乳酸作为信号分子作用的研究进展

在既往研究中乳酸常被认为是糖酵解代谢废物,尤其被认为是肌肉疲劳的罪魁祸首。然而,越来越多的研究表明,乳酸在多种细胞生理与病理过程中扮演重要角色。乳酸不但可以作为能量来源参与机体脑神经元、心脏以及骨骼肌等组织细胞供能,而且还可作为一种特殊的信号分子借助其运输载体单羧酸转运体和特异性受体G蛋白偶联受体81在能量调节、肿瘤细胞生长转移和免疫逃逸、神经元能量代谢、突触可塑性、学习记忆和神经发育、细胞增殖分化等多种细胞生理病理过程中发挥重要调节作用。在此,该文就乳酸转运、信号转导及其在相关细胞生理病理过程中的重要生理作用进行综述,希望为深入理解乳酸的生物学特性及基础应用提供新的参考依据。     

乳酸——运动改善认知功能的明星分子

既往的研究中,乳酸一直被认为是细胞糖酵解产生的代谢废物。然而,近年的研究表明,乳酸可作为重要的能量代谢底物和信号分子影响多组织器官的生理进程,其运输载体单羧酸转运体及受体G蛋白偶联受体81可能在神经保护过程中发挥关键作用。在中枢神经系统内,乳酸可作用于多种细胞如神经元、星形胶质细胞、小胶质细胞、少突胶质细胞和血管内皮细胞等,参与改善脑能量代谢,增强神经发生,提高突触可塑性,降低神经炎症,缓解神经毒性,促使髓鞘再生,进而影响个体认知功能。适宜的运动有利于脑健康,但运动能否通过调节乳酸及相关生物学机制改善认知功能未见详尽报道。该文通过分析运动如何调控乳酸及其运输载体和受体的生理水平,以及乳酸如何调节认知功能,探讨乳酸作为运动改善认知功能中介分子的可能性,为借助运动疗法缓解认知衰退的相关疾病提供理论支持。     

血清和糖皮质激素调节激酶1在中枢神经系统疾病中的作用机制及其药物干预研究现状

血清和糖皮质激素调节激酶1(serum and glucocorticoid-regulated kinase 1, SGK1)在神经系统激素释放、神经元兴奋和细胞增殖等生理过程中均发挥重要作用，SGK1也参与了中枢神经系统炎症及细胞凋亡等病理生理过程。越来越多的证据表明，SGK1可能作为干预神经退行性疾病的关键性靶点。本文就SGK1在中枢神经系统功能调控中的作用及其分子机制的研究进展作一综述，并对最新发现的以SGK1为干预靶点的药物在中枢神经系统疾病中的潜力进行了讨论。     

运动性肌乳酸对慢性病的潜在作用机制

运动性肌乳酸作为运动时糖酵解的代谢终产物,是导致运动性疲劳的重要机制之一.运动性肌乳酸还作为重要的信号分子,调控骨骼肌及线粒体的能量代谢相关基因表达;抑制促炎因子的释放,并作为内分泌性信号分子干扰脂多糖信号的激活而减轻慢性炎症的发生;作为一种能量传感器和信号分子调节脂肪代谢和参与白色脂肪棕色化的调节,对慢性病的运动防治...     

胞质钙信号

胞质钙作为信使对细胞各种生理活动具有广泛调控作用。早期的研究揭示,钙在肌肉收缩,激素、消化酶类和神经递质的释放中起重要作用;近期的研究发现,钙参与更广泛的生理过程,如生物膜通透性及细胞兴奋性的控制、细胞代谢、细胞形态的维持、细胞周期的调控以及生殖细胞...     

NMDA受体信号复合体中蛋白质的相互作用

谷氨酸能兴奋性突触的突触后密集区(postsynaptic density,PSD)包含多种受体蛋白、骨架蛋白和信号蛋白,它们通过分子中特定的结构域相互识别并动态地结合,形成多个信号复合体,参与突触后受体功能的调节及其下游特异性信号转导通路的激活。其中,NMDA受体信号复合体中蛋白质-蛋白质的相互作用及其调控机制的阐明,对于深入了解神经发育、突触可塑性、兴奋性毒性等生理病理的分子机制有重要意义。     

锌离子对配体门控型离子通道的调节作用

在中枢神经系统(central nervous system,CNS)中,锌离子对配体门控型离子通道具有重要的调节作用。锌离子随着神经元的活动从突触前膜的囊泡中释放到突触间隙,对突触内受体进行调控。锌离子抑制N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)型谷氨酸受体的活性,而对非NMDA型谷氨酸受体的调控具有多样性。由γ氨基丁酸(γ-aminobutyric acid,GABA)受体所介导的抑制性突触传递活动也受到锌离子的抑制;而锌离子对glycine受体则呈现出浓度依赖的双向调节效应。病理条件下,锌离子参与了兴奋性细胞毒作用所触发的神经元凋亡过程。本文主要阐述了在CNS中,锌离子对配体门控型离子通道所介导的突触传递活动的调控作用,以及这些调控作用的生理功能和病理意义。     

SIRT2在糖脂代谢调节中的作用北大核心CSCD

Sirtuins是一类进化上高度保守,NAD^+依赖的去乙酰化酶家族。Sirtuins(SIRT1-SIRT7)可通过不同的机制和作用靶点参与衰老、代谢,应激反应、炎症反应、肿瘤形成等生理或病理生理过程,其中SIRT2主要分布于胞质和细胞核中,可以通过对不同的底物去乙酰化,从而调节底物的活性,参与机体一系列生理病理过程。本篇综述主要讨论了SIRT2的表达调控以及在糖脂代谢过程中的作用。     

Sirtuins基因家族与癫痫的研究进展

NAD~+依赖的沉默信息调节因子2(silent information regulator 2,Sir2)通过对组蛋白和多种转录因子进行去乙酰化调节,调控神经元的生存和线粒体生物学包括线粒体能量产生、信号传递和凋亡等。细胞具有通过细胞核与线粒体之间的信号网络自身调节的机制,sirtuins途径可能参与其中。近年研究指出线粒体功能障碍可能是难治性癫痫的核心发病机制,sirtuins家族参与了癫痫发生发展的病理生理过程,深入研究sirtuins途径对癫痫的治疗和预防具有深远的意义。     

鞘氨醇-1-磷酸与免疫细胞的调节

鞘氨醇-1-磷酸（sphingosine-1 phosphate,S1P）是来源于鞘脂代谢途径的多效性信号分子,其代谢受到多种因素调控。S1P由细胞内的鞘氨醇激酶（sphingosine kinases,SphKs）催化鞘氨醇的磷酸化而合成,可通过转运蛋白释放至细胞外。S1P可通过在胞外结合其特异性G蛋白偶联受体及胞内作用而调节多种重要生物学效应。作为细胞外介质和细胞内信使,S1P在免疫系统中也发挥重要的调节作用。S1P参与免疫细胞的迁移、增殖、分化及死亡细胞清除等过程。本文对S1P的代谢以及其对于免疫细胞的调节作用进行综述。     

Tissue plasminogen activator as a modulator of neuronal survival and function

The tissue plasminogen activator (tPA)/plasmin proteolytic system has been implicated in both physiological and pathological processes in the mammalian brain. The physiological roles include facilitating neurite outgrowth and pathfinding. The pathological role involves mediating a critical step in the progression of excitotoxin-induced neurodegeneration. Mechanistically, tPA appears to function through two pathways. The first pathway proceeds via its well established ability to convert plasminogen into plasmin. Plasmin then either promotes neuronal death via both the degradation of the extracellular matrix and the establishment of chemoattractant gradients for microglia, or facilitates neurite outgrowth through the processing of extracellular matrix proteoglycans. The second pathway for tPA does not involve its proteolytic activity: rather tPA functions as an agonist to stimulate a cell-surface receptor on microglia (the macrophage-like immunocompetent cells of the central nervous system) and results in their activation. Once activated after neuronal injury, microglia contribute to the ensuing neurodegeneration. Using tPA as a link between neurons and microglia, we are focusing on understanding their communication and interactions in the normal and diseased central nervous system.     

Recent behavioral findings of pathophysiological involvement of lactate in the central nervous system

Lactate was initially thought of as a fatigue substance. In recent years, however, lactate not only functions as an energy carrier and contributes to ATP production, but also its role as a signal transmitter has been attracting attention due to the identification of lactate receptors. Lactate is synthesized from glucose and glycogen through the glycolytic system. The central nervous system is a major organ of glucose metabolism and is rich in glycogen. Therefore, this review summarizes the recent findings on the contribution of lactate to the pathophysiology of the central nervous system.     

Global profiling of lysine lactylation in human lungs

Lactate is closely related to various cellular processes, such as angiogenesis, responses to hypoxia, and macrophage polarization, while regulating natural immune signaling pathways and promoting neurogenesis and cognitive function. Lysine lactylation (Kla) is a novel posttranslational modification, the examination of which may lead to new understanding of the nonmetabolic functions of lactate and the various physiological and pathological processes in which lactate is involved, such as infection, tumorigenesis and tumor development. Using liquid chromatography–tandem mass spectrometry (LC‒MS/MS), researchers have identified lactylation in human gastric cancer cells and some other species, but no research on lactylation in human lungs has been reported. In this study, we performed global profiling of lactylation in human lungs under normal physiological conditions, and 724 Kla sites in 451 proteins were identified. After comparing the identified proteins with those reported in human lactylation datasets, 141 proteins that undergo lactylation were identified for the first time in this study. Our work expands the database on human lactylation and helps advance the study on lactylation function and regulation under physiological and pathological conditions.     

Targeting reactive astrogliosis by novel biotechnological strategies

Neuroglial cells are fundamental for control of brain homeostasis and synaptic plasticity. Decades of pathological and physiological studies have focused on neurons in neurodegenerative disorders, but it is becoming increasingly evident that glial cells play an irreplaceable part in brain homeostasis and synaptic plasticity. Animal models of brain injury and neurodegenerative diseases have largely contributed to current understanding of astrocyte-specific mechanisms participating in brain function and neurodegeneration. Specifically, gliotransmission (presence of glial neurotransmitters, and their receptors and active transporters), trophic support (release, maturation and degradation of neurotrophins) and metabolism (production of lactate and GSH components) are relevant aspects of astrocyte function in neuronal metabolism, synaptic plasticity and neuroprotection. Morpho-functional changes of astrocytes and microglial cells after traumatic or toxic insults to the central nervous system (namely, reactive gliosis) disrupt the complex neuro-glial networks underlying homeostasis and connectivity within brain circuits. Thus, neurodegenerative diseases might be primarily regarded as gliodegenerative processes, in which profound alterations of glial activation have a clear impact on progression and outcomes of neuropathological processes. This review provides an overview of current knowledge of astrocyte functions in the brain and how targeting glial-specific pathways might ultimately impact the development of therapies for clinical management of neurodegenerative disorders.     

The roles of GRP81 as a metabolic sensor and inflammatory mediator

GPR81 (also named as HCA1) is a member of a subfamily of orphan G-protein coupled receptors (GPCRs), coupled to G_i-type G proteins. GPR81 was discovered in 2001 and identified as the only known endogenous receptor of lactate under physiological conditions in 2008, which opened a new field of research on how lactate may act as a signal molecule along with the GPR81 expression in the roles of metabolic process and inflammatory response. Recent studies showed that the physiological functions of GPR81 include lipid metabolism in adipose tissues, metabolic excitability in the brain, cellular development, and inflammatory response modulation. These findings may reveal a novel therapeutic strategy to treat clinical, metabolic, and inflammatory diseases. This article will summarize past research on GPR81, including its characteristics of distribution and expression, functional residues, pharmacological, and physiological agonists, involvement in signal transduction, and pharmacological applications.     

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging.

Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood flow and energy metabolism. Positron emission tomography (PET) signals detect blood flow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identifies the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic fluxes in purified preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identified the neurotransmitter glutamate and astrocytes, a specific type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This effect is mediated by specific glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na+. This Na(+)-dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na+/K(+)-ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na+ ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one 'turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule. These data suggest that during activation the brain may transiently resort to aerobic glycolysis occurring in astrocytes, followed by the oxidation of lactate by neurons. The proposed model provides a direct mechanism to couple synaptic activity with glucose use and is consistent with the notion that the signals detected during physiological activation with 18F-deoxyglucose (DG)-PET may reflect predominantly uptake of the tracer into astrocytes. This conclusion does not question the validity of the 2-DG-based techniques, rather it provides a cellular and molecular basis for these functional brain imaging techniques.     

Glial glutamate transporters: New actors in brain signaling

Glutamate, the main excitatory amino acid in the vertebrate brain, is critically involved in most of the physiological functions of the central nervous system. It has traditionally been assumed that glutamate triggers a wide array of signaling cascades through the activation of specific membrane receptors. The extracellular levels are tightly regulated to prevent neurotoxic insults. Electrogenic Na(+)-dependent glial glutamate transporters remove the bulk of the neurotransmitter from the synaptic cleft. An exquisitely ordered coupling between glutamatergic neurons and surrounding glia cells is fundamental for excitatory transmission. The glutamate/glutamine and astrocyte/neuron lactate shuttles provide the biochemical framework of this compulsory association. In this context, recent advances show that glial glutamate transporters act as signal transducers that regulate the expression of proteins involved in their compartmentalization with neurons in the so-called tripartite synapse.     

气体信号分子硫化氢在植物中的生理功能及作用机制

硫化氢（hydrogen sulfide,H2S）是继一氧化氮（nitric oxide,NO）和一氧化碳（carbon monoxide,CO）之后发现的第3种气体信号分子,它能参与生物体内的多种生理生化过程并发挥特定功能。在动物体内,H2S能够调节血管及神经系统功能。植物也能通过产生内源H2S来提高对环境的适应能力,缓解多种逆境胁迫造成的损伤和毒害,参与特定的生理代谢过程,诸如参与气孔运动和延缓衰老等。本文从H2S产生和代谢途径、已发现的生理功能和信号转导机制等方面综述H2S在植物中的最新研究进展,同时也探讨了H2S与其它信号分子的相互作用以及H2S对蛋白质的修饰机制。     

Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate,signal transduction and gene regulation

Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell–cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen–glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance.