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Showing papers in "Frontiers in Bioscience in 2009"


Journal ArticleDOI
TL;DR: This review will address the vertebrate mechanisms of these barriers as a guide to identify the possible targets of these large numbers of known salivary proteins with unknown function.
Abstract: When attempting to feed on their hosts, ticks face the problem of host hemostasis (the vertebrate mechanisms that prevent blood loss), inflammation (that can produce itching or pain and thus initiate defensive behavior on their hosts) and adaptive immunity (by way of both cellular and humoral responses). Against these barriers, ticks evolved a complex and sophisticated pharmacological armamentarium, consisting of bioactive lipids and proteins, to assist blood feeding. Recent progress in transcriptome research has uncovered that hard ticks have hundreds of different proteins expressed in their salivary glands, the majority of which have no known function, and include many novel protein families (e.g., their primary structure is unique to ticks). This review will address the vertebrate mechanisms of these barriers as a guide to identify the possible targets of these large numbers of known salivary proteins with unknown function. We additionally provide a supplemental Table that catalogues over 3,500 putative salivary proteins from various tick species, which might assist the scientific community in the process of functional identification of these unique proteins. This supplemental file is accessble fromhttp://exon.niaid.nih.gov/transcriptome/tick_review/Sup-Table-1.xls.gz.

490 citations


Journal ArticleDOI
TL;DR: Recent studies indicate that the inhibition of cytokine induced increase in intestinal TJ permeability has an important protective effect against intestinal mucosal damage and development of intestinal inflammation.
Abstract: Cytokines play a crucial role in the modulation of inflammatory response in the gastrointestinal tract. Pro-inflammatory cytokines including tumor necrosis factor-alpha, interferon-gamma, interleukin-1beta?IL-1beta?, and interleukin-12 are essential in mediating the inflammatory response, while anti-inflammatory cytokines including interleukin-10 and transforming growth factor-beta are important in the attenuation or containment of inflammatory process. It is increasingly recognized that cytokines have an important physiological and pathological effect on intestinal tight junction (TJ) barrier. Consistent with their known pro-inflammatory activities, pro-inflammatory cytokines cause a disturbance in intestinal TJ barrier, allowing increased tissue penetration of luminal antigens. Recent studies indicate that the inhibition of cytokine induced increase in intestinal TJ permeability has an important protective effect against intestinal mucosal damage and development of intestinal inflammation. In this review, the effects of various pro-inflammatory and anti-inflammatory cytokines on intestinal TJ barrier and the progress into the mechanisms that mediate the cytokine modulation of intestinal TJ barrier are reviewed.

480 citations


Journal ArticleDOI
TL;DR: The BNP and NT-pro-BNP are the most widely studied and appear to be useful in patients with dyspnoea of unknown aetiology, and for risk assessment of patients with established HF, however these markers should be used as an addition tool, not as a substitute of clinical assessment.
Abstract: Nowadays, heart failure (HF) has an increasing prevalence, particularly in the elderly, and is becoming a clinical problem of epidemic proportion in terms of morbidity and mortality. Developing biological markers, that can aid in the diagnosis of HF and in the differentiation of congestive heart failure (CHF) from other causes of dyspnoea, will reduce the cost of health care. However, an ideal biomarker has not yet been identified. Potential markers of HF include neuro-hormonal mediators, markers of myocyte injury, and indicators of systemic inflammation. Among these, the BNP and NT-pro-BNP are the most widely studied and appear to be useful in patients with dyspnoea of unknown aetiology, and for risk assessment of patients with established HF. However these markers should be used as an addition tool, and not as a substitute of clinical assessment.

406 citations


Journal ArticleDOI
TL;DR: A model for crosstalk between Ca2+ and ROS signaling pathways within mitochondrial microdomains is presented, which helps clarify the role of mitochondria in redox sensitive enzymes and ion channels within the cell.
Abstract: Mitochondria are central to energy metabolism as the source of much of the cell's ATP, as well as being a hub for cellular Ca2+ signaling. Mitochondrial Ca2+ is a positive effector of ATP synthesis, yet Ca2+ overload can lead to mitochondrial dysfunction and cell death. Moreover, Ca2+ uptake by mitochondria is involved in shaping cellular Ca2+ dynamics by regulating the concentrations of Ca2+ within microdomains between mitochondria and sarco/endoplasmic reticulum and plasma membrane Ca2+ transporters. Reactive oxygen species (ROS) generated as a consequence of ATP production in the mitochondria are important for cellular signaling, yet contribute to oxidative stress and cellular damage. ROS regulate the activity of redox sensitive enzymes and ion channels within the cell, including Ca2+ channels. For both Ca2+ and ROS, a delicate balance exists between the beneficial and detrimental effects on mitochondria. In this review we bring together current data on mitochondrial Ca2+ uptake, ROS generation, and redox modulation of Ca2+ transport proteins. We present a model for crosstalk between Ca2+ and ROS signaling pathways within mitochondrial microdomains.

366 citations


Journal ArticleDOI
TL;DR: It is evident that further understanding of parthanatos opens up new avenues for therapy in ameliorating diseases related to PARP-1 overactivation, as evidence shows that poly-ADP ribose (PAR) polymer itself can act as a cell death effector downstream of PARp-1.
Abstract: Poly-ADP-ribose polymerase-1 (PARP-1)'s roles in the cell span from maintaining life to inducing death. The processes PARP-1 is involved in include DNA repair, DNA transcription, mitosis, and cell death. Of PARP-1's different cellular functions, its role in cell death is of particular interest to designing therapies for diseases. Genetic deletion of PARP-1 revealed that PARP-1 overactivation underlies cell death in models of stroke, diabetes, inflammation and neurodegeneration. Since interfering with PARP-1 mediated cell death will be clinically beneficial, great effort has been invested into understanding mechanisms downstream of PARP-1 overactivation. Recent evidence shows that poly-ADP ribose (PAR) polymer itself can act as a cell death effector downstream of PARP-1. We coined the term parthanatos after Thanatos, the personification of death in Greek mythology, to refer to PAR-mediated cell death. In this review, we will present evidence and questions raised by these recent findings, and summarize the proposed mechanisms by which PARP-1 overactivation kills. It is evident that further understanding of parthanatos opens up new avenues for therapy in ameliorating diseases related to PARP-1 overactivation.

345 citations


Journal ArticleDOI
TL;DR: Recent findings obtained from animal models with inhibition or activation of AMPK signaling pathway are discussed, including developments in transgenic and knockout mouse models.
Abstract: AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been proposed to function as a fuel gauge to monitor cellular energy status in response to nutritional environmental variations. AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Numerous observations obtained with pharmacological activators and agents that deplete intracellular ATP have been supportive of AMPK playing a role in the control of energy metabolism but none of these studies have provided conclusive evidence. Relatively recent developments in our understanding of precisely how AMPK complexes might operate to control energy metabolism is due in part to the development of transgenic and knockout mouse models. Although there are inevitable caveats with genetic models, some important findings have emerged. In the present review, we discuss recent findings obtained from animal models with inhibition or activation of AMPK signaling pathway.

293 citations


Journal ArticleDOI
TL;DR: Recent data suggesting that the high rates of comorbidity observed between major depression, fibromyalgia and neuropathic pain likely result from the fact that these disorders share multiple biological and environmental underpinnings are synthesized.
Abstract: This article synthesizes recent data suggesting that the high rates of comorbidity observed between major depression, fibromyalgia and neuropathic pain likely result from the fact that these disorders share multiple biological and environmental underpinnings. This perspective suggests that these biologically complex conditions result from similar genetic vulnerabilities interacting with environmental adversity. Shared genetic determinants include poorly functional alleles regulating monoaminergic, glutamatergic, neurotrophic, opioid and inflammatory cytokine signaling. Chief among environmental risk factors are psychosocial stress and illness, both of which promote, in vulnerable individuals, relative resistance to glucocorticoids, increased sympathetic/decreased parasympathetic activity and increased production and release of proinflamnmatory mediators. Dysregulation of stress/inflammatory pathways promotes alterations in brain circuitry that modulates mood, pain and the stress response. Over time, these functional changes likely promote disruptions in neurotrophic support and disturbances of glia-neuronal communication. These changes, in turn, have been associated with the related processes of central sensitization in pain disorders and "kindling" in depression, both of which may account for the progressive and self-perpetuating nature of these disorders, especially when inadequately treated.

290 citations


Journal ArticleDOI
TL;DR: Current findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes.
Abstract: Type 2 diabetes is one of the fastest growing public health problems worldwide, resulting from both genetic factors and inadequate adaptation to environmental changes. It is characterized by abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in skeletal muscle, liver and fat. AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, acts as an integrator of regulatory signals monitoring systemic and cellular energy status. The growing realization that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive concept for type 2 diabetes therapy. Recent findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes. Consistent with these results, physical exercise and major classes of antidiabetic drugs have recently been reported to activate AMPK. In the present review, we update these topics and discuss the concept of targeting the AMPK pathway for the treatment of type 2 diabetes.

269 citations


Journal ArticleDOI
TL;DR: The essential role of this kinase family in both cell survival and apoptosis suggests that specific isoforms may function as molecular sensors, promoting cell survival or cell death depending on environmental cues.
Abstract: The protein kinase C (PKC) family consists of 10 related serine/threonine protein kinases some of which are critical regulators of cell proliferation, survival and cell death. While early studies relied on broad spectrum chemical activators or inhibitors of this family, the generation of isoform specific tools has greatly facilitated our understanding of the contribution of specific PKC isoforms to cell proliferation and apoptosis. These studies suggest that PKC-alpha, PKC-epsilon, and the atypical PKC's, PKC-lambda/iota and PKC-zeta, preferentially function to promote cell proliferation and survival, while the novel isoform, PKC-delta is an important regulator of apoptosis. The essential role of this kinase family in both cell survival and apoptosis suggests that specific isoforms may function as molecular sensors, promoting cell survival or cell death depending on environmental cues. Given their central role in cell and tissue homeostasis, it is not surprising that the expression or activity of some of these kinases is altered in human diseases, particularly cancer.

250 citations


Journal ArticleDOI
TL;DR: The following review will highlight the current state of the art of NO-sGC research and illustrate disease processes which may benefit from novel drug development exploiting the NO- sGC pathway as well as NOS and cGMP-independent pathways.
Abstract: Nitric oxide is a multifunctional signaling molecule, intricately involved with maintaining a host of physiological processes including but not limited to host defense, neuronal communication and the regulation of vascular tone Many of the physiological functions first ascribed to NO are mediated through its primary receptor, soluble guanylyl cyclase Endogenous production of NO is a highly complex and regulated process involving the 5-electron oxidation of L-arginine requiring numerous substrates and cofactors The production of a highly reactive and diffusible free radical gas further complicates our established concept and model of specific and targeted receptor-ligand interaction to elicit cell signaling events Hence there are many steps in the endogenous pathway for altered production of NO and subsequent activation of sGC that may be targets for drug development as well as other molecular targets for NO The following review will highlight the current state of the art of NO-sGC research and illustrate disease processes which may benefit from novel drug development exploiting the NO-sGC pathway as well as NOS and cGMP-independent pathways

240 citations


Journal ArticleDOI
TL;DR: Bile acids have numerous physiological functions in the liver, biliary tract, and intestine resulting from their signaling and physicochemical properties.
Abstract: The features of the enterohepatic circulation of bile acids in mammals are reviewed. Inputs into the circulating bile acids are primary bile acids synthesized from cholesterol in the hepatocyte and secondary bile acids formed by bacterial modification of primary bile acids in the distal intestine. Intestinal conservation of bile acids generates pools of individual bile acids whose relative sizes determine biliary bile acid composition. Efficient hepatic clearance results in low plasma bile acid levels, and virtually no renal excretion. Methods for characterizing the enterohepatic circulation are summarized. Bile acids have numerous physiological functions in the liver, biliary tract, and intestine resulting from their signaling and physicochemical properties.

Journal ArticleDOI
TL;DR: The chemokine system is analyzed, with particular attention to available information on clinical situations in which chemokines or their receptors might assume diagnostic value.
Abstract: Chemokines are chemotactic cytokines orchestrating leukocyte recruitment in physiological and pathological conditions. This complex system includes 42 molecules and 19 receptors and is subjected to different levels of regulation, including ligand production, post-translational modifications and degradation, as well as receptor expression and signaling activity. Here we analyze the chemokine system, with particular attention to available information on clinical situations in which chemokines or their receptors might assume diagnostic value.

Journal ArticleDOI
TL;DR: The recent discovery that gamma oscillations could appear simultaneously in distinct areas at distinct frequencies and with different functional correlates further suggests the existence of a flexible multiplexing schema, integrating frequency bands within the gamma range but also at lower frequency bands.
Abstract: Oscillatory synchrony in the gamma (30-120 Hz) range has initially been related both theoretically and experimentally to visual grouping Its functional role in human visual cognition turns out to be much broader, especially when attention, memory or awareness are concerned Induced gamma oscillations are thus not related to a single cognitive function, and are probably better understood in terms of a population mechanism taking advantage of the neuron's fine temporal tuning: the 10-30 ms time precision imposed by gamma-band rhythms could favor the selective transmission of synchronized information (attention) and foster synaptic plasticity (memory) Besides, gamma oscillatory synchrony also seems related to the emergence of visual awareness The recent discovery that gamma oscillations could appear simultaneously in distinct areas at distinct frequencies and with different functional correlates further suggests the existence of a flexible multiplexing schema, integrating frequency bands within the gamma range but also at lower frequency bands Understanding how and when oscillations at different frequencies interact has become a major challenge for the years to come

Journal ArticleDOI
TL;DR: The possible mechanisms underlying the acute and longer-term of effects of exercise on salivary responses are examined, with particular emphasis on the potential role of the sympathetic nervous system and the expression and mobilisation of the polymeric Ig receptor.
Abstract: Decreased secretion rate of salivary markers of mucosal immunity, and in particular salivary immunoglobulin A (s-IgA), have been implicated as risk factors for subsequent episodes of respiratory infection in athletes. IgA is the predominant Ig in mucosal secretions and acts with innate mucosal defences to provide the 'first line of defence' against pathogens and antigens presented at the mucosa. As well as summarising the evidence concerning the effects of acute exercise and longer-term intensive training on these markers of mucosal immunity, this review explores the factors that impact upon salivary responses to exercise, such as method of saliva collection, stimulation of saliva collection and the method of reporting s-IgA data. The influence of adequate hydration and nutritional supplementation during exercise as well as exercising in extreme environmental conditions on salivary responses is also explored. Finally, the possible mechanisms underlying the acute and longer-term of effects of exercise on salivary responses are examined, with particular emphasis on the potential role of the sympathetic nervous system and the expression and mobilisation of the polymeric Ig receptor.

Journal ArticleDOI
TL;DR: The major goal of this chapter is to uncover intriguing interconnections between intrinsic disorder and human neurodegenerative diseases.
Abstract: Neurodegenerative diseases constitute a set of pathological conditions originating from the slow, irreversible and systematic cell loss within the various regions of the brain and/or the spinal cord. Neurodegenerative diseases are proteinopathies associated with misbehavior and disarrangement of a specific protein, affecting its processing, functioning, and/or folding. Many proteins associated with human neurodegenerative diseases are intrinsically disordered; i.e., they lack stable tertiary and/or secondary structure under physiological conditions in vitro. Intrinsically disordered proteins (IDPs) have broad presentation in nature. Functionally, they complement ordered proteins, being typically involved in regulation, signaling and control. Structures and functions of IDPs are intensively modulated by alternative splicing and posttranslational modifications. It is recognized now that nanoimaging offers a set of tools to analyze protein misfolding and self-assembly via monitoring the aggregation process, to visualize protein aggregates, and to analyze properties of these aggregates. The major goals of this review are to show the interconnections between intrinsic disorder and human neurodegenerative diseases and to overview a recent progress in development of novel nanoimaging tools to follow protein aggregation.

Journal ArticleDOI
TL;DR: It is becoming clear that this transcription factor plays a role in the progression of some tumor types, including breast and gastric cancer, and Interestingly, Slug expression is not always associated with down-regulation of E-cadherin, so the mode of action, the signaling pathways involved in its regulation, and the interplay with other EMT regulators need to be addressed in future studies in order to fully understand Slug's role in tumor progression.
Abstract: Epithelial-mesenchymal-transition (EMT) is a crucial process during morphogenesis of multi-cellular organisms. EMT not only is a normal developmental process but also plays a role in tumor invasion and metastasis. Indeed, molecules involved in EMT, such as the transcription factor and E-cadherin repressor Slug (SNAI2), have recently been demonstrated to be important for cancer cells to down-regulate epithelial markers and up-regulate mesenchymal markers in order to become motile and invasive. Here we summarize major studies focusing on Slug expression in human tumor samples. We review a total of 13 studies involving 1150 cases from 9 different types of tumors. It is becoming clear that this transcription factor plays a role in the progression of some tumor types, including breast and gastric cancer. Interestingly, Slug expression is not always associated with down-regulation of E-cadherin. The mode of action, the signaling pathways involved in its regulation, and the interplay with other EMT regulators need to be addressed in future studies in order to fully understand Slug's role in tumor progression.

Journal ArticleDOI
TL;DR: This review will first summarize the signaling events that are transduced by leukocyte engagement of endothelial cell-surface receptors like ICAM- 1 and VCAM-1, and discuss the newly characterized transmigratory cup structure and the recent advances made towards understanding the mechanisms of transcellular transendothelial migration.
Abstract: As the primary physical barrier between blood and tissue compartments within the body, blood vessel endothelial cells and integrity of the cell junctions connecting them must be carefully regulated to support leukocyte transendothelial migration only when necessary. Leukocytes utilize two independent routes across the endothelium: the paracellular route involves migration in-between adjacent endothelial cells and requires the transient disassembly of endothelial cell junctions, while the transcellular route occurs directly through an individual endothelial cell, likely requiring the formation of a channel or pore. In this review, I will first summarize the signaling events that are transduced by leukocyte engagement of endothelial cell-surface receptors like ICAM-1 and VCAM-1. Some of these signals include activation of GTPases, production of reactive oxygen species, and phosphorylation of target proteins. These signaling pathways converge to cause junctional disruption, cytoskeletal remodeling, and/or the membrane fusion events that are associated with leukocyte transendothelial migration. The review will conclude with a detailed discussion of the newly characterized transmigratory cup structure, and the recent advances made towards understanding the mechanisms of transcellular transendothelial migration.

Journal ArticleDOI
TL;DR: The origin of ticks is during the pre-mid Cretaceous period (with both the Argasidae and Ixodidae being established in the middleCretaceous).
Abstract: All species of ticks (Acari: Ixodida) are grouped into three families: Argasidae (186 species), Ixodidae (692 species) and Nuttalliellidae (monotypic). Molecular markers have been developed and applied for tick studies along with conventional techniques. The origin of ticks is during the pre-mid Cretaceous period (with both the Argasidae and Ixodidae being established in the middle Cretaceous). Primeval hosts were probably reptiles or amphibians. The Argasidae contains two to five subfamilies according to authors but relationships among its members are far from resolved. The Ixodidae were formed by the basal Prostriata group (genus Ixodes subfamily Ixodinae) and the Metastriata group (all others genera). Conventional classifications considered Metastriata to be divided into Amblyomminae, Haemaphysalinae, Hyalomminae and Rhipicephalinae but evidences shows that part of Amblyomminae (species considered previously as "indigenous Australian Aponomma") are now members of the basal Metastriata subfamily Bothriocrotinae, and Hyalomminae are part of Rhipicephalinae. The former genus Boophilus is included as a subgenus within Rhipicephalus. The validity of tick names is discussed in relation to latest world list of ticks.

Journal ArticleDOI
TL;DR: Roles of peroxynitrite in the redox regulation of key signalling pathways for cardiovascular homeostasis, including protein kinase B and C, the MAP kinases, Nuclear Factor Kappa B, as well as signalling dependent on insulin and the sympatho-adrenergic system are presented in detail in this review.
Abstract: Peroxynitrite is a potent oxidant and nitrating species formed from the reaction between the free radicals nitric oxide and superoxide. An excessive formation of peroxynitrite represents an important mechanism contributing to cell death and dysfunction in multiple cardiovascular pathologies, such as myocardial infarction, heart failure and atherosclerosis. Whereas initial works focused on direct oxidative biomolecular damage as the main route of peroxynitrite toxicity, more recent evidence, mainly obtained in vitro, indicates that peroxynitrite also behaves as a potent modulator of various cell signal transduction pathways. Due to its ability to nitrate tyrosine residues, peroxynitrite affects cellular processes dependent on tyrosine phosphorylation. Peroxynitrite also exerts complex effects on the activity of various kinases and phosphatases, resulting in the up- or downregulation of signalling cascades, in a concentration- and cell-dependent manner. Such roles of peroxynitrite in the redox regulation of key signalling pathways for cardiovascular homeostasis, including protein kinase B and C, the MAP kinases, Nuclear Factor Kappa B, as well as signalling dependent on insulin and the sympatho-adrenergic system are presented in detail in this review.

Journal ArticleDOI
TL;DR: A comprehensive summary on both recent findings and missing pieces of the RAGE puzzle is provided to provide a comprehensive summary of the biochemistry of RAGE.
Abstract: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor (PRR) that interacts with diverse endogenous ligands. Ligation of RAGE triggers a series of cellular signaling events, including the activation of transcription factor NF-kappaB, leading to the production of pro-inflammatory cytokines, and causing inflammation. While acute inflammation serves to resolve pathogen infection and stresses, which promote tissue repair, persistent inflammation results in maladaptive tissue remodeling and damage. RAGE signaling has been implicated in multiple detrimental human illnesses including diabetes, atherosclerosis, arthritis, and Alzheimer's disease. In addition, prolonged inflammation often serves as the precursor for arterial remodeling that underlies the exponential increase of age-associated arterial diseases. Despite the significant progress and exciting discoveries in RAGE research, little is known on the biochemistry of RAGE and the signaling mechanism of RAGE remains poorly defined. The biological impact of RAGE signaling in clinical situations and aging-associated diseases also remains to be fully realized. This review attempts to provide a comprehensive summary on both recent findings and missing pieces of the RAGE puzzle.

Journal ArticleDOI
TL;DR: Blood miR-210 is a novel sensitive biomarker for clinical diagnosis and prognosis in acute cerebral ischemia and level in stroke patients with good outcome was significantly higher than patients with poor outcome.
Abstract: MicroRNA-210 (miR-210), a master and pleiotropic hypoxia-microRNA, plays multiple roles in brain ischemia. However, miR-210 expression and its function in humans have not been explored. The aim of our study is to evaluate the correlation of blood miR-210 with clinical findings in acute ischemic stroke. Blood samples were obtained from stroke patients (n=112) and healthy controls (n= 60). MiR-210 was measured at within 3, 7 and 14 days after stroke using a quantitative PCR technique. Stroke severity and clinical outcome were evaluated by NIHSS and modified Rankin Score. Both blood and brain miR-210 in ischemic mice was examined and the correlation was investigated. Compared to healthy controls, blood miRNA-210 was significantly decreased in stroke patients (0.93 vs. 1.36; P=0.001), especially at 7 days (0.56 vs. 1.36; P=0.001) and 14 days of stroke onset (0.50 vs. 1.36; P=0.001). The cut off point of miR-210 in diagnosis was 0.505 with 88.3 per cent sensitivity. MiR-210 level in stroke patients with good outcome was significantly higher than patients with poor outcome (1.2 vs. 0.44; P=0.012). The correlation between blood and brain miR-210 in ischemic mice was positive (R2=0.57, P=0.001). Blood miR-210 is a novel sensitive biomarker for clinical diagnosis and prognosis in acute cerebral ischemia.

Journal ArticleDOI
TL;DR: Important inflammatory mediators like interleukin (IL)-1 beta, IL-6 and tumour necrosis factor (TNF) alpha, are targeted in compensatory anti-inflammatory response syndrome (CARS) in an attempt to control the development of SIRS.
Abstract: The early, delayed, and systemic effects of acute traumatic brain injury (TBI) are the result of inflammatory mediators which initiate systemic inflammatory response syndrome (SIRS), subsequent complement deficits and coagulopathy Once SIRS is triggered by acute inflammation, it can detrimentally self-propagate Systemic inflammation causes tissue damage leading to further inflammation and damage, leaving the body in a vicious cycle of hyperinflammation Therefore, important inflammatory mediators like interleukin (IL)-1 beta, IL-6 and tumour necrosis factor (TNF) alpha, are targeted in compensatory anti-inflammatory response syndrome (CARS) in an attempt to control the development of SIRS The hypothalamus-pituitary (HPA)-axis and sympathetic nervous system (SNS) efferent limbs in CARS provide negative feedback for the production of inflammatory mediators However, in the case of acute TBI, the activation of CARS often leads to the complication of immunosuppression which may result in multi-organ dysfunction syndrome (MODS) and mortality In light of this, the activation of the SIRS following acute TBI does not bode well If left uncontrolled, multiple systems will be implicated making it difficult to remedy

Journal ArticleDOI
TL;DR: C cultured MSCs were found to secrete various bioactive molecules that display anti-apoptotic, immunomodulatory, angiogenic, anti-scarring, and chemoattracted properties, providing a basis for their use as tools to create local regenerative environments in vivo.
Abstract: Mesenchymal stem cells (MSCs) are adult stem cells able to give rise to mature mesenchymal cell types. Plastic-adherent cells are operationally defined as MSCs based on their ability to proliferate and differentiate into cells such as osteoblasts, adipocytes and chondrocytes. In the past ten years, cultured MSCs have been shown to exhibit great plasticity in culture, as they can differentiate into cells with ectodermal and endodermal characteristics, suggesting their use as a source of cells to treat different diseases. More recently, cultured MSCs were found to secrete various bioactive molecules that display anti-apoptotic, immunomodulatory, angiogenic, anti-scarring, and chemoattractant properties, providing a basis for their use as tools to create local regenerative environments in vivo. Whereas the properties of cultured MSCs have been studied for a long time, their exact location in vivo is slowly becoming apparent as evidence indicates that pericytes behave as stem cells throughout the organism. In this review, we discuss some aspects of MSC basic biology, the methodology involved in MSC culture, and some clinical and pre-clinical applications of cultured MSCs.

Journal ArticleDOI
TL;DR: An overview of the direct effects of water-soluble cigarette smoke constituents on endothelial function, vascular ROS production and inflammatory gene expression and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation in cardiovascular complications in smokers are discussed.
Abstract: Cigarette smoking is the major cause of preventable morbidity and mortality in the United States and constitutes a major risk factor for atherosclerotic vascular disease, including coronary artery disease and stroke. Increasing evidence supports the hypothesis that oxidative stress and inflammation provide the pathophysiological link between cigarette smoking and CAD. Previous studies have shown that cigarette smoke activates leukocytes to release reactive oxygen and nitrogen species (ROS/RNS) and secrete pro-inflammatory cytokines, increases the adherence of monocytes to the endothelium and elicits airway inflammation. Here we present an overview of the direct effects of water-soluble cigarette smoke constituents on endothelial function, vascular ROS production and inflammatory gene expression. The potential pathogenetic role of peroxynitrite formation, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation in cardiovascular complications in smokers are also discussed.

Journal ArticleDOI
TL;DR: The concept of metabolic remodeling and signaling in tumors, specifically the various metabolites that participate in the regulation of gene expression in cancer cells are discussed, and several mitochondrial DNA mutations were reported in tumors.
Abstract: In this review, we discuss the concept of metabolic remodeling and signaling in tumors, specifically the various metabolites that participate in the regulation of gene expression in cancer cells. In particular, pyruvate, oxaloacetate, succinate and fumarate, four mitochondrial metabolites, activate genes relevant for tumor progression. When the balance between glycolysis and oxidative phosphorylation is altered, these metabolites accumulate in the cytoplasm and regulate the activity of the Hypoxia Inducible Factor 1alpha (HIF-1alpha). HIF is one of the main factors that orchestrate the metabolic switch observed during oncogenesis. There is also an important role for lactate, fructose 1-6 bisphosphate or citrate that leads to the diversion of glucose metabolites to anabolism. In addition reactive oxygen species, which are produced by the respiratory chain, could serve as an endogenous source of DNA-damaging agents to promote genetic instability. Accordingly, several mitochondrial DNA mutations were reported in tumors, and the construction of cybrids recently demonstrated their role in the control of tumor progression.

Journal ArticleDOI
TL;DR: The shared pathophysiology between both disorders and the importance of addressing all symptoms in patients with comorbid pain and depression are summarized and anatomical structures that are activated and/or altered in response to both depression and pain are described.
Abstract: Depression and pain disorders are often diagnosed in the same patients. Here we summarize the shared pathophysiology between both disorders and the importance of addressing all symptoms in patients with comorbid pain and depression. We describe anatomical structures that are activated and/or altered in response to both depression and pain--examples include the insular cortex, the prefrontal cortex, the anterior cingulate cortex, the amygdala, and the hippocampus. Both disorders activate common neurocircuitries (e.g. the hypothalamic-pituitary-adrenal axis, limbic and paralimbic structures, ascending and descending pain tracks), common neurochemicals (e.g. monoamines, cytokines, and neurotrophic factors), and are associated with common psychological alterations. One explanation for the interaction and potentiation of the disease burden experienced by patients affected by both pain and depression is provided by the concept of allostasis. In this model, patients accumulate allostatic load through internal and external stressors, which makes them more susceptible to disease. To break this cycle, it is important to treat all symptoms of a patient. Therapeutic approaches that address symptoms of both depression and pain include psychotherapy, exercise, and pharmacotherapy.

Journal ArticleDOI
TL;DR: The importance of vitagenes in the cellular stress response is discussed, the potential use of dietary antioxidants in the treatment of neurodegenerative disorders in humans is analyzed and dietary antioxidants, such as curcumin, L-carnitine/acetyl-L-c Carnitine and carnosine have recently been demonstrated in vitro to be neuroprotective.
Abstract: The ability of a cell to counteract stressful conditions, known as cellular stress response, requires the activation of pro-survival pathways and the production of molecules with anti-oxidant, anti-apoptotic or pro-apoptotic activities. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include heat shock proteins (Hsps) heme oxygenase-1 and Hsp70, as well as the thioredoxin/thioredoxin reductase system. Heat shock response contributes to establish a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. Dietary antioxidants, such as curcumin, L-carnitine/acetyl-L-carnitine and carnosine have recently been demonstrated in vitro to be neuroprotective through the activation of hormetic pathways, including vitagenes. In the present review we discuss the importance of vitagenes in the cellular stress response and analyse, from a pharmacological point of view, the potential use of dietary antioxidants in the treatment of neurodegenerative disorders in humans.

Journal ArticleDOI
TL;DR: Bioengineered corneas are also rapidly gaining importance in the area of in vitro toxicology, as alternatives to animal testing, and more complex, fully innervated, physiologically active, three-dimensional organotypic models are also being tested.
Abstract: Bioengineered corneas have been designed to replace partial or the full-thickness of defective corneas, as an alternative to using donor tissues. They range from prosthetic devices that solely addr ...

Journal ArticleDOI
TL;DR: A recent flurry of findings indicate that DLL4/Notch signalling decreases angiogenesis by suppressing endothelial tip cell formation but significantly reduces the growth of VEGF-sensitive and V EGF-resistant tumours.
Abstract: Angiogenesis is regulated by a number of angiogenic factors through many signalling pathways. The VEGF pathway and Notch signalling are perhaps two of the most important mechanisms in regulation of embryonic vascular development and tumour angiogenesis. Blockade of the VEGF pathway effectively inhibits tumour angiogenesis and growth in preclinical models. The successes in phase III trials have added anti-VEGF agents to standard cancer therapy in several major cancers. A recent flurry of findings indicate that DLL4/Notch signalling decreases angiogenesis by suppressing endothelial tip cell formation; importantly, blockade of DLL4/Notch signalling strikingly increases non-productive angiogenesis but significantly reduces the growth of VEGF-sensitive and VEGF-resistant tumours. The VEGF pathway interplays at several levels with DLL4/Notch signalling in vasculature. VEGF induces DLL4/Notch signalling while DLL4/Notch signalling modulates the VEGF pathway. DLL4 and VEGF emerge to be the yin and yang of angiogenesis. Combination therapy by blocking DLL4/Notch and VEGF pathways synergistically inhibits tumour growth in preclinical models. Thus, targeting the DLL4/Notch pathway, though still at an early stage, may lead to exciting new therapies for clinical application.

Journal ArticleDOI
TL;DR: Studies of these mechanisms in kidney cells and in whole-animal experimental models are beginning to provide insight into the role of TGF-beta in the pathogenesis of renal dysfunction and its potential treatment.
Abstract: Transforming growth factor (TGF)-beta is a central stimulus of the events leading to chronic progressive kidney disease, having been implicated in the regulation of cell proliferation, hypertrophy, apoptosis and fibrogenesis. The fact that it mediates these varied events suggests that multiple mechanisms play a role in determining the outcome of TGF-beta signaling. Regulation begins with the availability and activation of TGF-beta and continues through receptor expression and localization, control of the TGF-beta family-specific Smad signaling proteins, and interaction of the Smads with multiple signaling pathways extending into the nucleus. Studies of these mechanisms in kidney cells and in whole-animal experimental models, reviewed here, are beginning to provide insight into the role of TGF-beta in the pathogenesis of renal dysfunction and its potential treatment.