An update on the islet renin-angiotensin system

The traditional renin-angiotensin system (RAS) components have been studied extensively since the rate-limiting component of RAS, renin, was first characterized. The ongoing identification of various novel RAS components and signaling pathways continues to elaborate the complexity of this system. Regulation of RAS according to the conventional and contemporary views of its functions in various tissues under pathophysiological conditions is a main treatment strategy for many metabolic diseases. The local pancreatic RAS, first proposed to exist in pancreatic islets two decades ago, could regulate islet function and glycemic control via influences on islet cell mass, inflammation, and ion channels. Insulin secretion, the major function of pancreatic islets, is controlled by numerous factors. Among these factors and of particular interest are glucagon-like peptide-1 (GLP-1) and vitamin D, which may regulate islet function by directly binding receptors on islet beta cells. These factors may work with local RAS signaling in islets to protect and maintain islet function under diabetic and hyperglycemic conditions. In this concise review, the local islet RAS will be discussed with particular attention being paid to recent notable findings.     

Structural fingerprints,interactions, and signaling networks of RAS family proteins beyond RAS isoforms

Among the signaling molecules indirectly linked to many different cell surface receptors, RAS proteins essentially respond to a diverse range of extracellular cues. They control activities of multiple signaling pathways and consequently a wide array of cellular processes, including survival, growth, adhesion, migration, and differentiation. Any dysregulation of these pathway leads, thus, to cancer, developmental disorders, metabolic, and cardiovascular diseases. The biochemistry of RAS family proteins has become multifaceted since the discovery of the first members, more than 40 years ago. Substantial knowledge has been attained about molecular mechanisms underlying post-translational modification, membrane localization, regulation, and signal transduction through diverse effector molecules. However, the increasing complexity of the underlying signaling mechanisms is considerable, in part due to multiple effector pathways, crosstalks between them and eventually feedback mechanisms. Here, we take a broad view of regulatory and signaling networks of all RAS family proteins that extends beyond RAS paralogs. As described in this review, a lot is known but a lot has to be discovered yet.     

Transglutaminases and their substrates in biology and human diseases: 50 years of growing

Transglutaminase is an enzyme able to play more than one enzymatic action, acting on a variety of different substrates. The growth of knowledge about the members of the enzyme transglutaminase’s family and its substrates since the last 50 years indicates a large interest and curiosity about this protein, whose function and structure was, but still is, an important object of research. On the other hand, the involvement in a number of human diseases together with the lack of knowledge about the biological functions played by some of the most studied members of this family, make this enzyme a fascinating field of study. The history of this enzyme and its substrates, whose cross-linking action was reported for the first time 50 years ago, suggests that an effort to increase knowledge and communication among researchers is required. To achieve this important result, 10 years ago an internet web page called worldwide happening around transglutaminase (WHAT) was created. Driven by these experiences, novel points-of-view to look at Transglutaminase and its substrates may be identified.     

New insights and perspectives on intrarenal renin-angiotensin system: focus on intracrine/intracellular angiotensin II

Although renin, the rate-limiting enzyme of the renin-angiotensin system (RAS), was first discovered by Robert Tigerstedt and Bergman more than a century ago, the research on the RAS still remains stronger than ever. The RAS, once considered to be an endocrine system, is now widely recognized as dual (circulating and local/tissue) or multiple hormonal systems (endocrine, paracrine and intracrine). In addition to the classical renin/angiotensin I-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor (AT₁/AT₂) axis, the prorenin/(Pro)renin receptor (PRR)/MAP kinase axis, the ACE2/Ang (1-7)/Mas receptor axis, and the Ang IV/AT₄/insulin-regulated aminopeptidase (IRAP) axis have recently been discovered. Furthermore, the roles of the evolving RAS have been extended far beyond blood pressure control, aldosterone synthesis, and body fluid and electrolyte homeostasis. Indeed, novel actions and underlying signaling mechanisms for each member of the RAS in physiology and diseases are continuously uncovered. However, many challenges still remain in the RAS research field despite of more than one century's research effort. It is expected that the research on the expanded RAS will continue to play a prominent role in cardiovascular, renal and hypertension research. The purpose of this article is to review the progress recently being made in the RAS research, with special emphasis on the local RAS in the kidney and the newly discovered prorenin/PRR/MAP kinase axis, the ACE2/Ang (1-7)/Mas receptor axis, the Ang IV/AT₄/IRAP axis, and intracrine/intracellular Ang II. The improved knowledge of the expanded RAS will help us better understand how the classical renin/ACE/Ang II/AT₁ receptor axis, extracellular and/or intracellular origin, interacts with other novel RAS axes to regulate blood pressure and cardiovascular and kidney function in both physiological and diseased states.     

Diabetes and retinal vascular disorders: role of the renin-angiotensin system

Angiotensin II, the effector peptide of the renin-angiotensin system (RAS), has potent growth factor properties in a variety of organs. In the retina, a complete RAS exists, with components residing in the vasculature, neurons and glia. There is increasing interest in a pathogenetic role for angiotensin II in ischaemic retinopathies such as diabetic retinopathy and retinopathy of prematurity. In these situations, the retinal RAS becomes activated and stimulates growth factors such as vascular endothelial growth factor, which contribute to vascular leakage, pericyte migration, angiogenesis and fibrosis. Blockade of the RAS, with either angiotensin-converting enzyme (ACE) inhibitors or antagonists selective for angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors, attenuates many of the vascular abnormalities that develop in diabetic retinopathy and retinopathy of prematurity. Eagerly awaited are the findings of the Diabetic Retinopathy Candesartan Trial (DIRECT), evaluating the effects of AT1 receptor antagonism in patients with different stages of diabetic retinopathy. This review examines the role of the RAS in diabetic retinopathy and retinopathy of prematurity, and the potential of RAS blockade as a treatment strategy for these vision-threatening diseases.     

Recent developments in inhibiting cysteine and serine proteases

Some 20 years ago, affinity labelling was introduced to help gather information on active-site catalytic groups and the mechanisms of proteolytic enzymes. Now this knowledge is used to produce specific and selective inhibitors for these enzymes. The concept of "biospecific drug design" has stimulated progress in turning the inhibitors into therapeutically applicable agents. For instance, sales of antihypertensive drugs based on inhibitors of the angiotensin converting enzyme are expected to be over 2 billion US-$ in 1992. This partly illustrates the efforts made by many researchers to introduce strategies in potease inhibition for medicinal purposes. This review discusses some of the concepts.     

Informatics integration: the bedrock of NCE selection

The life-science domain has been discussing the merits of data integration for several years. Approximately five years ago, knowledge management promised to solve many of the bottlenecks of the drug discovery pipeline. It was envisioned that companies would purchase off-the-shelf software solutions or hire consultants or informaticians to solve their informatics problems. However, knowledge management has not delivered all that it promised. Better investment in integration is required to deliver a system that significantly reduces the time-to-market and R&D overheads, and increase the rate at which novel chemical entities (NCEs) progress through the pipeline. Such investments require strategic decisions that, if implemented successfully, deliver substantial benefits and act as the bedrock for NCE selection.     

Characteristics of neural and humoral systems involved in the regulation of blood pressure in snakes

Cardiovascular function is affected by many mechanisms, including the autonomic system, the kallikrein-kinin system (KKS), the renin-angiotensin system (RAS) and the endothelin system. The function of these systems seems to be fairly well preserved throughout the vertebrate scale, but evolution required several adaptations. Snakes are particularly interesting for studies related to the cardiovascular function because of their elongated shape, their wide variation in size and length, and because they had to adapt to extremely different habitats and gravitational influences. To keep the normal cardiovascular control the snakes developed anatomical and functional adaptations and interesting structural peculiarities are found in their autonomic, KKS, RAS and endothelin systems. Our laboratory has characterized some biochemical, pharmacological and physiological properties of these systems in South American snakes. This review compares the components and function of these systems in snakes and other vertebrates, and focuses on differences found in snakes, related with receptor or ligand structure and/or function in autonomic system, RAS and KKS, absence of components in KKS and the intriguing identity between a venom and a plasma component in the endothelin system.     

Decision making in the NICU--strategies,statistics, and "satisficing"

As science progresses, new issues in bioethics grab the headlines, but in neonatal medicine communication and decision making for sick and premature infants is as important today as it was thirty years ago. Decisions have to be made and made well, despite suboptimal time, data, or knowledge. To this end, the authors propose good communication and a cooperative model as key to interpreting the best interest standard in a way that respects parental rights and responsibility and allows best interest to be decided from an amalgam of medical facts and human values.     

L.S. Vygotsky and Reform of Today's School

The name Lev Semenovich Vygotsky is by now very well known to scholars and scientists in many of the humanities, especially to psychologists and educators and even teachers in some countries. Although Vygotsky died almost sixty years ago, considerable interest may be observed at the present time in his theoretical views and in how these views influence the process of improving and even reforming modern education. What are the reasons for such a paradoxical circumstance? I submit that these reasons are to be found, first, in the profoundly hypothetical nature of Vygotsky's views; they have therefore required a long time to be empirically confirmed and substantiated. Second, there is a discrepancy between these views and the needs and requirements of education in preceding decades. It was only about ten years ago that our Russian education began to sense a general need for a new and substantial reform. One of the pillars of these reforms was Vygotsky's views, which concentrated the ideas of many other outstanding people in our education in the first third of this century (for example, the ideas of Blonskii, Shatskii, and others).     

Plant cystatins

Plant cystatins have been the object of intense research since the publication of a first paper reporting their existence more than 20 years ago. These ubiquitous inhibitors of Cys proteases play several important roles in plants, from the control of various physiological and cellular processes in planta to the inhibition of exogenous Cys proteases secreted by herbivorous arthropods and pathogens to digest or colonize plant tissues. After an overview of current knowledge about the evolution, structure and inhibitory mechanism of plant cystatins, we review the different roles attributed to these proteins in plants. The potential of recombinant plant cystatins as effective pesticidal proteins in crop protection is also considered, as well as protein engineering approaches adopted over the years to improve their inhibitory potency and specificity towards Cys proteases of biotechnological interest.     

Les premières étapes de la colonisation de l’Europe et l’arrivée de l’Homme sur les rives de la Méditerranée

Over recent years, many discoveries have renewed our knowledge about the oldest stone industries and also about the behaviour and lifestyle of the hominids that made them, not only in East Africa, but also in the Near East, in Trans Caucasia and in southern Europe. If the first tools making hominids appear in East Africa as early as 2.55 million years ago, they are present in the Levant a little over 2 million years ago, as early as 1.81 million years ago at the gates of Europe in Trans-Caucasia, and a little over 1.4 million years ago on the Mediterranean coasts of Europe.     

Cross-talk of the renin-angiotensin and kallikrein-kinin systems

The renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems play a key role in multiple physiological and pathophysiological conditions, including growth and development, inflammation, blood pressure regulation and control of renal function. In many instances, kinins and angiotensin II work together, e.g., during development, whereas they oppose each other's actions in the regulation of vascular tone and renal function. The RAS and KKS systems also interact at multiple levels, so that changes in the activity of one system greatly impact the activity of the other. The purpose of this brief review is to highlight recent knowledge regarding interactions at the cellular and molecular levels between the two systems, with an emphasis on the coordinate developmental regulation of these phylogenetically conserved vasoactive systems.     

Obesity Research and Medical Journalism

With publication of the first number of volume 3 of OBESITY RESEARCH, the time is ripe to review where we have been and where we are going. There are now two widely accepted journals covering the field of obesity. It was not always so. Until 20 years ago only one journal had appeared with the word “obesity” in its title, and its publication was short lived (Table 1). The growth of medical journalism in this field over the past 20 years, as in other fields, is a reflection of the growth of scientific manpower and knowledge which had its beginnings in the scientific revolution more than 300 years ago. The frustration engendered by this steady and rapid growth of scientific journals has been reflected in the quotations from many scholars. Below are a few of these.     

MAP kinase pathways: the first twenty years

The MAP kinases, discovered approximately 20 years ago, together with their immediate upstream regulators, are among the most highly studied signal transduction molecules. This body of work has shaped many aspects of our present views of signal transduction by protein kinases. The effort expended in this area reflects the extensive participation of these regulatory modules in the control of cell fate decisions, i.e., proliferation, differentiation and death, across all eukaryotic phylla and in all tissues of metazoans. The discovery of these kinases is reviewed, followed by a discussion of some of the features of this signaling module that account for its broad impact on cell function and its enormous interest to many investigators.     

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli, some of which might finally lead up to a maladaptive state. An integral part of the pathogenesis of the hypertrophic cardiomyopathy disease (HCM) is the activation of the rat sarcoma (RAS)/RAF/MEK (mitogen-activated protein kinase kinase)/MAPK (mitogen-activated protein kinase) cascade. Therefore, the molecular signaling involving RAS has been the subject of intense research efforts, particularly after the identification of the RASopathies. These constitute a class of developmental disorders caused by germline mutations affecting proteins contributing to the RAS pathway. Among other phenotypic features, a subset of these syndromes is characterized by HCM, prompting researchers and clinicians to delve into the chief signaling constituents of cardiac hypertrophy. In this review, we summarize current advances in the knowledge of the molecular signaling events involved in the pathogenesis of cardiac hypertrophy through work completed on patients and on genetically manipulated animals with HCM and RASopathies. Important insights are drawn from the recognition of parallels between cardiac hypertrophy and cancer. Future research promises to further elucidate the complex molecular interactions responsible for cardiac hypertrophy, possibly pointing the way for the identification of new specific targets for the treatment of HCM.     

Liposomes: an overview of manufacturing techniques

During the last few decades liposomes have attracted great interest as ideal models for biological membranes as well as efficient carriers for drugs, diagnostics, vaccines, nutrients and other bioactive agents. The extensive and ever increasing literature covering the field of liposomology written by researchers with diverse backgrounds is an indication of increasing interest in this field. Many techniques and methodologies have evolved for the manufacture of liposomes, on small and large scales, since their introduction to the scientific community around 40 years ago. This article intends to provide an overview of the advantages and disadvantages of liposome preparation methods in general with particular emphasis on the heating method, developed in our laboratory, as a model technique for fast production of the lipid vesicles.