究结果不一致。有的研究表明缺硼或硼污染对人体健康均有害。本文对近30年来有关硼的生物效应及其对人体健康影响的研究进展进行了总结，并对今后研究方向提出了建议。     

The analytical concept of a chemical element in the work of Bergman and Scheele

In Thomas Thomson's System of chemistry of 1802 Bergman and Scheele are actually considered as creators of the analytical concept of an element. With regard to this, a detailed investigation of the work of Bergman and Scheele shows that Thomson's statement contains mistakes as well as inadmissable simplifications and generalizations. It is correct, however, that Bergman in 1774–1777 specifically anticipated in essential aspects the analytical element concept proposed by Lavoisier in 1787–1789.     

Chemical properties of alcohols and their protein binding sites

Alcohols affect a wide array of biological processes including protein folding, neurotransmission and immune responses. It is becoming clear that many of these effects are mediated by direct binding to proteins such as neurotransmitter receptors and signaling molecules. This review summarizes the unique chemical properties of alcohols which contribute to their biological effects. It is concluded that alcohols act mainly as hydrogen bond donors whose binding to the polypeptide chain is stabilized by hydrophobic interactions. The electronegativity of the O atom may also play a role in stabilizing contacts with the protein. Properties of alcohol binding sites have been derived from X-ray crystal structures of alcohol-protein complexes and from mutagenesis studies of ion channels and enzymes that bind alcohols. Common amino acid sequences and structural features are shared among the protein segments that are involved in alcohol binding. The alcohol binding site is thought to consist of a hydrogen bond acceptor in a turn or loop region that is often situated at the N-terminal end of an alpha-helix. The methylene chain of the alcohol molecule appears to be accommodated by a hydrophobic groove formed by two or more structural elements, frequently a turn and an alpha-helix. Binding at these sites may alter the local protein structure or displace bound solvent molecules and perturb the function of key proteins.     

Über den gegenwärtigen Stand des Hauptproblems der Strahlenbiologie

Summary Two possibilities for the action of radiations on biological objects are still remaining: the effect by radiation-hits and the action by photochemical or radiochemical effects. By means of irradiating well-known chemical «model-substances» one may be able to decide between these two possibilities and to understand the biological primary effect of radiations.Both of the theoretical perceptions are discussed and compared with the empirical facts. It is shown that in all well examinated cases of radiation effects upon biological elements or chemical systems, water or an other diluting is of essential importance. Radiation-energy is conducted from point of absorption to point of action by means of electronic transport or diffusion. Diffusion seems much more probable in biological systems.     

Substrate specificity of bacterial DD-peptidases (penicillin-binding proteins)

The DD-peptidase enzymes (penicillin-binding proteins) catalyze the final transpeptidation reaction of bacterial cell wall (peptidoglycan) biosynthesis. Although there is now much structural information available about these enzymes, studies of their activity as enzymes lag. It is now established that representatives of two low-molecular-mass classes of DD-peptidases recognize elements of peptidoglycan structure and rapidly react with substrates and inhibitors incorporating these elements. No members of other DD-peptidase classes, including the high-molecular-mass enzymes, essential for bacterial growth, appear to interact strongly with any particular elements of peptidoglycan structure. Rational design of inhibitors for these enzymes is therefore challenging.     

Cytokine-mediated proteolysis in tissue remodelling

Summary Proteolytic enzymes play a key role in a variety of physiological processes in which the degradation of macromolecules is essential: angiogenesis, embryogenesis, bone and tissue remodelling, blood hemostasis and cell migration. The action of these enzymes is also crucial in the development of many pathological conditions such as wound healing, neoplasia, inflammation and arthritic disorders.the activity of proteases is negatively affected by specific protease-inhibitors. Various growth factors and other cytokines modulate the synthesis and secretion of both proteases and protease-inhibitors. The study of this regulation results in a better insight into (patho)physiology at the molecular level and promises to result in alternative treatment strategies.     

Cytokine-mediated proteolysis in tissue remodelling

Proteolytic enzymes play a key role in a variety of physiological processes in which the degradation of macromolecules is essential: angiogenesis, embryogenesis, bone and tissue remodelling, blood hemostasis and cell migration. The action of these enzymes is also crucial in the development of many pathological conditions such as wound healing, neoplasia, inflammation and arthritic disorders. The activity of proteases is negatively affected by specific protease-inhibitors. Various growth factors and other cytokines modulate the synthesis and secretion of both proteases and protease-inhibitors. The study of this regulation results in a better insight into (patho)physiology at the molecular level and promises to result in alternative treatment strategies.     

Deoxyribozymes: new activities and new applications

DNA in its single-stranded form has the ability to fold into complex three-dimensional structures that serve as highly specific receptors or catalysts. Only protein enzymes and ribozymes are known to be responsible for biological catalysis, but deoxyribozymes with kinetic parameters that rival ribozymes can be created in the laboratory. Some of these engineered DNA catalysts are showing surprising potential as therapeutic agents, which makes them biologically relevant if not biologically derived. If DNA's natural role is strictly genomic, how significant is its innate catalytic prowess? New examples of engineered deoxyribozymes serve as empirical examples of the potential for catalysis by DNA. These results indicate that the true catalytic power of DNA is limited by discovery and not by chemistry.     

GPR120: a critical role in adipogenesis,inflammation, and energy metabolism in adipose tissue

It is well known that adipose tissue has a critical role in the development of obesity and metabolic diseases and that adipose tissue acts as an endocrine organ to regulate lipid and glucose metabolism. Accumulating in the adipose tissue, fatty acids serve as a primary source of essential nutrients and act on intracellular and cell surface receptors to regulate biological events. G protein-coupled receptor 120 (GPR120) represents a promising target for the treatment of obesity-related metabolic disorders for its involvement in the regulation of adipogenesis, inflammation, glucose uptake, and insulin resistance. In this review, we summarize recent studies and advances regarding the systemic role of GPR120 in adipose tissue, including both white and brown adipocytes. We offer a new perspective by comparing the different roles in a variety of homeostatic processes from adipogenic development to adipocyte metabolism, and we also discuss the effects of natural and synthetic agonists that may be potential agents for the treatment of metabolic diseases.     

La FAM fatale: USP9X in development and disease

Deubiquitylating enzymes (DUBs), act downstream of ubiquitylation. As such, these post-post-translational modifiers function as the final arbitrators of a protein substrate’s ubiquitylation status, thus regulating its fate. In most instances, DUBs moderate the absolute level of a substrate, its locality or activity, rather than being an “all-or-none” phenomenon. Yet, disruption of this quantitative regulation can produce dramatic qualitative differences. The ubiquitin-specific protease 9X (USP9X/FAM) is a substrate-specific DUB, which displays an extraordinarily high level of sequence conservation from Drosophila to mammals. It is primarily the recent revelations of USP9X’s pivotal role in human cancers, both as oncogene or tumour suppressor, in developmental disorders including intellectual disability, epilepsy, autism and developmental delay that has led to a subsequent re-examination of its molecular and cellular functions. Results from experimental animal models have implicated USP9X in neurodegeneration, including Parkinson’s and Alzheimer’s disease, as well as autoimmune diseases. In this review, we describe the current and accumulated knowledge on the molecular, cellular and developmental aspects of USP9X function within the context of the biological consequences during normal development and disease.