Endorphins: structure, roles and biogenesis

The knowledge of the amino acid sequence of both beta-lipotropin (beta-LPH) and gamma-LPH was the starting point that led to the hypothesis, considered revolutionary in 1967, that hormonal precursors exist. This concept was simultaneously proposed for proinsulin and applied later to other polypeptide hormones. The discovery of endorphins brought together two fields of research that were not related: the opiates and the so-called pituitary lipotropic hormones. The demonstration of specific brain opiate receptors led to the hypothesis of the existence of endogenous opiate ligands which could act as neurotransmittors. The isolation of such substances in the brain, first named enkephalins, revealed through their amino acid sequence their structural homology with the pituitary lipolytic hormones. The finding of a more potent opioid substance in the pituitary (beta-endorphin) that comprises the last 31 amino acids of beta-LPH shed a new light on the hypothesis proposed earlier which gave to beta-LPH a role as a precursor molecule. Finally, the addition of ACTH completed a putative multipotent precursor model that has been recently named pro-opiomelanocortin. Pulse-chase experiments have definitely proven that beta-endorphin is a maturation product of a large precursor also containing ACTH and MSH. In other studies, many groups have suggested that endorphins play important roles as possible neuromodulators in pain transmission, in analgesia, in tolerance and dependence, as well as on behavior and endocrine regulations, mainly those related to the hypothalamo-pituitary axes. The elucidation of the biosynthetic process or processes of cerebral endorphins (either enkephalins or beta-endorphin) is of primary importance in order ot understand better their biological as well as regulatory functions. These studies should also be applicable to the biosynthesis of all the other neuronal peptide hormones. It is hoped that they will provide new tools for the study of some important central nervous system functions, such as pain and endocrine control and the physiopathology of behavioral diseases.     

Mitophagy: mechanisms, pathophysiological roles, and analysis

Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.     

Bradykinin receptors: towards new pathophysiological roles

In addition to being a pro-inflammatory mediator, bradykinin is now recognized as a neuromediator and regulator of several vascular and renal functions. New breakthroughs point to unusual and atypical signalling pathways for a G-protein coupled receptor that could explain the anti-proliferative and anti-fibrogenic effects of bradykinin. The availability of transgenic and knock out animal models for bradykinin receptors or bradykinin-synthesizing or -catabolic enzymes confirms these cardiac and renal protective roles for this peptide system. Bradykinin receptors are involved in the therapeutic action of angiotensin-1 converting enzyme inhibitors that are used in the treatment of arterial hypertension, heart failure and diabetes. Nevertheless, recent evidence highlights dissimilar mechanisms in the regulation and function of these receptors between the central nervous system and peripheral tissues. Therefore, the development of more specific bradykinin receptor agonists or antagonists devoid of central actions seems to evolve as a new therapeutic approach.     

Expression analysis of phytohormone-regulated microRNAs in rice, implying their regulation roles in plant hormone signaling

Twenty-two conserved miRNAs were chosen to investigate the expression pattern in response to phytohormone treatments, in which the effects of five classic plant hormone stresses were surveyed in Oryza sativa. The results showed that 11 miRNAs were found to be dysregulated by one or more phytohormone treatments. The target genes of these miRNAs were validated in vivo and their expression profiling were revealed. We also analyzed the promoter regions of the 22 conserved miRNAs for phytohormone-responsive elements and the existence of the elements provided further evidences supporting our results. These findings enable us to further investigate the role of miRNAs in phytohormone signaling.     

Physiological and pathophysiological roles of adenosine

Adenosine is a candidate sleep substance. It can be both a distress signal of importance in pathology and a physiological regulator. Key factors in determining which of these possibilities pertain are: (i) the number of receptors expressed, and (ii) the mechanisms that establish extracellular adenosine levels. The roles of adenosine are studied by means of antagonists and/or animals (mostly mice) with targeted deletions of receptors or enzymes involved in adenosine metabolism. Whereas adaptive changes in the genetically modified mice can occur for the physiologically important effects, such adaptive changes are less likely to occur in situations where adenosine acts as a distress signal. The relevance to sleep will be covered only in general terms in this review and will be covered in other contributions to this volume.

     

串珠素的生理与病理生理作用

串珠素 (perlecan)是细胞外基质中主要的蛋白聚糖之一 ,由核心蛋白和硫酸肝素侧链组成 ,可以通过调节生长因子的结合和活性影响血管壁细胞的增殖、迁移 ,并影响细胞与基质的粘附 ,在机体心血管和软骨发育、血管生成与功能调控等多种生命过程中均具有重要作用     

UsnRNP biogenesis: mechanisms and regulation

Macromolecular complexes composed of proteins or proteins and nucleic acids rather than individual macromolecules mediate many cellular activities. Maintenance of these activities is essential for cell viability and requires the coordinated production of the individual complex components as well as their faithful incorporation into functional entities. Failure of complex assembly may have fatal consequences and can cause severe diseases. While many macromolecular complexes can form spontaneously in vitro, they often require aid from assembly factors including assembly chaperones in the crowded cellular environment. The assembly of RNA protein complexes implicated in the maturation of pre-mRNAs (termed UsnRNPs) has proven to be a paradigm to understand the action of assembly factors and chaperones. UsnRNPs are assembled by factors united in protein arginine methyltransferase 5 (PRMT5)- and survival motor neuron (SMN)-complexes, which act sequentially in the UsnRNP production line. While the PRMT5-complex pre-arranges specific sets of proteins into stable intermediates, the SMN complex displaces assembly factors from these intermediates and unites them with UsnRNA to form the assembled RNP. Despite advanced mechanistic understanding of UsnRNP assembly, our knowledge of regulatory features of this essential and ubiquitous cellular function remains remarkably incomplete. One may argue that the process operates as a default biosynthesis pathway and does not require sophisticated regulatory cues. Simple theoretical considerations and a number of experimental data, however, indicate that regulation of UsnRNP assembly most likely happens at multiple levels. This review will not only summarize how individual components of this assembly line act mechanistically but also why, how, and when the UsnRNP workflow might be regulated by means of posttranslational modification in response to cellular signaling cues.     

Adrenomedullin receptors: pharmacological features and possible pathophysiological roles

Three receptor activity modifying proteins (RAMPs) chaperone calcitonin-like receptor (CLR) to the cell surface. RAMP2 enables CLR to form an adrenomedullin (AM)-specific receptor that is sensitive to AM-(22-52) (AM(1) receptor). RAMP3 enables CLR to form an AM receptor sensitive to both calcitonin gene-related peptide (CGRP)-(8-37) and AM-(22-52) (AM(2) receptor), though rat and mouse AM(2) receptors show a clear preference for CGRP alpha-(8-37) over AM-(22-52). RAMP1 enables CRL to form the CGRP-(8-37)-sensitive CGRP(1) receptor, which can also be activated by higher concentrations of AM. Here we review the available information on the pharmacological features and possible pathophysiological roles of the aforementioned AM receptors.     

Identification,expression analysis,and potential roles of microRNAs in the regulation of polysaccharide biosynthesis in Polygonatum cyrtonema Hua

Journal of Plant Biochemistry and Biotechnology - MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs with important roles in plant growth, development, and metabolic processes....     

A panoramic review of IL-6: Structure,pathophysiological roles and inhibitors

Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory cytokine. Its deregulation is associated with chronic inflammation, and multifactorial auto-immune disorders. It mediates its biological roles through a hexameric complex composed of IL-6 itself, its receptor IL-6R, and glycoprotein 130 (IL-6/IL-6R/gp130). This complex, in turn, activates different signaling mechanisms (classical and trans-signaling) to execute various biochemical functions. The trans-signaling mechanism activates various pathological routes, like JAK/STAT3, Ras/MAPK, PI3K–PKB/Akt, and regulation of CD4+ T cells and VEGF levels, which cause cancer, multiple sclerosis, rheumatoid arthritis, anemia, inflammatory bowel disease, Crohn’s disease, and Alzheimer’s disease. Involvement of IL-6 in pathophysiology of these complex diseases makes it an important target for the treatment of these diseases. Though some anti-IL-6 monoclonal antibodies are being used clinically, but their high cost, only parenteral administration, and possibility of immunogenicity have limited their use, and warranted the development of novel small non-peptide molecules as IL-6 inhibitors. In the present report, all molecules reported in literature as IL-6 inhibitors have been classified as IL-6 production, IL-6R, and IL-6 signaling inhibitors. Reports available till date are critically studied to identify important and salient structural features common in these molecules. These analyses would assist medicinal chemists to design novel and potent IL-6 production and signaling inhibitors, through knowledge- and/or computer-based approaches, for the treatment of complex multifactorial diseases.     

Apolipoproteins in human fetal colon: Immunolocalization,biogenesis, and hormonal regulation

The present investigation aimed at defining the localization of apolipoproteins (apo) A-I, A-IV, B-48, and B-100 along the crypt-villus axis of the human fetal colon, their biogenesis during gestation, and their hormonal regulation. Using immunofluoresence, the distribution of apo A-I and A-IV appeared as a gradient, increasing from the developing crypt to the tip of the villus. On the other hand, apo B-100 staining was found in the crypt and the lower mid-villus region with varying intensities in the upper villus cells, while the 2D8 antibody which recognizes both apo B-100 and B-48, revealed uniform staining along the crypt-villus axis. Apolipoprotein synthesis, determined by [³⁵S] methionine labeling, immunoprecipitation, and SDS-PAGE showed a predominance of apo A-IV (53%), followed by apo A-I (23.9%), apo B-48 (13.4%), and apo B-100 (9.7%). The synthesis of each apolipoprotein was significantly modulated by hydrocortisone, insulin and epidermal growth factor (EGF). Apart from a decrease in apo B-100 exerted by EGF and a reduction in apo A-I resulting from the addition of insulin, the other apolipoproteins were all enhanced. Our data confirm that the fetal colon has the capacity to synthesize apolipoprotein A-I, A-IV, B-48, and B-100 and establish that their synthesis are modulated by hormonal and growth factors known to be involved in the regulatory mechanism of the functional development of human jejunum. J. Cell. Biochem. 70:354–365, 1998. © 1998 Wiley-Liss, Inc.     

Tumor-derived extracellular vesicles and microRNAs: Functional roles,diagnostic, prognostic and therapeutic options

In the last few years cancer research more and more highlighted the importance of cell to cell communication in tumor progression. Among many other functional mechanisms, results evidenced the importance of miRNAs loaded into exosomes and their actions as mediators in intercellular communication, either in the tumor microenvironment or at distant sites. Deregulation of miRNA levels is a prerogative of cancer cells and is reflected in the miRNA cargo of tumor derived exosomes. Thus, learning of circulating miRNA activities add the missing piece we need to understand some unclear aspects of cancer biology.Here we summarized the current knowledge on exosome transfer capabilities between cancer cells and all the cells constituting tumor microenvironment with a particular focus on their miRNA cargos and regulatory functions. The clinical relevance of these molecular aspects is emphasized by numerous cell interactions that ultimately result in normal cell function defeat, relevant to increase tumor malignancy. The quantitative and qualitative evaluation of circulating miRNAs offers new perspective for better diagnosis and prognosis of cancer patients, eventually improving their management.     

Structure,function, and epigenetic regulation of BNIP3: a pathophysiological relevance

BCL-2 [B-cell leukemia/lymphoma 2]/adenovirus E1B 19KD interacting protein 3 (BNIP3) is an atypical BH3 domain only containing member of Bcl2 family of proteins. BNIP3 is known to be involved in various cellular processes depending on the cell type and conditions and also shown to play a role in various disease conditions including myocardial ischemia, autophagy and apoptosis. Though its role in autophagy and its pro-death activity have been reported in various studies, recent findings have shown its contradictory role in the regulation of these cellular processes. The various studies have shown its epigenetic regulation in disease development and progression and also found to be cytoprotective. In this review, we have focused on the structural and functional aspects of BNIP3 in relation to recent advances of its role in autophagy and apoptosis. Also its role of epigenetic regulation of several genes involved in various diseases was also discussed.     

microRNA与神经系统发育

microRNA(miRNA)介导的基因沉默是生物体内普遍存在的重要基因表达调控方式,其调控失常与很多人类疾病相关.miRNA在神经组织表达丰富.神经系统miRNA的功能研究是近年非常活跃的新领域.基于近期的研究进展,本文重点讨论了miRNA在神经轴模式化、神经元命运决定、神经细胞发生、神经元突触形成及成熟神经元突触重塑中的重要作用.     

Potential roles of microRNAs in redox state: An update

Oxidative stress is an important underlying cause of many disease processes and may arise due to either increasing free radical generation or decreasing antioxidant defense systems. MicroRNAs (miRs) are 22-nucleotide non-coding RNAs that may regulate many intracellular processes; and, more recently, they have been implicated in the pathways for free radical generation leading to oxidative stress. However, conversely, there is evidence that miRs may have an antioxidant effect, thus miR expression may be critical for the maintenance of the normal redox state and cell homeostasis. This review addresses these discrepant and opposing miR actions on how they may modify and regulate the oxidative balance.