Neonatal tolerance to hypoxia: a comparative-physiological approach.

Newborn mammals exhibit a number of physiological reactions which differ from normal adult physiology and are often regarded as signs of immaturity. However, when looked upon from a comparative point of view, it becomes obvious that some of these 'physiological peculiarities' bear striking similarity to adaptation mechanisms known from hypoxia-tolerant animals and may thus contribute to the well-established, yet poorly understood, phenomenon of neonatal hypoxia tolerance. As the mammalian fetus lives at oxygen partial pressures corresponding to 8000 m altitude, the first line of perinatal hypoxia defense consists of long-term adaptations to limited intrauterine oxygen supply: (1) improved O2 transport by fetal acclimatization to high altitude, (2) reduced metabolic rate by hibernation-like deviation from metabolic size allometry, (3) diminished cerebral vulnerability by functional analogies to diving turtle brain, and (4) enhanced metabolic flexibility by optional repartitioning of energy supply from growth to maintenance metabolism. In the case of birth asphyxia, these background mechanisms are complemented by short-term responses to acute oxygen lack: (1) reduction of body temperature as in natural torpor, (2) reduction of heart rate and redistribution of circulation as in diving mammals, (3) reduction of respiration rate typical of 'hypoxic hypometabolism', and (4) reduction of blood pH according to the concept of 'acidotic torpidity'. Although anaerobic metabolism is improved in neonatal mammals by increased glycogen stores, reduced metabolic demands, and sustained wash-out of acid metabolites, neonatal hypoxia tolerance seems to be primarily based on the ability to maintain tissue aerobiosis as long as possible. This is even reflected by isoenzyme patterns which do not consistently favour anaerobic glycolysis and, thus, are reminiscent of the 'lactate paradox' found in high altitude adaptation. Altogether, from a biological point of view, the perinatal period appears as a source of adaptive mechanisms that can be refound, in varying combinations, in many survival strategies. From a clinical point of view, the interplay of long- and short-term mechanisms offers a novel approach to estimation of the newborn's ability to withstand temporary oxygen lack. However, most of these mechanisms are not unambiguous and, above all, not unlimited in their protective effect so that they do not release obstetricians or neonatologists from their obligation to counteract fetal or neonatal hypoxia without delay.     

植物盐胁迫应答蛋白质组学分析

土壤盐渍化是限制植物生长和分布的关键因素之一,揭示植物盐胁迫应答的分子机理是借助分子生物学手段提高植物耐盐性的基础.近年来,人们利用高通量蛋白质组学技术分析了拟南芥、水稻等19种植物的盐胁迫应答蛋白质表达图谱.从植物类群(盐生植物和甜土植物)、组织器官(根、地上部分/茎、胚根和胚轴、叶片、花序和配子体)、细胞(悬浮培养细胞、愈伤组织细胞和单细胞生物)和亚细胞结构(叶绿体、质膜和质外体)几方面整合分析了植物盐胁迫应答蛋白质组表达模式特征,主要特征包括:(1)盐生植物通过全面调节细胞骨架重塑、离子转运和区隔化、渗透平衡、活性氧(ROS)清除、信号转导、光合作用和能量代谢等信号与代谢网络体系,获得相对较高的抗/耐盐能力;(2)植物地上部分(叶片、茎、配子体)或光合组织细胞(悬浮培养细胞、愈伤组织细胞和单细胞盐藻)通过调节参与光合作用、碳和能量代谢、ROS清除过程蛋白质的表达模式应对盐胁迫环境;(3)植物地下部分(根、胚根)通过调控信号转导和离子转运相关蛋白质感知/传递盐胁迫信号并维持离子平衡;(4)花序中参与渗透调节、转录调控、蛋白质加工和ROS清除的蛋白质在盐胁迫条件下变化显著;(5)叶绿体通过调控参与光合作用、蛋白质加工和周转,以及氧化还原系统平衡等过程应对盐胁迫;(6)质外体中参与细胞壁代谢、胁迫防御和信号转导过程的蛋白质受盐胁迫影响明显;(7)细胞膜中参与维持膜结构稳定、物质/离子运输和信号转导过程的蛋白质对植物盐胁迫应答具有重要作用.这些分析为深入研究植物耐盐的分子机制提供了重要信息.     

Glutathione content and adaptation to endogenously induced energy depletion in Mv1Lu cells

Transfection of genes that code for enzymes of energy metabolism provides alternative models to study the adaptive response to energy restriction induced by endogenous changes instead of by unfavorable environmental conditions. Overexpression of the glycolytic enzyme fructose-2,6-bisphosphatase reduced the content of fructose 2,6-bisphosphate, inducing energy limitation in the mink lung epithelial cell line Mv1Lu. This metabolic stress reduced the ATP available in transfected cells by 20%, which downregulated active ion transport and protein turnover. Ion homeostasis and cell function require concomitant reductions in cell membrane ion permeability and protein damage. Our results indicate that glutathione content linked these features of the adaptive response to the endogenously induced metabolic downregulation.     

Why mammalian lineages respond differently to sexual selection: metabolic rate constrains the evolution of sperm size

The hypothesis that sperm competition should favour increases in sperm size, because it results in faster swimming speeds, has received support from studies on many taxa, but remains contentious for mammals. We suggest that this may be because mammalian lineages respond differently to sexual selection, owing to major differences in body size, which are associated with differences in mass-specific metabolic rate. Recent evidence suggests that cellular metabolic rate also scales with body size, so that small mammals have cells that process energy and resources from the environment at a faster rate. We develop the 'metabolic rate constraint hypothesis' which proposes that low mass-specific metabolic rate among large mammals may limit their ability to respond to sexual selection by increasing sperm size, while this constraint does not exist among small mammals. Here we show that among rodents, which have high mass-specific metabolic rates, sperm size increases under sperm competition, reaching the longest sperm sizes found in eutherian mammals. By contrast, mammalian lineages with large body sizes have small sperm, and while metabolic rate (corrected for body size) influences sperm size, sperm competition levels do not. When all eutherian mammals are analysed jointly, our results suggest that as mass-specific metabolic rate increases, so does maximum sperm size. In addition, species with low mass-specific metabolic rates produce uniformly small sperm, while species with high mass-specific metabolic rates produce a wide range of sperm sizes. These findings support the hypothesis that mass-specific metabolic rates determine the budget available for sperm production: at high levels, sperm size increases in response to sexual selection, while low levels constrain the ability to respond to sexual selection by increasing sperm size. Thus, adaptive and costly traits, such as sperm size, may only evolve under sexual selection when metabolic rate does not constrain cellular budgets.     

Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems

Oxidative stress is an unavoidable consequence of life in an oxygen-rich atmosphere. Oxygen radicals and other activated oxygen species are generated as by-products of aerobic metabolism and exposure to various natural and synthetic toxicants. The "Oxygen Paradox" is that oxygen is dangerous to the very life-forms for which it has become an essential component of energy production. The first defense against oxygen toxicity is the sharp gradient of oxygen tension, seen in all mammals, from the environmental level of 20% to a tissue concentration of only 3-4% oxygen. These relatively low tissue levels of oxygen prevent most oxidative damage from ever occurring. Cells, tissues, organs, and organisms utilize multiple layers of antioxidant defenses and damage removal, and replacement or repair systems in order to cope with the remaining stress and damage that oxygen engenders. The enzymes comprising many of these protective systems are inducible under conditions of oxidative stress adaptation, in which the expression of over 40 mammalian genes is upregulated. Mitotic cells have the additional defensive ability of entering a transient growth-arrested state (in the first stages of adaptation) in which DNA is protected by histone proteins, energy is conserved by diminished expression of nonessential genes, and the expression of shock and stress proteins is greatly increased. Failure to fully cope with an oxidative stress can switch mitotic cells into a permanent growth-arrested, senescence-like state in which they may survive for long periods. Faced with even more severe oxidative stress, or the declining protective enzymes and adaptive capacity associated with aging, cells may "sacrifice themselves" by apoptosis, which protects surrounding healthy tissue from further damage. Only under the most severe oxidative stress conditions will cells undergo a necrotic death, which exposes surrounding tissues to the further vicissitudes of an inflammatory immune response. This remarkable array of systems for defense; damage removal, replacement, and repair; adaptation; growth modulation; and apoptosis make it possible for us to enjoy life in an oxygen-rich environment.     

Differential metabolic adaptation to acute and long-term hypoxia in rat primary cortical astrocytes

Brain astrocytes provide structural and metabolic support to surrounding cells during ischemia. Glucose and oxygen are critical to brain function, and glucose uptake and metabolism by astrocytes are essential to their metabolic coupling to neurons. To examine astrocyte metabolic response to hypoxia, cell survival and metabolic parameters were assessed in rat primary cortical astrocytes cultured for 3 weeks in either normoxia or in either 1 day or 3 weeks sustained hypoxia (5% O2). Although cell survival and proliferation were not affected by the mildly hypoxic environment, substantial differences in glucose consumption and lactate release after either acute or prolonged hypoxia suggest that astrocyte metabolism may contribute to their adaptation. Hypoxia over a period of 1 day increased glucose uptake, lactate release, and glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1) expression, whereas hypoxia over a period of 3 weeks resulted in a decrease of all parameters. Furthermore, increased glucose uptake at 1 day of hypoxia was not inhibited by cytochalasin B suggesting the involvement of additional glucose transporters. We uncovered hypoxia-regulated expression of sodium-dependent glucose transporters (SGLT1) in astrocytes indicating a novel adaptive strategy involving both SGLT1 and GLUT1 to regulate glucose intake in response to hypoxia. Overall, these findings suggest that although increased metabolic response is required for the onset of astrocyte adaptation to hypoxia, prolonged hypoxia requires a shift to an energy conservation mode. These findings may contribute to the understanding of the relative tolerance of astrocytes to hypoxia compared with neurons and provide novel therapeutic strategies aimed at maintaining brain function in cerebral pathologies involving hypoxia.     

Globular adiponectin inhibits GnRH secretion from GT1-7 hypothalamic GnRH neurons by induction of hyperpolarization of membrane potential

Reproduction is accurately regulated by metabolic states in mammals. Adiponectin regulates luteinizing hormone (LH) secretion in the pituitary and energy homeostasis in the hypothalamus. We further investigated the gonadotropin-releasing hormone (GnRH) secretion regulation by adiponectin and its related molecular and electrophysiological mechanisms. The results showed that adiponectin receptors (AdipR1 and 2) were expressed in GT1-7 cells derived from hypothalamus neurons. GnRH secretion was inhibited via activation of AMP-activated protein kinase (AMPK). Moreover, we revealed that hyperpolarization of plasma membrane potentials and reduction of calcium influx was also caused by adiponectin.     

An assessment of proposed mechanisms for sensing hydrogen peroxide in mammalian systems

Despite much recent interest in the biochemistry of reactive oxygen species, the mechanisms by which hydrogen peroxide (H2O2) functions in mammalian cells remain poorly defined. Proposed mechanisms for sensing H2O2 in mammalian cells include inactivation of protein tyrosine phosphatases and dual specificity phosphatases as well as inactivation of peroxiredoxins. In this critical review, proteins proposed to serve as sensors for H2O2 in mammals will be compared to peroxidases, catalases, and the bacterial H2O2 sensor OxyR for their ability to react with H2O2, in the context of our current knowledge concerning the concentrations of H2O2 present in cells.     

Oxygen toxicity is not related to mammalian body size

1. Small mammals have been used to study the effects of O2 toxicity. The aim of the present study was to investigate whether body size should be considered when applying the results of these studies to man. 2. Oxygen toxicity is enhanced as perfusion and metabolism increase: specific animal tissues of high perfusion are more susceptible to O2 toxicity. Exercise, high metabolic rate, and increased brain blood flow enhance O2 toxicity. 3. Increased specific O2 consumption and perfusion as body mass decreases may enhance O2 toxicity in small mammals. 4. Survival time in normobaric hyperoxia (1 atm O2) and the time to first appearance of convulsions in hyperbaric oxygen (4-5 atm) were collected from the literature and showed no relation to body size. 5. Known difference in antioxidant enzyme activity cannot explain the findings. 6. Independence of tissue PO2 on body size, or equal rates of free radical formation and degradation, are suggested as possible mechanisms. 7. Small mammals can serve as a good model for O2 toxicity in man.     

Mitochondrial energy metabolism and redox responses to hypertriglyceridemia

In this work we review recent findings that explain how mitochondrial bioenergetic functions and redox state respond to a hyperlipidemic in vivo environment and may contribute to the maintenance of a normal metabolic phenotype. The experimental model utilized to evidence these adaptive mechanisms is especially useful for these studies since it exhibits genetic hypertriglyceridemia and avoids complications introduced by high fat diets. Liver from hypertrigliceridemic (HTG) mice have a greater content of glycerolipids together with increased mitochondrial free fatty acid oxidation. HTG liver mitochondria have a higher resting respiration rate but normal oxidative phosphorylation efficiency. This is achieved by higher activity of the mitochondrial potassium channel sensitive to ATP (mitoK_ATP). The mild uncoupling mediated by mitoK_ATP accelerates respiration rates and reduces reactive oxygen species generation. Although this response is not sufficient to inhibit lipid induced extra-mitochondrial oxidative stress in whole liver cells it avoids amplification of this redox imbalance. Furthermore, higher mitoK_ATP activity increases liver, brain and whole body metabolic rates. These mitochondrial adaptations may explain why these HTG mice do not develop insulin resistance and obesity even under a severe hyperlipidemic state. On the contrary, when long term high fat diets are employed, insulin resistance, fatty liver and obesity develop and mitochondrial adaptations are inefficient to counteract energy and redox imbalances.     

Role of mitochondrial Ca2+ in the regulation of cellular energetics

Calcium is an important signaling molecule involved in the regulation of many cellular functions. The large free energy in the Ca(2+) ion membrane gradients makes Ca(2+) signaling inherently sensitive to the available cellular free energy, primarily in the form of ATP. In addition, Ca(2+) regulates many cellular ATP-consuming reactions such as muscle contraction, exocytosis, biosynthesis, and neuronal signaling. Thus, Ca(2+) becomes a logical candidate as a signaling molecule for modulating ATP hydrolysis and synthesis during changes in numerous forms of cellular work. Mitochondria are the primary source of aerobic energy production in mammalian cells and also maintain a large Ca(2+) gradient across their inner membrane, providing a signaling potential for this molecule. The demonstrated link between cytosolic and mitochondrial Ca(2+) concentrations, identification of transport mechanisms, and the proximity of mitochondria to Ca(2+) release sites further supports the notion that Ca(2+) can be an important signaling molecule in the energy metabolism interplay of the cytosol with the mitochondria. Here we review sites within the mitochondria where Ca(2+) plays a role in the regulation of ATP generation and potentially contributes to the orchestration of cellular metabolic homeostasis. Early work on isolated enzymes pointed to several matrix dehydrogenases that are stimulated by Ca(2+), which were confirmed in the intact mitochondrion as well as cellular and in vivo systems. However, studies in these intact systems suggested a more expansive influence of Ca(2+) on mitochondrial energy conversion. Numerous noninvasive approaches monitoring NADH, mitochondrial membrane potential, oxygen consumption, and workloads suggest significant effects of Ca(2+) on other elements of NADH generation as well as downstream elements of oxidative phosphorylation, including the F(1)F(O)-ATPase and the cytochrome chain. These other potential elements of Ca(2+) modification of mitochondrial energy conversion will be the focus of this review. Though most specific molecular mechanisms have yet to be elucidated, it is clear that Ca(2+) provides a balanced activation of mitochondrial energy metabolism that exceeds the alteration of dehydrogenases alone.     

Mitochondrial metabolism in hibernation and daily torpor: a review

Hibernation and daily torpor involve substantial decreases in body temperature and metabolic rate, allowing birds and mammals to cope with cold environments and/or limited food. Regulated suppression of mitochondrial metabolism probably contributes to energy savings: state 3 (phosphorylating) respiration is lower in liver mitochondria isolated from mammals in hibernation or daily torpor compared to normothermic controls, although data on state 4 (non-phosphorylating) respiration are equivocal. However, no suppression is seen in skeletal muscle, and there is little reliable data from other tissues. In both daily torpor and hibernation, liver state 3 substrate oxidation is suppressed, especially upstream of electron transport chain complex IV. In hibernation respiratory suppression is reversed quickly in arousal even when body temperature is very low, implying acute regulatory mechanisms, such as oxaloacetate inhibition of succinate dehydrogenase. Respiratory suppression depends on in vitro assay temperature (no suppression is evident below ~30 degrees C) and (at least in hibernation) dietary polyunsaturated fats, suggesting effects on inner mitochondrial membrane phospholipids. Proton leakiness of the inner mitochondrial membrane does not change in hibernation, but this also depends on dietary polyunsaturates. In contrast proton leak increases in daily torpor, perhaps limiting reactive oxygen species production.     

中国海兽研究进展

中国是海兽大国,共有46种海兽在中国水域有分布,包括鲸类38种（Cetartiodactyla, Cetacea）,海牛目儒艮科（Sirenia, Dugongidae）1种,食肉目鳍足类（Carnivora, Pinnipedia）5种和水獭亚科（Lutrinae）2种。从20世纪20年代开始,中国科学家围绕中国水域海兽的生物学与保护,通过多学科手段开展了一系列研究,特别是在白暨豚(Lipotes vexillifer)、江豚(Neophocaena spp.)和中华白海豚(Sousa chinensis)的生态学与保护、鲸类次生性水生适应的演化历史与适应机制、种群遗传多样性等方面,取得了一系列重要的创新进展,不仅促进了对中国海兽的认识,也推动中国海兽的保护工作取得成效。本文从海兽多样性、生态与保护生物学、形态与解剖学、饲养与繁殖生物学、声行为学、遗传与演化生物学以及基因组学等7个方面,较为系统地综述了中国海兽的研究进展。同时指出,海兽次生性水生适应历史及其演化机制,将是今后值得特别关注和需要深入揭示的重要科学问题;并且通过多学科手段揭示海兽的濒危机制与特点以提出促进其资源保护与管理措施,也具有十分重要的意义。     

Mechanisms of sensing and adaptive responses to low oxygen conditions in mammals and yeasts

Oxygen is required for effective production of ATP and plays a key role in the maintenance of life for all organisms, excepting strict anaerobes. The ability of aerobic organisms to sense and respond to changes in oxygen level is a basic requirement for their survival. Eukaryotes have developed adaptive mechanisms to sense and respond to decreased oxygen concentrations (hypoxia) through adjustment of oxygen homeostasis by upregulating hypoxic and downregulating aerobic nuclear genes. This review summarizes recent data on mechanisms of cells sensing and responding to changes in oxygen availability in mammals and in yeasts. In the first part of the review, prominence is given to functional regulation and stabilization of hypoxia-inducible factors (HIFs), HIF-mediated regulation of electron transport flux and repression of lipogenesis, as well as to hypoxia-induced mitochondrial permeability transition (pore) opening, cell death, and autophagy. In the second part of the review emphasis is placed on oxygen sensing in nonpathogenic yeasts by heme, unsaturated fatty acids, and sterols, as well as on responses to hypoxia in fungal pathogens.     

RGD-containing molecules induce macropinocytosis in ascidian hyaline amoebocytes

Phagocytes of the compound ascidian Botryllus schlosseri are capable of constitutive macropinocytosis (MP) at sites of membrane ruffling along the leading edge. This gives rise to the formation of initially irregular vesicles which then move to the inside of the cells and acquire a more regular morphology. Both phagocyte spreading and MP are enhanced by the recognition of molecules containing the sequence Arg-Gly-Asp (RGD): this suggests that, as in mammals, integrin activation is involved in the induction of both cell spreading and endocytosis. The occurrence of MP is associated with increased oxygen consumption and a rise in the production of superoxide anion, as indicated by nitroblue tetrazolium reduction, and ATP, as indicated by increased cytochrome oxidase activity. On the whole, our results indicate the conservation of common mechanisms of MP induction throughout the Chordate phylum.     

Some insights into energy metabolism for osmoregulation in fish

A sufficient and timely energy supply is a prerequisite for the operation of iono- and osmoregulatory mechanisms in fish. Measurements of whole-fish or isolated-gill (or other organs) oxygen consumption have demonstrated regulation of the energy supply during acclimation to different osmotic environments, and such regulation is dependent on species, the situation of acclimation or acclimatization, and life habits. Carbohydrate metabolism appears to play a major role in the energy supply for iono- and osmoregulation, and the liver is the major source supplying carbohydrate metabolites to osmoregulatory organs. Compared with carbohydrates, the roles of lipids and proteins remain largely unclear. Energy metabolite translocation was recently found to occur between fish gill ionocytes and neighboring glycogen-rich (GR) cells, indicating the physiological significance of a local energy supply for gill ion regulatory mechanisms. Spatial and temporal relationships between the liver and other osmoregulatory and non-osmoregulatory organs in partitioning the energy supply for ion regulatory mechanisms during salinity challenges were also proposed. A novel glucose transporter was found to specifically be expressed and function in gill ionocytes, providing the first cue for investigating energy translocation among gill cells. Advanced molecular physiological approaches can be used to examine energy metabolism relevant to a particular cell type (e.g., gill ionocytes), and functional genomics may also provide another powerful approach to explore new metabolic pathways related to fish ion regulation.     

Survival of the fittest: metabolic adaptations in cancer

Malignant transformation is often a multistep process characterized by an initial period of avascular growth. Rapid cell proliferation creates areas within the emerging preneoplastic lesion with limited diffusion of oxygen and nutrients. In this context, activation of oncogenes, loss of tumor suppressors as well as additional adaptive mechanisms drive a profound metabolic rewiring to overcome the environmental constraints. The emerging cells are in principle better suited to proliferate and survive in the hostile tumor microenvironment. Furthermore, some of the acquired metabolic traits impact their metastatic behavior and response to therapy. It is becoming increasingly clear that malignant cells are highly dependent on certain nutrients, an Achilles' heel of cancer and an opportunity for therapeutic intervention.     

Cross-talk of phosphoinositide- and cyclic nucleotide-dependent signaling pathways in differentiating avian nasal gland cells

In many bird species, the nasal glands secrete excess salt ingested with drinking water or food. In ducks (Anas platyrhynchos), osmotic stress results in adaptive cell proliferation and differentiation in the gland. Using naive nasal gland cells isolated from animals that had never ingested excess salt or differentiated cells from animals fed with a 1% NaCl solution for 48 h, we investigated the allocation of metabolic energy to salt excretory processes and to other cellular activities. Activation of muscarinic acetylcholine receptors (carbachol) or -adrenergic receptors (isoproterenol) in nasal gland cells resulted in a transient peak in metabolic rate followed by an elevated plateau level that was maintained throughout the activation period. Activation of cells using vasoactive intestinal peptide, however, had only marginal effects on metabolic rate. In differentiated cells, sequential stimulation with carbachol and isoproterenol resulted in additive changes in metabolic rate during the plateau phase. Naive cells, however, developed supra-additive plateau levels in metabolic rates indicating cross-talk of both signaling pathways. Using bumetanide, TEA or barium ions to block different components of the ion transport machinery necessary for salt secretion, the relative proportion of energy needed for processes related to ion transport or other cellular processes was determined. While differentiated cells in the activated state allocated virtually all metabolic energy to processes related to salt secretion, naive cells reserved a significant amount of energy for other processes, possibly sustaining cellular signaling and regulating biosynthetic mechanisms related to adaptive growth and differentiation.Communicated by G. Heldmaier