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Therapeutic Hypothermia: Critical Review of the Molecular Mechanisms of Action  [PDF]
Fernando Pavel González-Ibarra,Joseph Varon,Elmer G. López-Meza
Frontiers in Neurology , 2011, DOI: 10.3389/fneur.2011.00004
Abstract: Therapeutic hypothermia (TH) is nowadays one of the most important methods of neuroprotection. The events that occur after an episode of ischemia are multiple and hypothermia can affect the various steps of this cascade. The mechanisms of action of TH are varied and the possible explanation for the benefits of this therapy is probably the multiple mechanisms of action blocking the cascade of ischemia on many levels. TH can affect many metabolic pathways, reactions of inflammation, apoptosis processes, and promote neuronal integrity. To know the mechanisms of action of TH will allow a better understanding about the indications for this therapy and the possibility of searching for other therapies when used in conjunction with hypothermia will provide a therapeutic synergistic effect.
Facts and Fiction: The Impact of Hypothermia on Molecular Mechanisms following Major Challenge
Michael Frink,Sascha Flohé,Martijn van Griensven,Philipp Mommsen,Frank Hildebrand
Mediators of Inflammation , 2012, DOI: 10.1155/2012/762840
Abstract: Numerous multiple trauma and surgical patients suffer from accidental hypothermia. While induced hypothermia is commonly used in elective cardiac surgery due to its protective effects, accidental hypothermia is associated with increased posttraumatic complications and even mortality in severely injured patients. This paper focuses on protective molecular mechanisms of hypothermia on apoptosis and the posttraumatic immune response. Although information regarding severe trauma is limited, there is evidence that induced hypothermia may have beneficial effects on the posttraumatic immune response as well as apoptosis in animal studies and certain clinical situations. However, more profound knowledge of mechanisms is necessary before randomized clinical trials in trauma patients can be initiated.
Molecular Mechanisms Underlying Hepatocellular Carcinoma  [PDF]
Philippe Merle,Christian Trepo
Viruses , 2009, DOI: 10.3390/v1030852
Abstract: Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21Cip1 and p16INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis.
Conserved Molecular Mechanisms Underlying Homeostasis of the Golgi Complex  [PDF]
Cathal Wilson,Antonella Ragnini-Wilson
International Journal of Cell Biology , 2010, DOI: 10.1155/2010/758230
Abstract: The Golgi complex performs a central function in the secretory pathway in the sorting and sequential processing of a large number of proteins destined for other endomembrane organelles, the plasma membrane, or secretion from the cell, in addition to lipid metabolism and signaling. The Golgi apparatus can be regarded as a self-organizing system that maintains a relatively stable morphofunctional organization in the face of an enormous flux of lipids and proteins. A large number of the molecular players that operate in these processes have been identified, their functions and interactions defined, but there is still debate about many aspects that regulate protein trafficking and, in particular, the maintenance of these highly dynamic structures and processes. Here, we consider how an evolutionarily conserved underlying mechanism based on retrograde trafficking that uses lipids, COPI, SNAREs, and tethers could maintain such a homeodynamic system. 1. Introduction Despite the ancient origin of the Golgi and the differences in its structure across species, there is a striking conservation of a number of molecular machineries and principles that appear to operate in intra-Golgi trafficking. We sought to use these observations as a starting point from which to discuss how the maintenance of Golgi structure might be intrinsically related with the conservation of the basic molecular machineries that regulate intra-Golgi trafficking. In most organisms the Golgi apparatus is composed of a series of flattened, membrane-bounded sacks (cisternae) arranged in a cis-to-trans fashion to form a stack. These stacks are laterally linked to form a ribbon-like membrane system in mammalian cells [1] but this ribbon-like structure does not link the Golgi stacks in plants and Drosophila [2, 3]. In the yeast Saccharomyces cerevisiae the Golgi compartments are not arranged as a stack at all but exist as separate scattered compartments in the cell [4, 5] while in some developmental stages of Drosophila no stacks are present [3]. Yet, the basic functions of the Golgi in transport and sorting appear to be conserved across species, so neither the stacked structure nor the ribbon can be considered as fundamental for the basic functions of the Golgi apparatus in transport and sorting of secretory cargo molecules. In addition, it is possible to argue that ER-to-Golgi transport and the COPII complex, which is required for cargo selection and packaging at the ER [6], is not part of the self-organizing system per se. Many, but not all, Golgi-associated proteins recycle through the ER and
The Underlying Molecular and Network Level Mechanisms in the Evolution of Robustness in Gene Regulatory Networks  [PDF]
Mario Pujato ,Thomas MacCarthy ,Andras Fiser ,Aviv Bergman
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1002865
Abstract: Gene regulatory networks show robustness to perturbations. Previous works identified robustness as an emergent property of gene network evolution but the underlying molecular mechanisms are poorly understood. We used a multi-tier modeling approach that integrates molecular sequence and structure information with network architecture and population dynamics. Structural models of transcription factor-DNA complexes are used to estimate relative binding specificities. In this model, mutations in the DNA cause changes on two levels: (a) at the sequence level in individual binding sites (modulating binding specificity), and (b) at the network level (creating and destroying binding sites). We used this model to dissect the underlying mechanisms responsible for the evolution of robustness in gene regulatory networks. Results suggest that in sparse architectures (represented by short promoters), a mixture of local-sequence and network-architecture level changes are exploited. At the local-sequence level, robustness evolves by decreasing the probabilities of both the destruction of existent and generation of new binding sites. Meanwhile, in highly interconnected architectures (represented by long promoters), robustness evolves almost entirely via network level changes, deleting and creating binding sites that modify the network architecture.
Molecular Mechanisms Underlying Memory Consolidation of Taste Information in the Cortex  [PDF]
Kobi Rosenblum
Frontiers in Behavioral Neuroscience , 2012, DOI: 10.3389/fnbeh.2011.00087
Abstract: The senses of taste and odor are both chemical senses. However, whereas an organism can detect an odor at a relatively long distance from its source, taste serves as the ultimate proximate gatekeeper of food intake: it helps in avoiding poisons and consuming beneficial substances. The automatic reaction to a given taste has been developed during evolution and is well adapted to conditions that may occur with high probability during the lifetime of an organism. However, in addition to this automatic reaction, animals can learn and remember tastes, together with their positive or negative values, with high precision and in light of minimal experience. This ability of mammalians to learn and remember tastes has been studied extensively in rodents through application of reasonably simple and well defined behavioral paradigms. The learning process follows a temporal continuum similar to those of other memories: acquisition, consolidation, retrieval, relearning, and reconsolidation. Moreover, inhibiting protein synthesis in the gustatory cortex (GC) specifically affects the consolidation phase of taste memory, i.e., the transformation of short- to long-term memory, in keeping with the general biochemical definition of memory consolidation. This review aims to present a general background of taste learning, and to focus on recent findings regarding the molecular mechanisms underlying taste–memory consolidation in the GC. Specifically, the roles of neurotransmitters, neuromodulators, immediate early genes, and translation regulation are addressed.
The Molecular Genetics and Cellular Mechanisms Underlying Pulmonary Arterial Hypertension  [PDF]
Rajiv D. Machado
Scientifica , 2012, DOI: 10.6064/2012/106576
Abstract: Pulmonary arterial hypertension (PAH) is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards. 1. Pulmonary Vascular Development Three distinct models have been put forward in an attempt to shed light on the processes underlying the development of the pulmonary vascular bed and, in particular, the respective roles played by the key morphological events of vasculogenesis and angiogenesis. Vasculogenesis is defined by recruitment and differentiation of the endothelial progenitor cells into mature endothelial cells which proliferate, migrate, differentiate, and organise into a vascular plexus that forms the foundation for the early vascular system. Angiogenesis is the process of branching growth from existing vessels. Favouring angiogenesis as the predominant mechanism in pulmonary vascular development, Parera et al. suggest that expansion of the lung bud is resultant upon the formation of new capillary structures from previously established vessels [1]. By contrast, Hall et al. support vasculogenesis as the central process driving the generation of arteries and veins from the central vascular plexus [2]. Finally, deMello and Reid implicate both processes in vascular development, positing the theory that the early events involve the differentiation of mesenchymal cells to endothelial populations that is succeeded by angiogenic
Molecular Mechanisms Underlying Cell Death in Spinal Networks in Relation to Locomotor Activity After Acute Injury in vitro  [PDF]
Anujaianthi Kuzhandaivel,Andrea Nistri,Graciela L. Mazzone,Miranda Mladinic
Frontiers in Cellular Neuroscience , 2011, DOI: 10.3389/fncel.2011.00009
Abstract: Understanding the pathophysiological changes triggered by an acute spinal cord injury is a primary goal to prevent and treat chronic disability with a mechanism-based approach. After the primary phase of rapid cell death at the injury site, secondary damage occurs via autodestruction of unscathed tissue through complex cell-death mechanisms that comprise caspase-dependent and caspase-independent pathways. To devise novel neuroprotective strategies to restore locomotion, it is, therefore, necessary to focus on the death mechanisms of neurons and glia within spinal locomotor networks. To this end, the availability of in vitro preparations of the rodent spinal cord capable of expressing locomotor-like oscillatory patterns recorded electrophysiologically from motoneuron pools offers the novel opportunity to correlate locomotor network function with molecular and histological changes long after an acute experimental lesion. Distinct forms of damage to the in vitro spinal cord, namely excitotoxic stimulation or severe metabolic perturbation (with oxidative stress, hypoxia/aglycemia), can be applied with differential outcome in terms of cell types and functional loss. In either case, cell death is a delayed phenomenon developing over several hours. Neurons are more vulnerable to excitotoxicity and more resistant to metabolic perturbation, while the opposite holds true for glia. Neurons mainly die because of hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) with subsequent DNA damage and mitochondrial energy collapse. Conversely, glial cells die predominantly by apoptosis. It is likely that early neuroprotection against acute spinal injury may require tailor-made drugs targeted to specific cell-death processes of certain cell types within the locomotor circuitry. Furthermore, comparison of network size and function before and after graded injury provides an estimate of the minimal network membership to express the locomotor program.
Evolution of the fruit endocarp: molecular mechanisms underlying adaptations in seed protection and dispersal strategies.  [PDF]
Chris Dardick
Frontiers in Plant Science , 2014, DOI: 10.3389/fpls.2014.00284
Abstract: Plant evolution is largely driven by adaptations in seed protection and dispersal strategies that allow diversification into new niches. This is evident by the tremendous variation in flowering and fruiting structures present both across and within different plant lineages. Within a single plant family a staggering variety of fruit types can be found such as fleshy fruits including berries, pomes, and drupes and dry fruit structures like achenes, capsules and follicles. What are the evolutionary mechanisms that enable such dramatic shifts to occur in a relatively short period of time? This remains a fundamental question of plant biology today. On the surface it seems that these extreme differences in form and function must be the consequence of very different developmental programs that require unique sets of genes. Yet as we begin to decipher the molecular and genetic basis underlying fruit form it is becoming apparent that simple genetic changes in key developmental regulatory genes can have profound anatomical effects. In this review we discuss recent advances in understanding the molecular mechanisms of fruit endocarp tissue differentiation that have contributed to species diversification within three plant lineages.
Molecular Mechanisms Underlying the Enhanced Analgesic Effect of Oxycodone Compared to Morphine in Chemotherapy-Induced Neuropathic Pain  [PDF]
Karine Thibault, Bernard Calvino, Isabelle Rivals, Fabien Marchand, Sophie Dubacq, Stephen B. McMahon, Sophie Pezet
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091297
Abstract: Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone.
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