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     

Physiological and pathophysiological roles of ATP-sensitive K+ channels

ATP-sensitive potassium (K(ATP)) channels are present in many tissues, including pancreatic islet cells, heart, skeletal muscle, vascular smooth muscle, and brain, in which they couple the cell metabolic state to its membrane potential, playing a crucial role in various cellular functions. The K(ATP) channel is a hetero-octamer comprising two subunits: the pore-forming subunit Kir6.x (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptor SUR (SUR1 or SUR2). Kir6.x belongs to the inward rectifier K(+) channel family; SUR belongs to the ATP-binding cassette protein superfamily. Heterologous expression of differing combinations of Kir6.1 or Kir6.2 and SUR1 or SUR2 variant (SUR2A or SUR2B) reconstitute different types of K(ATP) channels with distinct electrophysiological properties and nucleotide and pharmacological sensitivities corresponding to the various K(ATP) channels in native tissues. The physiological and pathophysiological roles of K(ATP) channels have been studied primarily using K(ATP) channel blockers and K(+) channel openers, but there is no direct evidence on the role of the K(ATP) channels in many important cellular responses. In addition to the analyses of naturally occurring mutations of the genes in humans, determination of the phenotypes of mice generated by genetic manipulation has been successful in clarifying the function of various gene products. Recently, various genetically engineered mice, including mice lacking K(ATP) channels (knockout mice) and mice expressing various mutant K(ATP) channels (transgenic mice), have been generated. In this review, we focus on the physiological and pathophysiological roles of K(ATP) channels learned from genetic manipulation of mice and naturally occurring mutations in humans.     

Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids

Recently, a family of phospholipid mediators has received much attention because of its variety of biological activities. Lysophosphatidic acid (LPA) is a central member of the phospholipid autacoid family that exerts diverse effects through binding to and activation of several specific receptors coupled to G-proteins. In accordance with its function as a receptor agonist, there are pathways for extracellular generation of LPA in vivo. One pathway involves a novel lysophospholipase D activity that was originally found in rat plasma. LPA is also produced in significant amounts after incubation of various plasma-derived body fluids such as human follicular fluid at 25-37 degrees C. In animal models, LPA was shown to stimulate oocyte maturation, embryonic development and transport in the oviduct. An increase in serum lysophospholipase D activity was observed during pregnancy in human. These results suggest that LPA generated by lysophospholipase D is likely to play an important role in reproductive biology. LPA produced by lysophospholipase D activity in body fluids has also been observed under pathophysiological conditions: serum and ascitic fluid from ovarian cancer patients and serum from hypercholesterolemic rabbits. Hence, excess generation of LPA by lysophospholipase D activity in body fluids has been suggested to be relevant to the pathogenesis of cancer and atherosclerosis.     

Physiological and pathophysiological aspects of ceramide

Activation of cells by receptor- and nonreceptor-mediated stimuli not only requires a change in the activity of signaling proteins but also requires a reorganization of the topology of the signalosom in the cell. The cell membrane contains distinct domains, rafts that serve the spatial organization of signaling molecules in the cell. Many receptors or stress stimuli transform rafts by the generation of ceramide. These stimuli activate the acid sphingomyelinase and induce a translocation of this enzyme onto the extracellular leaflet of the cell membrane. Surface acid sphingomyelinase generates ceramide that serves to fuse small rafts and to form large ceramide-enriched membrane platforms. These platforms cluster receptor molecules, recruit intracellular signaling molecules to aggregated receptors, and seem to exclude inhibitory signaling factors. Thus ceramide-enriched membrane platforms do not seem to be part of a specific signaling pathway but may facilitate and amplify the specific signaling elicited by the cognate stimulus. This general function may enable these membrane domains to be critically involved in the induction of apoptosis by death receptors and stress stimuli, bacterial and viral infections of mammalian cells, and the regulation of cardiovascular functions.     

Physiological roles of adenosine derivatives which are released during neurotransmission in mammalian brain.

1. Experiments using synaptosome beds suggested that ATP was released from presynaptic sites and degraded to adenosine in the synaptic cleft and that the resulting adenosine was taken up again into nerve endings where it was re-phosphorylated to ATP. 2. Adenosine derivatives in the synaptic cleft inhibited the postsynaptic potentials in olfactory cortex slices in vitro, presumably by the inhibition of Ca2+ influx into nerve endings which resulted in the reduction of transmitter release. 3. The adenosine derivatives also increased the level of cyclic AMP in the slices under the same conditions as above. 4. Although the nature of the "adenosine receptors" for both functions was remarkably similar, the increase of cyclic AMP did not mediate the inhibitory action, but the presynaptic increase of cyclic AMP induced by adenosine derivatives might mediate the facilitation observed in the olfactory cortex. 5. Possible physiological roles of extracellular adenosine derivatives in mammalian brain were classified, at different sites of action around the synapses, with different time courses and modes of action, directly or via the increase of intracellular cyclic AMP.     

Biological and pathophysiological roles of end-products of DHA oxidation

BackgroundPolyunsaturated fatty acids (PUFA) are known to be present and/or enriched in vegetable and fish oils. Among fatty acids, n-3 PUFA are generally considered to be protective in inflammation-related diseases. The guidelines for substituting saturated fatty acids for PUFAs have been highly publicized for decades by numerous health organizations. Recently, however, the beneficial properties of n-3 PUFA are questioned by detailed analyses of multiple randomized controlled clinical trials. The reported heterogeneity of results is likely due not only to differential effects of PUFAs on various pathological processes in humans, but also to the wide spectrum of PUFA's derived products generated in vivo.Scope of reviewThe goal of this review is to discuss the studies focused on well-defined end-products of PUFAs oxidation, their generation, presence in various pathological and physiological conditions, their biological activities and known receptors. Carboxyethylpyrrole (CEP), a DHA-derived oxidized product, is especially emphasized due to recent data demonstrating its pathophysiological significance in many inflammation-associated diseases, including atherosclerosis, hyperlipidemia, thrombosis, macular degeneration, and tumor progression.Major conclusionsCEP is a product of radical-based oxidation of PUFA that forms adducts with proteins and lipids in blood and tissues, generating new powerful ligands for TLRs and scavenger receptors. The interaction of CEP with these receptors affects inflammatory response, angiogenesis, and wound healing.General significanceThe detailed understanding of CEP–mediated cellular responses may provide a basis for the development of novel therapeutic strategies and dietary recommendations.     

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.     

Physiological and pathophysiological aspects of gastrointestinal peptide hormones.

The author made a review about the origin, the biochemistry the physiological and pathological roles of gastrointestinal peptide hormones. They originate from the APUD cell system, chemically from the ancient growth hormone, or placental lactogen. The theoretical prosecgastrin's first sequencies form the "secretin family", the tail sequencies form the "gastrin family". The author describes many details of their effects on the different gastrointestinal organs, they behave mainly antagonistic way to each other. Finally a discussions is given about their role in the development of peptic ulcer, in the WDHA syndrome and in malabsorption.     

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.     

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.     

Functions and pathophysiological roles of phospholipase D in the brain

Ten years after the isoforms of mammalian phospholipase D (PLD), PLD1 and 2, were cloned, their roles in the brain remain speculative but several lines of evidence now implicate these enzymes in basic cell functions such as vesicular trafficking as well as in brain development. Many mitogenic factors, including neurotransmitters and growth factors, activate PLD in neurons and astrocytes. Activation of PLD downstream of protein kinase C seems to be a required step for astroglial proliferation. The characteristic disruption of the PLD signaling pathway by ethanol probably contributes to the delay of brain growth in fetal alcohol syndrome. The post-natal increase of PLD activities concurs with synapto- and myelinogenesis in the brain and PLD is apparently involved in neurite formation. In the adult and aging brain, PLD activity has antiapoptotic properties suppressing ceramide formation. Increased PLD activities in acute and chronic neurodegeneration as well as in inflammatory processes are evidently due to astrogliosis and may be associated with protective responses of tissue repair and remodeling. ARF-regulated PLD participates in receptor endocytosis as well as in exocytosis of neurotransmitters where PLD seems to favor vesicle fusion by modifications of the shape and charge of lipid membranes. Finally, PLD activities contribute free choline for the synthesis of acetylcholine in the brain. Novel tools such as RNA interference should help to further elucidate the roles of PLD isoforms in brain physiology and pathology.     

Physiological roles of prolactin-releasing peptide

Prolactin-releasing peptide (PrRP) was first isolated from bovine hypothalamus as an orphan G-protein-coupled receptor using the strategy of reverse pharmacology. The initial studies showed that PrRP was a potent and specific prolactin-releasing factor. Morphological and physiological studies, however, indicated that PrRP may play a wide range of roles in neuroendocrinology other than prolactin release, i.e., metabolic homeostasis, stress responses, cardiovascular regulation, gonadotropin secretion, GH secretion and sleep regulation. This review will provide the current knowledge of PrRP, especially its roles in energy metabolism and stress responses.     

Physiological, pathophysiological and pharmacological aspects of exogenous and endogenous opiates

Endogenous opioid peptides have been detected not only in the central nervous system but also in the peripheral autonomic nervous system of the gastrointestinal tract and pancreas and several other organs. In addition opioid active peptides have been found in certain nutrients such as wheat gluten and bovine and human milk. Functional studies have presented evidence for a participation of endogenous opioids in the regulation of certain pituitary and gastrointestinal functions. Apart from being a physiological neuroregulator there is evidence that endogenous opioids might play a role as a pathogenetic factor in various clinical disorders. The evidence for these different aspects of opioid function is reviewed in the present article.     

Physiological roles of protein inhibitors

Protein inhibitors of proteases are widespread in nature. They are found in many sources, such as seeds, blood, eggs, and in many types of cells and tissues. Many physiological roles have been attributed to the protein inhibitors. Germination, wound healing, blood clotting, angiogenesis, etc., are some of the normal physiological activities in which protein inhibitors of proteases are involved. Lung destruction during emphysema and cartilage breakdown due to inflammation are two of the pathological conditions in which deficiency of protein inhibitors contributes to tissue breakdown by proteases.     

Metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor and its pathophysiological roles

Heparin-binding EGF-like growth factor (HB-EGF) exists as a membrane-anchored form (proHB-EGF) and as its soluble cleaved product (sHB-EGF). The conversion (ectodomain shedding) of proHB-EGF to sHB-EGF is tightly regulated by specific metalloproteinases. Ectodomain shedding plays a central role in GPCR-mediated EGFR transactivation. Antagonizing metalloproteinases can inhibit EGFR transactivation and might be of therapeutic value, for example in cardiac hypertrophy, skin remodeling and tumor growth.     

Biochemical properties and pathophysiological roles of cytosolic phospholipase A2s

Phospholipase A(2) (PLA(2)) (EC 3.1.1.4) catalyzes hydrolysis of the sn-2 ester bond of glycerophospholipids. The enzyme is essential for the production of two classes of lipid mediators, fatty acid metabolites and lysophospholipid-related lipids, as well as being involved in the remodeling of membrane phospholipids. Among many mammalian PLA(2)s, cytosolic PLA(2)alpha (cPLA(2)alpha) plays a critical role in various physiological and pathophysiological conditions through generating lipid mediators. Here, we summarize the in vivo significance of cPLA(2)alpha, revealed from the phenotypes of cPLA(2)alpha-null mice, and properties of newly discovered cPLA(2) family enzymes. We also briefly introduce a quantitative lipidomics strategy using liquid chromatography-mass spectrometry, a powerful tool for the comprehensive analysis of lipid mediators.     

肾脏中肾素-血管紧张素系统的生理和病理生理作用

肾脏中肾素-血管紧张素系统(RAS)在肾脏生理功能的调节中有重要作用.近年来,肾脏RAS的新成分及新作用机制不断被发现.转基因动物研究使肾脏血管紧张素Ⅱ(AngⅡ)在血压及水钠平衡调节中的作用进一步阐明;AngⅡ的非血流动力学作用已经确立;血管紧张素转换酶2(ACE2)及Ang 1～7对肾功能的调节作用也已得到认可.肾素/前肾素特异性受体、ACE的信号转导功能,以及AT1受体的转激活功能等,已成为肾脏生理科学研究的热点.这些研究对于人们认识肾脏局部RAS功能,探讨延缓慢性肾脏病的进展的治疗策略具有重要意义.